Swaiman’s Pediatric Neurology. Principles and Practice [6 ed.] 9780323371018, 9780323374811

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Swaiman’s Pediatric Neurology Principles and Practice SIXTH EDITION

KENNETH F. SWAIMAN, MD

RICHARD S. FINKEL, MD

Director Emeritus, Division of Pediatric Neurology; Professor Emeritus of Neurology and Pediatrics University of Minnesota Medical School Minneapolis, MN, USA

Chief, Division of Neurology Nemours Children’s Hospital; Professor of Neurology University of Central Florida College of Medicine Orlando, FL, USA

STEPHEN ASHWAL, MD Distinguished Professor of Pediatrics; Chief, Division of Child Neurology Department of Pediatrics Loma Linda University School of Medicine Loma Linda, CA, USA

DONNA M. FERRIERO, MD, MS

ANDREA L. GROPMAN, MD Chief, Neurogenetics and Neurodevelopmental Disabilities Department of Neurology Children’s National Medical Center George Washington University of the Health Sciences Washington, DC, USA

PHILLIP L. PEARL, MD

W.H. And Marie Wattis Distinguished Professor and Chair Department of Pediatrics; Physician-in-Chief UCSF Benioff Children’s Hospital San Francisco, CA, USA

Director of Epilepsy and Clinical Neurophysiology Boston Children’s Hospital; William G. Lennox Chair and Professor of Neurology Harvard Medical School Boston, MA, USA

NINA F. SCHOR, MD, PHD

MICHAEL I. SHEVELL, MDCM, FRCP(C), FCAHS

William H. Eilinger Professor and Chair Department of Pediatrics; Professor, Departments of Neurology and Neuroscience; Pediatrician-in-Chief, Golisano Children’s Hospital University of Rochester School of Medicine and Dentistry Rochester, NY, USA

Professor, Departments of Pediatrics, Neurology and Neurosurgery; Chair, McGill Department of Pediatrics; Pediatrician-in-Chief, Montreal Children’s Hospital-McGill University Health Centre (MUHC) Harvey Guyda Professor Department of Pediatrics, Faculty of Medicine, McGill University Montreal, QC, Canada

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Edinburgh  London  New York  Oxford  Philadelphia  St Louis  Sydney  Toronto  2018

© 2017, Elsevier Inc. All rights reserved. First edition 1989 Second edition 1994 Third edition 1999 Fourth edition 2006 Fifth edition 2012 Sixth edition 2018

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: 978-0-323-37101-8 eISBN: 978-0-323-37481-1

Printed in China Last digit is the print number:  9  8  7  6  5  4  3  2  1

With pleasure and appreciation we dedicate this book to our spouses and children, who made it possible for us to bring this text to fruition and who taught us what was really important in development over the lifespan. It is impossible to adequately describe the value of their encouragement and support. We also would like to express our appreciation to the Elsevier editorial staff who are extremely talented and helpful in keeping track of all the details necessary to complete such a task as well as their judicious editorial skills. Furthermore, no dedication of a book embracing this field would be meaningful without a tribute to the courage and perseverance of neurologically impaired children and their caretakers.

Content Strategist: Lotta Kryhl/Sarah Barth Content Development Specialist: Humayra Rahman Khan Content Coordinator: Joshua Mearns Project Manager: Andrew Riley Design: Miles Hitchen Marketing Manager: Michele Milano

Preface to the First Edition It is concurrently tiring, humiliating, and intellectually revitalizing to compile a book containing the essence of the information that embraces one’s life work and professional preoccupation. For me, there is a certain moth-to-the-flame phenomenon that cannot be resisted; therefore this new book has been produced. Pediatric neurology has come of age since my initial interest and subsequent immersion in the field. Concentrated attention to the details of brain development and function has brought much progress and understanding. Studies of disease processes by dedicated and intelligent individuals accompanied by a cascade of new technology (e.g., neuroimaging techniques, positron emission tomography, DNA probes, synthesis of gene products, sophisticated lipid chemistry) have propelled the field forward. The simultaneous increase of knowledge and capability of pediatric neurologists and others who diagnose and treat children with nervous system dysfunction has been extremely gratifying. Although once within the realm of honest delusion of a seemingly sane (but unrealistic) devotee of the field, it is no longer possible to believe that a single individual can fathom, much less explore, the innumerable rivulets that coalesce to form the river of knowledge that currently is pediatric neurology. Streams of information in certain areas sometimes peacefully meander for years; suddenly, when knowledge of previously obscure areas is advanced and the newly gained information becomes central to understanding basic pathophysiologic entities, a once small stream gains momentum and abruptly flows with torrential force. This text is an attempt to gather the most important aspects of current pediatric neurology and display them in

a comprehensible manner. The task, although consuming great energies and concentration, cannot be accomplished completely because new conditions are described daily. The advancement of the field necessitated that preparation of this text keep pace with current knowledge and present new and valuable techniques. My colleagues and I have made every effort to discharge this responsibility. Because of continuous scientific progress, controversies are extant in some areas for varying periods; wherever possible, these areas of conflict are indicated. This book is divided into four unequal parts. Part I contains a discussion of the historic and clinical examination. Part II contains information concerning laboratory examination. Chapters relating to the symptom complexes that often reflect the chief complaints of neurologically impaired children compose Part III. Part IV provides detailed discussion of various neurologic diseases that afflict children. Although every precaution has been taken to avoid error, bias, and prejudice, inevitably some of these demons have become embedded in the text. The editor assumes full responsibility for these indiscretions. It is my fervent hope that the reader will find this book informative and stimulating and that the contents will provide an introduction to the understanding of many of the conditions that remain mysterious and poorly explained. Kenneth F. Swaiman, MD Autumn 1988

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Preface to the Sixth Edition In 1975, a little over 40 years ago, the first two-volume reference text concerning Pediatric Neurology was published. In 1971, Dr Swaiman was approached by an executive editor of C.V. Mosby to discuss publishing a book on pediatric neurology based on papers he had read from a University of Minnesota Continuing Medical Education Course. This was a year before the first Child Neurology Society meeting and thus before the formal organization of pediatric neurologists. Drs. Ken Swaiman and Frank Wright began this project, immediately facing the challenge of delineating the field. At that time, the importance of neurochemistry and genetics was being emphasized, there were questions as to whether learning disabilities or autism were legitimate components of child neurology, and recruiting authors for various chapters was difficult as sub-specialties of the discipline were in their infancy or under- or undeveloped. The first edition preface of The Practice of Pediatric Neurology stated, “We have aspired to create a well-illustrated book that stresses the mainstays of modern pediatric neurology—the staggering array of neuromuscular and metabolic diseases described in the past 30 years, the relationship of embryology to congenital malformations, the growing number of recognized but yet unexplained degenerative diseases of childhood, and higher cortical function as related to learning capabilities of the child.” The book and the subsequent 1982 edition were internationally well received. Pediatric Neurology and subsequently Swaiman’s Pediatric Neurology were first published in 1989 and then in 1994, 1999, 2005 and 2012. Elsevier succeeded C.V. Mosby as the publisher in 2012. The growth of the discipline is documented by the fact that the number of pages and chapters has grown greatly: from 40 chapters/1082 pages in 1975 to 108 chapters/2290 pages in 2012. This sixth edition of Swaiman’s Pediatric Neurology: Principles & Practice reflects the remarkable increase in knowledge and complexity of the field since the fifth edition. Keeping abreast of all new information required us to increase the size and scope of this book from 108 to 170 chapters. To avoid publishing an overwhelming and oversized tome, we meticulously curated the most immediately necessary information and guidance in the print book, while providing the full text, our most comprehensive edition ever, online. We are proud of our mobile-optimized, downloadable e-book, which is included with your print purchase, and which provides easy and complete searchable and annotatable access to the content. Between the portable print book and the expansive online text, this reference offers a remarkable collection of well written chapters on topics of importance to professionals around the world who care for children with neurological disorders. To accomplish these goals, we have increased the number of editors from four in the last edition (Ken Swaiman, Stephen Ashwal, Donna Ferriero, Nina Schor) to eight by adding four new and accomplished individuals with expertise in specific

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areas: Andrea Gropman (neurogenetics and metabolic disorders); Richard Finkel (neuromuscular disorders); Phillip Pearl (pediatric epilepsy); and Michael Shevell (neurodevelopmental disabilities). We also had some unofficial expert guidance for specific sections of the book on neurodevelopmental malformations (Bill Dobyns); pediatric movement disorders (Jon Mink); and pediatric neurooncology (Roger Packer). Major changes in the book that the reader will find of interest include: • Completely new sections on pediatric immune mediated nervous system disorders (4 chapters), cerebrovacular diseases (6 chapters), neurooncology (13 chapters), neuromuscular disorders (18 chapters), and clinical care care of the child with neurologic disorders (11 chapters). • Major expansions of the sections on perinatal acquired and congenital disorders (7 chapters), neurodevelopmental disabilities (11 chapters), pediatric epilepsy (23 chapters), and nonepiletiform paroxysmal disorders and disorders of sleep (7 chapters). • Three new chapters for the section on emerging concepts in child neurology including topics related to the developmental connectome, stem cell transplantation, and cellular and animal models of neurological disease. • Updates of all remaining chapters by an international group of authors who are experts in their respective fields. • Other new chapters in different sections of the book include: neuropsychological assessement; development of a neonatal neurointensive care unit; neonatal traumatic brain, spine and peripheral nervous system injury; an overview of the conceptual framework of the developmental encephalopathies; an overview of how to evaluate patients with a suspected metabolic disorder; a review of conditions associated with vitamin metabolism; and a chapter on nutrition and malnutrition and the developing brain. We hope that the reader will find this book a useful resource and that the information will benefit the many children who suffer from these conditions. It is our wish that the greater world community will increase support for the care of neurologically impaired children and the research necessary to provide further understanding of, and improved treatment and preventive measures for, neurologic diseases. This support will improve the survival and quality of life of these brave children and their families. Kenneth F. Swaiman Stephen Ashwal Donna M. Ferriero Nina F. Schor Richard S. Finkel Andrea L. Gropman Phillip L. Pearl Michael I. Shevell

Acknowledgments We wish to thank all of the authors who graciously gave of their time to prepare and review their chapters, as well as the editorial and publishing staff at Elsevier, especially Charlotta

Kryhl, Humayra Rahman Khan, Joshua Mearns, Andrew Riley and many others. Without their diligence and persistence, we would have never been able to complete this project.

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Contributors The editors would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition would not have been possible. Gregory S. Aaen, MD

Russell C. Bailey, MD

Brenda Bartnik-Olson, PhD

Assistant Professor of Pediatrics and Neurology Loma Linda University School of Medicine Loma Linda, CA, USA

Assistant Professor of Neurology and Pediatrics Department of Neurology University of Virginia Charlottesville, VA, USA

Associate Professor of Radiology Radiology Loma Linda University School of Medicine Loma Linda, CA, USA

Nicholas Scott Abend, MD MSCE

James F. Bale, Jr., MD

Ori Barzilai

Associate Professor of Neurology and Pediatrics Departments of Neurology and Pediatrics University of Pennsylvania and Children’s Hospital of Philadelphia Philadelphia, PA, USA

Professor of Pediatrics and Neurology; Vice Chair-Education, Department of Pediatrics University of Utah Health Care Salt Lake City, UT, USA

Resident Neurosurgeon Tel Aviv Medical Center Tel Aviv, Israel

Amal Abou-Hamden, FRACS

Neurosurgeon University of Adelaide, Wakefield Hospital Royal Adelaide Hospital Adelaide, SA, Australia Jeffrey C. Allen, MD

Professor of Pediatrics and Neurology NYU Langone Medical Center New York, NY, USA Anthony A. Amato, MD

Vice-chairman, Department of Neurology Chief, Neuromuscular Division Brigham and Women’s Hospital Professor of Neurology Harvard Medical School Boston, MA, USA

Brenda Banwell, MD

Chief of Neurology The Children’s Hospital of Philadelphia Professor of Neurology and Pediatrics Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA Kristin W. Barañano, MD, PhD

Assistant Professor of Neurology; Clinical Associate Johns Hopkins University School of Medicine Department of Neurology Baltimore, MD, USA A. James Barkovich, MD

Professor of Radiology and Biomedical Imaging, Neurology, Pediatrics and Neurosurgery University of California San Francisco, CA, USA

Catherine Amlie-Lefond, MD

Richard J. Barohn, MD

Professor of Neurology University of Washington; Director Pediatric Vascular Neurology Program Seattle Children’s Hospital Seattle, WA, USA

Gertrude and Dewey Ziegler Professor of Neurology; Chair, Department of Neurology University of Kansas Medical Center Kansas City, KS, USA

Stephen Ashwal, MD

Professor The Paediatric Brain Tumour Program The Hospital for Sick Children University of Toronto Toronto, ON, Canada

Distinguished Professor of Pediatrics and Neurology; Chief, Division of Pediatric Neurology Loma Linda University School of Medicine Loma Linda, CA, USA

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Ute K. Bartels, MD

Alexander Bassuk, MD, PhD

Associate Professor Pediatrics University of Iowa Graduate College Iowa City, IA, USA David R. Bearden, MD

Assistant Professor of Neurology and Pediatrics Department of Neurology, Division of Child Neurology University of Rochester School of Medicine Rochester, NY, USA Liat Ben-Sira, MD

Director Imaging (Pediatrics) Tel Aviv Sourasky Medical Center Tel Aviv, Israel Timothy J. Bernard, MD, MSCS

Associate Professor Department of Pediatrics, Section of Child Neurology University of Colorado School of Medicine Aurora, CO, USA Elizabeth Berry-Kravis, MD, PhD

Professor Departments of Pediatrics, Neurological Sciences, and Biochemistry Rush University Medical Center Chicago, IL, USA Lauren A. Beslow, MD, MSCE

Assistant Professor of Neurology and Pediatrics The Perelman School of Medicine of The University of Pennsylvania Division of Neurology The Children’s Hospital of Philadelphia Philadelphia, PA, USA



Contributors

Jaclyn A. Biegel, PhD

Daniel J. Bonthius, MD, PhD

Jeffrey Buchalter, MD

Chief, Division of Genomic Medicine; Director, Center for Personalized Medicine Department of Pathology and Laboratory Medicine Children’s Hospital Los Angeles; Professor of Clinical Pathology (Clinical Scholar) University of Southern California Keck School of Medicine Los Angeles, CA, USA

Professor Departments of Pediatrics and Neurology University of Iowa Iowa City, IA, USA

Chairman Pain Management Gulf Coast Pain Institute Pensacola, FL, USA

Breck Borcherding, MD

Assistant Professor Department of Psychiatry Weill Cornell Medicine New York, NY, USA

Researcher Department of Pediatrics, Dalhousie University IWK Health Centre, Halifax, NS, Canada

Brian R. Branchford, MD

Peter R. Camfield, MD, FRCPC

Assistant Professor Center for Cancer and Blood Disorders Children’s Hospital Colorado Hemophilia and Thrombosis Center University of Colorado School of Medicine Aurora, CO, USA

Researcher Department of Pediatrics, Dalhousie University IWK Health Centre Halifax, NS, Canada

Lori Billinghurst, MD, MSc, FRCPC

Attending Physician Division of Neurology The Children’s Hospital of Philadelphia; Clinical Assistant Professor of Neurology Perelman School of Medicine The University of Pennsylvania Philadelphia, PA, USA Angela K. Birnbaum, PhD

Professor PHARM Experimental and Clinical Pharm University of Minnesota Twin Cities, MN, USA Joanna S. Blackburn, MD

Assistant Professor Department of Pediatrics Ann, Robert H. Lurie Children’s Hospital of Chicago Northwestern Feinberg School of Medicine Chicago, IL, USA Nuala Bobowski, PhD

Postdoctoral Fellow Monell Chemical Senses Center Philadelphia, PA, USA Adrienne Boire, MD, PhD

Neuro-Oncologist Neurology Memorial Sloan Kettering Cancer Center New York, NY, USA Carsten G. Bönnemann, MD

Senior Investigator Division of Intramural Research National Institute of Neurological Disorders and Stroke Bethesda, MD, USA Sonia L. Bonifacio, MD

Clinical Associate Professor of Pediatrics; Associate Medical Director, NeuroNICU Stanford University School of Medicine Division of Neonatal, Developmental Medicine Palo Alto, CA, USA

John Brandsema, MD

Assistant Professor of Clinical Neurology Perelman School of Medicine at the University of Pennsylvania; Attending Physician The Children’s Hospital of Philadelphia Philadelphia, PA, USA Kathryn M. Brennan, MBChB, PhD

Consultant Neurologist Department of Neurology Queen Elizabeth University Hospital Glasgow, Scotland, UK J. Nicholas Brenton, MD

Assistant Professor Department of Neurology, Division of Pediatrics University of Virginia Charlottesville, VA, USA Amy R. Brooks-Kayal, MD

Professor, Departments of Pediatrics and Neurology, University of Colorado, School of Medicine, Aurora; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego; Chief and Ponzio Family Chair, Pediatric Neurology, Children’s Hospital Colorado Colorado Aurora, CO, USA Lawrence W. Brown, MD

Associate Professor Departments of Neurology and Pediatrics The Children’s Hospital of Philadelphia Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA

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Carol S. Camfield, MD, FRCPC

Cristina Campoy, MD, PhD

Professor of Pediatrics University of Granada Granada, Spain Jessica L. Carpenter, MD

Assistant Professor Department of Neurology Children’s National Health System (CNHS) George Washington University Washington, DC, USA Taeun Chang, MD

Associate Professor Child Neurology Children’s National Health System Washington, DC, USA Vann Chau, MD, FRCPC

Assistant Professor of Pediatrics Department of Pediatrics (Neurology) The Hospital for Sick Children, University of Toronto Toronto, ON, Canada Susan N. Chi, MD

Assistant Professor of Pediatrics Dana-Farber Cancer Institute Boston Children’s Hospital Harvard Medical School Boston, MA, USA Claudia A. Chiriboga, MD, MPH

Professor of Neurology and Pediatrics Division of Pediatric Neurology Columbia University Medical Center New York, NY, USA Yoon-Jae Cho, MD

Assistant Professor Neurology Stanford University Stanford, CA, USA Cindy W. Christian, MD

Professor, Department of Pediatrics The Perelman School of Medicine University of Pennsylvania Philadelphia, PA, USA

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Contributors

Nicolas Chrestian, MD, FRCPC

David L. Coulter, MD

Jeremy K. Deisch, MD

Department of Child Neurology Centre Hospitalier Mère-Enfant-Soleil Université Laval (CHUL) Quebec City Quebec, Canada

Senior Associate in Neurology; Associate Professor of Neurology Harvard Medical School Boston, MA, USA

Assistant Professor of Pathology Loma Linda University Loma Linda, CA, USA

Maria Roberta Cilio, MD, PhD

Tina M. Cowan, PhD

Associate Professor Department of Pathology Stanford University Stanford, CA, USA

Professor, Department of Neurology Laboratoire de Neurophysiologie CHU Brugmann – Université Libre de Bruxelles Bruxelles, Belgium

Russell C. Dale, MRCP, PhD

Jay Desai, MD

Professor of Paediatric Neurology Child and Adolescent Health University of Sydney Sydney, NSW, Australia

Assistant Professor of Clinical Neurology Keck School of Medicine University of Southern California Los Angeles, CA, USA

Professor, Neurology and Pediatrics; Director of Pediatric Epilepsy Research Division of Epilepsy and Clinical Neurophysiology University of California San Francisco, CA, USA Robin D. Clark, MD

Professor Department of Pediatrics, Medical Genetics Loma Linda University School of Medicine Loma Linda, CA, USA Bruce H. Cohen, MD

Professor of Pediatrics, Northeast Ohio Medical University; Director, NeuroDevelopmental Science Center and Neurology Department of Pediatrics Children’s Hospital Medical Center of Akron Akron, OH, USA Ronald D. Cohn, MD, FACMG

Paediatrician in Chief, The Hospital for Sick Children Professor and Chair Department of Paediatrics The University of Toronto Toronto, ON, Canada

Benjamin Darbro, MD, PhD

Director, Shivanand R. Patil Cytogenetics and Molecular Laboratory; Assistant Professor of Pediatrics Medical Genetics University of Iowa Iowa City, IA, USA Basil T. Darras, MD

Joseph J. Volpe Professor of Neurology Harvard Medical School; Associate Neurologist-in-Chief; Chief, Division of Clinical Neurology; Director, Neuromuscular Program; Boston Children’s Hospital Boston, MA, USA Jahannaz Dastgir, DO

Professor of Neurology and Pediatrics Washington University School of Medicine Saint Louis, MO, USA

Department of Pediatric Neurology Goryeb Children’s Hospital/Atlantic Health System Morristown, NJ, USA Assistant Professor, Department of Pediatrics Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA

Todd Constable, PhD

Linda De Meirleir, MD, PhD

Professor of Radiology and Biomedical Imaging and of Neurosurgery; Director MRI Research Yale University New Haven, CT, USA

Professor Neurology and Pediatric Neurology Catholic University of Leuven Leuven, Belgium

Shlomi Constantini, MD

Sidney Carter Professor of Neurology and Pediatrics Department of Neurology Columbia University Medical Center New York, NY, USA

Anne M. Connolly, MD

Department of Pediatric Neurosurgery The Israeli Neurofibromatosis Center Dana Children’s Hospital Tel Aviv Medical Center Tel Aviv, Israel Jeannine M. Conway, PharmD

Associate Professor Department of Experimental and Clinical Pharmacology College of Pharmacy, University of Minnesota Minneapolis, MN, USA

Darryl C. De Vivo, MD

Linda S. de Vries, MD, PhD

Professor Department of Neonatology University Medical Centre Utrecht/ Wilhelmina Children’s Hospital Utrecht, The Netherlands

Paul Deltenre, MD, PhD

Maria Descartes, MD

Professor Department of Genetics University of Alabama in Birmingham Birmingham, AL, USA Gabrielle deVeber, MD

Professor of Pediatrics University of Toronto; Director, Children’s Stroke Program, Division of Neurology Hospital for Sick Children; Senior Scientist, Research Institute, Hospital for Sick Children Toronto, ON, Canada Sameer C. Dhamne

Biomedical Research Manager Boston Children’s Hospital Harvard Medical School Boston, MA, USA Jullianne Diaz

Clinic Coordinator Children’s National Health System Washington, DC, USA Salvatore DiMauro, MD

Lucy G. Moses Professor of Neurology Department of Neurology Columbia University Medical Center New York, NY, USA William B. Dobyns, MD

Center for Integrative Brain Research Seattle Children’s Research Institute Seattle, WA, USA Dan Doherty, MD, PhD

Associate Professor Department of Pediatrics Divisions of Genetic and Developmental Medicine Seattle Children’s Hospital University of Washington School of Medicine Seattle, WA, USA



Contributors

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Elizabeth J. Donner, MD MSc FRCPC

S. Ali Fatemi, MD

Nicholas K. Foreman, MB.ChB. MRCP

Director, Comprehensive Epilepsy Program Division of Neurology, The Hospital for Sick Children Associate Professor, Department of Paediatrics University of Toronto Toronto, ON, Canada

Director Neurogenics and Moser Centre for Leukodystrophies Kennedy Krieger Institute Baltimore, MD, USA

Seebaum-Tschetter Chair of Neuro-Oncology Professor, Department of Pediatrics; University of Colorado Denver, CO, USA

Darcy L. Fehlings, MD, FRCPC, MSc

Israel Franco, MD, FACS, FAAP

Professor Division of Developmental Paediatrics, Department of Paediatrics Holland Bloorview Kids Rehabilitation Hospital University of Toronto Toronto, ON, Canada

Director Yale New Haven Children’s Bladder and Continence Program New Haven, CT, USA; Professor of Urology New York Medical College Valhalla, NY, USA

Michelle Lauren Feinberg, MD

Resident Department of Neurosurgery George Washington University Washington, DC, USA

Clinical Professor Pediatrics, Neurology, Psychiatry Icahn School of Medicine at Mount Sinai New York, NY, USA

Donna M. Ferriero, MD MS

Douglas R. Fredrick, MD

W.H. And Marie Wattis Distinguished Professor; Chair, Department of Pediatrics; Physician-in-Chief UCSF Benioff Children’s Hospital San Francisco, CA, USA

Clinical Professor Department of Ophthalmology Byers Eye Institute Stanford University Palo Alto, CA, USA

Pauline A. Filipek, MD

Director Human Genetics Program Sanford Burnham Prebys Medical Discovery Institute La Jolla, CA, USA

Nico U.F. Dosenbach, MD, PhD

Assistant Professor Department of Neurology Washington University School of Medicine St. Louis, MO, USA James J. Dowling, MD, PhD

Senior Scientist, Program for Genetics and Genome Biology; Staff Clinician, Division of Neurology Hospital for Sick Children; Associate Professor, Departments of Paediatrics and Molecular Genetics University of Toronto Toronto, ON, Canada James M. Drake, BSE, MB, BCh, MSc, FRCSC

Head Neurosurgery The Hospital for Sick Children Toronto, ON, Canada Cecile Ejerskov, MD

Department of Pediatrics Aarhus University Hospital Aarhus, Denmark Andrew G. Engel, MD

McKnight-3M Professor of Neuroscience Department of Neurology Mayo Clinic College of Medicine Rochester, MN, USA Gregory M. Enns, MB, ChB

Professor Department of Pediatrics Stanford University Stanford, CA, USA María Victoria Escolano-Margarit, MD

Professor Department of Pediatrics University of Granada Granada, Spain Iris Etzion, MD

Senior visiting fellow Department of Neurology Division of Neurogenetics and Developmental Pediatrics Children’s National Medical Center and the George Washington University of the Health Sciences, Washington, DC, USA

Director, The Autism Center at CLI; Professor of Pediatrics Children’s Learning Institute and the Division of Child, Adolescent Neurology University of Texas Health Science Center Houston, TX, USA Richard S. Finkel, MD

Chief, Division of Neurology Nemours Children’s Hospital; Professor of Neurology University of Central Florida College of Medicine Orlando, FL, USA Paul G. Fisher, MD

Professor, Neurology and Pediatrics, and by courtesy Neurosurgery and Human Biology; Beirne Family Professor of Pediatric Neuro-Oncology; Bing Director of Human Biology Stanford University Stanford, CA, USA Kevin Flanigan, MD

Robert F. and Edgar T. Wolfe Foundation Endowed Chair In Neuromuscular Research Professor of Pediatrics and Neurology, The Ohio State University; Director, Center for Gene Therapy The Research Institute of Nationwide Children’s Hospital Columbus, OH, USA

Yitzchak Frank, MD

Hudson H. Freeze, PhD

Cristina Fuente-Mora, PhD

Research Scientist Department of Neurology New York University School of Medicine New York, NY, USA Joseph M. Furman, MD, PhD

Professor Departments of Otolaryngology and Neurology University of Pittsburgh Pittsburgh, PA, USA Renata C. Gallagher, MD, PhD

Associate Professor of Clinical Pediatrics; Director, Biochemical Genetics Department of Pediatrics UCSF Benioff Children’s Hospital San Francisco, CA, USA Catherine Garel, MD

Hôpital d’enfants Armand-Trousseau Department of Radiology Paris, France Emily Gertsch, MD

Referring Physician Raleigh Neurology Associates Raleigh, NC, USA

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Contributors

Donald L. Gilbert, MD MS FAAN FAAP

Hernan Dario Gonorazky, MD

Jin S. Hahn, MD

Professor of Pediatrics and Neurology; Program Director; Child Neurology Residency Director Tourette Syndrome and Movement Disorders Clinics Director Transcranial Magnetic Stimulation Laboratory Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA

Clinical and Research Neuromuscular Fellow Division of Neurology Genetics and Genome Biology Program PGCRL, Hospital for Sick Children University of Toronto Toronto, ON, Canada

Professor Department of Neurology and Pediatrics Stanford University, School of Medicine Stanford, CA, USA

Elizabeth E. Gilles, MD

Pediatric Neurologist Child Neurology Solutions, PLLC Saint Paul, MN, USA Christopher C. Giza, MD

Physician Pediatrics, Pediatric Neurology Ronald Reagan UCLA Medical Center Los Angeles, CA, USA

Rodolfo Gonzalez, PhD

Principal Scientist International Stem Cell Corporation Carlsbad, CA, USA Howard P. Goodkin, MD, PhD

The Shure Professor of Neurology and Pediatrics Department of Neurology University of Virginia Charlottesville, VA, USA John M. Graham, Jr., MD, ScD

Chief, Encephalitis and Special Investigations Section Division of Communicable Disease Control Richmond, CA, USA

Professor Emeritus Department of Pediatrics Cedars-Sinai Medical Center and Harbor-UCLA Medical Center David Geffen School of Medicine at UCLA Los Angeles, CA, USA

Hannah C. Glass, MDCM, MAS

Alexander L. Greninger, MD, PhD

Associate Professor Departments of Neurology, Pediatrics and Epidemiology, Biostatistics University of California, San Francisco San Francisco, CA, USA

Laboratory of Medicine University of Washington Seattle, WA, USA

Carol A. Glaser, MD

Tracy Glauser, MD

Associate Director, Cincinnati Children’s Research Foundation; Director, Comprehensive Epilepsy Center; Co-Director, Genetic Pharmacology Service Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA Joseph Glykys, MD, PhD

Instructor in Neurology Department of Neurology Division of Child Neurology Massachusetts General Hospital Harvard Medical School Boston, MA, USA Amy Goldstein, MD

Director, Neurogenetics, Metabolism; Assistant Professor of Pediatrics University of Pittsburgh School of Medicine Division of Child Neurology Children’s Hospital of Pittsburgh Pittsburgh, PA, USA

Gary Gronseth, MD

Professor and Vice-Chairman Department of Neurology University of Kansas Medical Center Kansas City, KS, USA Andrea L. Gropman, MD

Chief, Neurogenetics and Neurodevelopmental Disabilities Department of Neurology Children’s National Medical Center George Washington University of the Health Sciences Washington, DC, USA Richard Grundy, MD

Professor of Paediatric Neuro-Oncology and Cancer Biology Children’s Brain Tumour Research Centre University of Nottingham Nottingham, UK Renzo Guerrini, MD, FRCP

Professor and Head Neuroscience Department University of Florence and Children’s Hospital Anna Meyer Florence, Italy Nalin Gupta, MD, PhD

UCSF Benioff Professor in Children’s Health Departments of Neurological Surgery and Pediatrics University of California San Francisco San Francisco, CA, USA

Milton H. Hamblin, PhD

Assistant Professor Department of Pharmacology Tulane University School of Medicine, New Orleans, LA, USA Abeer J. Hani, MD

Assistant Professor of Pediatrics and Neurology Lebanese American University Beirut, Lebanon Sharyu Hanmantgad

Department of Radiology Memorial Sloan-Kettering Cancer Center New York, NY, USA Mary J. Harbert, MD

Director of Neonatal Neurology Sharp Mary Birch Hospital for Women and Newborns; Assistant Professor of Neurosciences University of California San Diego San Diego, CA, USA Chellamani Harini, MBBS, MD

Instructor Department of Neurology Boston Children’s Hospital Boston, MA, USA Andrea M. Harriott, MD

Fellow Department of Neurology Brigham and Women’s Hospital Massachusetts General Hospital Boston, MA, USA Chad Heatwole, MD, MS-CI

Associate Professor of Neurology Department of Neurology University of Rochester Rochester, MN, USA Andrew D. Hershey, MD, PhD, FAHS

Endowed Chair and Director of Neurology; Director, Headache Center Cincinnati Children’s Hospital Medical Center; Professor of Pediatrics and Neurology University of Cincinnati, College of Medicine Cincinnati, OH, USA Deborah G. Hirtz, MD

Professor Neurological Sciences and Pediatrics University of Vermont School of Medicine Burlington, VT, USA



Contributors

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Gregory L. Holmes, MD

Joanne Kacperski, MD

John T. Kissel, MD

Professor of Neurological Sciences and Pediatrics; Chair, Department of Neurological Sciences University of Vermont College of Medicine Burlington, VT, USA

Assistant Professor of Neurology and Pediatrics University of Cincinnati, College of Medicine Department of Pediatrics and Neurology Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA

Professor of Neurology, Pediatrics, Neuroscience; Chairman, Department of Neurology The Gilbert and Kathryn Mitchell Chair in Neurology The Ohio State University Wexner Medical Center Department of Neurology Columbus, OH, USA

Peter B. Kang, MD

Kelly G. Knupp, MD

Associate Professor of Pediatrics and Chief, Division of Pediatric Neurology Department of Pediatrics University of Florida College of Medicine Gainesville, FL, USA

Associate Professor of Neurology and Pediatrics University of Colorado School of Medicine Children’s Hospital Colorado Aurora, CO, USA

Barbara A. Holshouser, PhD

Professor Department of Radiology Loma Linda University School of Medicine Loma Linda, CA, USA Kathleen A. Hurwitz, MD

Physician Hurwitz Pediatrics Murrieta, CA, USA Eugene Hwang, MD

Attending, Pediatric Neuro-oncology Director, Clinical Neuro-oncology Immunotherapeutics Program Center for Cancer and Blood Disorders Children’s National Medical Center Washington, DC, USA Rebecca N. Ichord, MD

Associate Professor, Neurology University of Pennsylvania School of Medicine; Director, Pediatric Stroke Program Philadelphia, PA, USA Paymaan Jafar-Nejad, MD

Assistant Director Department of Neuro Drug Discovery Ionis Pharmaceuticals, Inc. Carlsbad, CA, USA Sejal V. Jain, MD

Associate Director of the Sleep Center; Director, Neurology-Sleep Program; Assistant Professor of Pediatrics and Neurology Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA Lori Jordan, MD, PhD

Assistant Professor Departments of Pediatrics and Neurology Vanderbilt University Medical Center Nashville, TN, USA Marielle A. Kabbouche, MD, FAHS

Professor of Pediatrics and Neurology University of Cincinnati, College of Medicine; Director, Inpatient Headache Program Department of Pediatrics and Neurology Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA

Matthias A. Kariannis, MD, MS

Associate Professor of Pediatrics and Otolaryngology Division of Pediatric Hematology/ Oncology NYU Langone Medical Center and Perlmutter Cancer Center New York, NY, USA Horacio Kaufmann, MD

Felicia B. Axelrod Professor of Dysautonomia Research Department of Neurology NYU School of Medicine New York, NY, USA Harper L. Kaye, MD

Neurologist Clinical Neuromodulation Boston Children’s Hospital Boston, MA, USA Robert Keating, MD

Chief Neurosurgery Children’s National Washington, DC, USA Colin R. Kennedy, MBBS, MD

Professor in Neurology and Paediatrics Faculty of Medicine University of Southampton Southampton, UK Yasmin Khakoo, MD

Child Neurology Director; Associate Attending Pediatric Neurologist/Neuro-oncologist Memorial Sloan Kettering Cancer Center New York, NY, USA Adam Kirton, MD, MSc, FRCPC

Associate Professor Pediatrics and Clinical Neurosciences Cumming School of Medicine University of Calgary Alberta Children’s Hospital Research Institute Calgary, AB, Canada

Bruce R. Korf, MD, PhD

Wayne H. and Sara Crews Finley Chair in Medical Genetics; Professor and Chair, Department of Genetics; Director, Heflin Center for Genomic Sciences University of Alabama at Birmingham Birmingham, AL, USA Eric H. Kossoff, MD

Professor Departments of Neurology and Pediatrics Johns Hopkins Hospital Baltimore, MD, USA Sanjeev V. Kothare, MD

Director, Pediatric Sleep Program New York University Langone Medical Center; Pediatric Neurologist and Epileptologist NYU Comprehensive Epilepsy Center Department of Neurology New York, NY, USA Oren Kupfer, MD

Assistant Professor of Pediatrics Pediatric Pulmonary Medicine University of Colorado School of Medicine Children’s Hospital Colorado Aurora, CO, USA W. Curt LaFrance, Jr., MD, MPH, FAAN, FANPA, DFAPA

Director Neuropsychiatry and Behavioral Neurology Rhode Island Hospital Providence, RI, USA Beatrice Latal, MD, MPH

Professor Child Development Center University Children’s Hospital Zurich Zurich, Switzerland

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Contributors

Steven M. Leber, MD, PhD

Tobias Loddenkemper, MD

Kiran P. Maski, MD

Professor Departments of Pediatrics and Neurology University of Michigan Ann Arbor, MI, USA

Director of Clinical Epilepsy Research; Associate Professor, Harvard Medical School Division of Epilepsy and Clinical Neurophysiology Boston Children’s Hospital Boston, MA, USA

Instructor, Harvard Medical School Department of Neurology Boston Children’s Hospital Boston, MA, USA

Jean-Pyo Lee, PhD

Assistant Professor Department of Neurology Tulane University School of Medicine New Orleans, LA, USA Ilo E. Leppik, MD

Professor of Neurology and Pharmacy University of Minnsota Minneapolis, MN, USA Tally Lerman-Sagie, MD

Professor Neurosurgery Edith Wolfson Medical Center Jerusalem, Israel Jason T. Lerner, MD

Associate Professor Division of Pediatric Neurology David Geffen School of Medicine at UCLA Los Angeles, CA, USA Richard J. Leventer, MD

Professor Division of Medicine The Royal Children’s Hospital Melbourne Melbourne, Australia Daniel J. Licht, MD

Associate Professor of Neurology; Director of the Wolfson Family Laboratory for Clinical and Biomedical Optics Department of Neurology The Children’s Hospital of Philadelphia Philadelphia, PA, USA Uta Lichter-Konecki, MD, PhD

Visiting Professor of Pediatrics Director of the Metabolism Program Division of Medical Genetics/PKU Program Children’s Hospital of Pittsburgh Pittsburgh, PA, USA Zvi Lidar, MD

Consultant Physician Neurosurgery Herzliya Medical Center Tel Aviv-Yafo, Israel Djin Gie Liem, PhD

Senior Lecturer School of Exercise, Nutrition Sciences Deakin University Burwood, NSW, Australia

Roger K. Long, MD

Associate Professor Department of Pediatrics University of California, San Francisco San Francisco, CA, USA Quyen N. Luc, MD

Clinical Assistant Professor of Neurology Keck School of Medicine University of Southern California Los Angeles, CA, USA Mark Mackay, MBBS, PhD, FRACP

Director, Children’s Stroke Program Department of Neurology, Royal Children’s Hospital; Honorary Research Fellow, Clinical Sciences Theme, Murdoch Childrens Research Institute; Honorary Professorial Research Fellow Florey Institute of Neurosciences and Mental Health University of Melbourne Melbourne, VIC, Australia Annette Majnemer, MD

Professor; Director and Associate Dean School of Physical and Occupational Therapy McGill University Montreal, Canada

Mudit Mathur, MD, MBA, FAAP, FCCM

Associate Professor Department of Pediatrics, Division of Pediatric Critical Care Loma Linda University School of Medicine Loma Linda, CA, USA Dennis J. Matthews, MD

Professor; Chairman Physical Medicine and Rehabilitation University of Colorado Denver, CO, USA Kelly McMahon, MD

Genetic Counselor University of Rochester Medical Center Rochester, NY, USA Megan B. DeMara-Hoth

Clinical Research Associate (Volunteer) Neurology Medical College of Wisconsin Milwaukee, WI, USA Bryce Mendelsohn, MD, PhD

Assistant Clinical Professor Department of Pediatrics, Division of Medical Genetics University of California San Francisco, CA, USA Julie A. Mennella, PhD

Member Monell Chemical Senses Center Philadelphia, PA, USA

Naila Makhani, MD, MPH

Laura R. Ment, MD

Assistant Professor Departments of Pediatrics and Neurology Yale University School of Medicine New Haven, CT, USA

Professor, Departments of Pediatrics and Neurology; Associate Dean Yale School of Medicine New Haven, CT, USA

Gustavo Malinger, MD

Eugenio Mercuri, MD

Associate Professor Obstetrics and Gynecology Tel-Aviv University Tel-Aviv, Israel

Professor of Pediatric Neurology Catholic University Sacred Heart Rome, Italy

David E. Mandelbaum, MD

Professor Neurology, Pediatrics Brown University Providence, RI, USA

Assistant Professor Departments of Pediatrics and Neurology Loma Linda University Health Loma Linda, CA, USA

Stephen M. Maricich, PhD, MD

Mohamad A. Mikati, MD

Mellon Foundation Scholar Assistant Professor Department of Pediatrics Division of Neurology Pittsburgh, PA, USA

Wilburt C. Davison Professor of Pediatrics; Professor of Neurobiology; Chief, Division of Pediatric Neurology Duke University Medical Center Durham, NC, USA

David J. Michelson, MD



Contributors

Fady M. Mikhail, MD

Umrao R. Monani, PhD

Jeffrey L. Neul, MD, PhD

Co-Director Department of Genetics University of Birmingham Birmingham, AL, USA

Associate Professor Pathology, Cell Biology Columbia University Medical Center New York, NY, USA

Steven Paul Miller, MDCM, MAS

Michelle Monje Deisseroth, MD, PhD

Chief of Child Neurology; Professor and Vice Chair Department of Neurosciences University of California San Diego, CA, USA

Division Head and Professor of Pediatrics Bloorview Children’s Hospital Chair in Pediatric Neuroscience Department of Pediatrics (Neurology) The Hospital for Sick Children, University of Toronto Toronto, ON, Canada

Anne T. and Robert M. Bass Endowed Faculty Scholar in Pediatric Cancer and Blood Diseases Assistant Professor of Neurology, and by courtesy, Neurosurgery, Pathology and Pediatrics Stanford University Palo Alto, CA, USA

Yoram Nevo, MD

Jeff M. Milunsky, MD

Manikum Moodley, MD, FCP, FRCP

Co-Director, Center for Human Genetics; Director, Clinical Genetics; Senior Director, Molecular Genetics Center for Human Genetics Cambridge, MA, USA

Staff Pediatric Neurologist Center for Pediatric Neurology Neurological Institute, Cleveland Clinic Cleveland, OH, USA

Scientist Genetic Disease Program Sanford - Burnham - Prebys Medical Discovery Institute La Jolla, CA, USA

Andrew Mower, MD

Katherine C. Nickels, MD

Neurology Children’s Hospital of Orange County Orange County, CA, USA

Assistant Professor Department of Neurology Mayo Clinic Rochester, MN, USA

Jonathan W. Mink, MD, PhD

Frederick A. Horner, MD Endowed Professor in Pediatric Neurology Departments of Neurology, Neuroscience, and Pediatrics University of Rochester Rochester, NY, USA Ghayda M. Mirzaa, MD

Assistant Professor Center for Integrative Brain Research Children’s Research Institute Seattle, WA, USA Wendy G. Mitchell, MD

Professor, Clinical Neurology Keck School of Medicine University of Southern California Children’s Hospital Los Angeles Los Angeles, CA, USA Michael A. Mohan, MD

Department of Sleep Medicine Boston Children’s Hospital Beth Israel Deaconess Medical Center Boston, MA, USA Payam Mohassel, MD

Clinical Fellow National Institutes of Health, National Institute of Neurological Disorders and Stroke Bethesda, MD, USA Mahendranath Moharir, MD, MSc, FRACP

Pediatric Neurologist and Associate Professor Division of Neurology, Department of Pediatrics The Hospital for Sick Children and University of Toronto Toronto, ON, Canada

Richard T. Moxley III, MD

Professor of Neurology and Pediatrics University of Rochester Medical Center School of Medicine and Dentistry Rochester, NY, USA Sabine Mueller, MD, PhD, MAS

Associate Professor Department of Neurology, Neurosurgery and Pediatrics University of California, San Francisco San Francisco, CA, USA Alysson R. Muotri, PhD

Associate Professor Departments of Pediatrics and Cellular, Molecular Medicine University of California San Diego La Jolla, CA, USA Sandesh C.S. Nagamani, MBBS, MD

Assistant Professor Molecular and Human Genetics Baylor College of Medicine Houston, TX, US Mohan J. Narayanan, MD

Barrow Neurological Institute Phoenix, AZ, USA Vinodh Narayanan, MD

Medical Director Center for Rare Childhood Disorders The Translational Genomics Research Institute (TGen) Phoenix, AZ, USA Ruth D. Nass, MD

Nancy Glickenhaus Pier Professor of Pediatric Neuropsychiatry; Professor, Department of Child and Adolescent Psychiatry; Professor, Department of Pediatrics NYU Langone Medical Center NYU Child Study Center New York, NY, USA

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Professor and chair Institute of Neurology Schneider Children’s Medical Center of Israel Tel-Aviv University Tel Aviv, Israel Bobby G. Ng, BS

Graeme A.M. Nimmo, MBBS, MSc

Resident Clinical and Metabolic Genetics The Hospital for Sick Children University of Toronto Toronto, ON, Canada Michael J. Noetzel, MD

Professor of Neurology and Pediatrics; Vice Chair, Division of Pediatric and Developmental Neurology Washington University School of Medicine; Medical Director, Clinical and Diagnostic Neuroscience Services St. Louis Children’s Hospital St. Louis, MO, USA Lucy Norcliffe-Kaufmann, PhD

Assistant Professor, Physiology and Neuroscience NYU Langone Medical Center New York, NY, USA Douglas R. Nordli, Jr., MD

Chief of the Division of Pediatric Neurology and co-director of the Neuroscience Institute Children’s Hospital Los Angeles Los Angeles, CA, USA Ulrike Nowak-Göttl, MD

Professor; Deputy Director Campus Kiel Institute of Clinical Chemistry Universitätsklinikum Schleswig-Holstein Kiel, Germany

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Contributors

Hope L. O’Brien, MD, FAHS

Julie A. Parsons, MD

John Phillips, MD

Associate Professor of Pediatrics and Neurology University of Cincinnati, College of Medicine; Director, Young Adult Headache Clinic; Program Director, Headache Medicine Education Department of Pediatrics and Neurology Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA

Associate Professor of Pediatrics and Neurology Child Neurology University of Colorado School of Medicine Aurora, CO, USA

Professor and Director of Child Neurology Department of Neurology University of New Mexico Health Science Center Albuquerque, NM, USA

John Colin Partridge, MD

Barbara Plecko, MD

Professor, Emeritus Pediatrics (Neonatology) University of California San Francisco UCSF Benioff Children’s Hospital San Francisco, CA, USA

Professor Department of Child Neurology University Children’s Hospital Zurich Zurich, Switzerland

Gregory M. Pastores, MD

Head, Pediatric Neuropsychiatry Program Child and Adolescent Psychiatry; Associate Professor of Psychiatry and Behavioral Sciences Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL, USA

Joyce Oleszek, MD

Associate Professor Department of Rehabilitation University of Colorado at Denver Denver, CO, USA Maryam Oskoui, MDCM, MSc, FRCPC

Assistant Professor Departments of Pediatrics and Neurology/Neurosurgery McGill University Montreal, QC, Canada Alex R. Paciorkowski, MD

Assistant Professor Department of Neurology University of Rochester Medical Center Rochester, MN, USA Roger J. Packer, MD

Senior Vice-President, Center for Neuroscience and Behavioral Medicine; Gilbert Family Neurofibromatosis Family Distinguished Professor in Neurofibromatosis; Director, Brain Tumor Institute; Director, Neurofibromatosis Institute Children’s National Health System; Professor, Neurology and Pediatrics George Washington University Washington, DC, USA Seymour Packman, MD

Professor Emeritus Department of Pediatrics, Division of Medical Genetics University of California San Francisco, CA, USA Jose-Alberto Palma, MD

Assistant Professor, Department of Neurology; Assistant Director, Dysautonomia Research Laboratory NYU Langone Medical Center New York, NY, USA Andrea C. Pardo, MD, FAAP

Assistant Professor Department of Pediatrics and Neurology Ann and Robert H. Lurie Children’s Hospital of Chicago Northwestern Feinberg School of Medicine Chicago, IL, USA

Clinical Professor, Medicine (Genetics) University College Dublin Dublin, Ireland Marc C. Patterson, MD

Chair, Division of Child and Adolescent Neurology Professor of Neurology, Pediatrics and Medical Genetics Director, Child Neurology Training Program Mayo Clinic Rochester, MMN, USA William J. Pearce, PhD

Professor of Physiology Center for Perinatal Biology Loma Linda University School of Medicine Loma Linda, CA, USA Phillip L. Pearl, MD

Director of Epilepsy and Clinical Neurophysiology Boston Children’s Hospital; William G. Lennox Professor of Neurology Harvard Medical School Boston, MA, USA

Sigita Plioplys, MD

Annapurna Poduri, MD, MPH

Associate Professor Department of Neurology Boston Children’s Hospital, Harvard Medical School Boston, MA, USA Sharon Poisson, MD

Assistant Professor Neurology Clinic University of Colorado Hospital Aurora, CO, USA Scott L. Pomeroy, MD, PhD

Bronson Crothers Professor and Chairman Department of Neurology Harvard Medical School Boston, MA, USA

Melanie Penner, MD, FRCP(C)

Andrea Poretti, MD

Clinician Investigator and Developmental Pediatrician Holland Bloorview Kids Rehabilitation Hospital Toronto, ON, Canada

Assistant Professor Division of Pediatric Radiology Russell H. Morgan Department of Radiology and Radiological Science The John Hopkins University School of Medicine Baltimore, MD, USA

Leila Percival, RN

Clinical Research Nurse NYU Langone Medical Center New York, NY, USA Marcia Pereira, PhD

Instructor Department of Neurology Tulane University School of Medicine New Orleans, LA, USA Stefan M. Pfister, MD

Professor of Pediatrics Division of Pediatric Neurooncology German Cancer Research Center (DKFZ) Heidelberg, Germany

Scott W. Powers, PhD, ABPP, FAHS

Professor of Pediatrics and CCRF Endowed Chair University of Cincinnati College of Medicine; Director of Clinical and Translational Research Cincinnati Children’s Research Foundation; Co-Director, Headache Center; Director, Center for Child Behavior and Nutrition Research and Training Division of Behavioral Medicine and Clinical Psychology Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA



Contributors

Michael R. Pranzatelli, MD

Lance H. Rodan, MD

Courtesy Professor of Neurology University of Central Florida College of Medicine Orlando, FL, USA; Adjoint Professor of Neurology University of Colorado School of Medicine Founder and President National Pediatric Neuroinflammation Organization, Inc. Orlando, FL, USA

Instructor in Pediatrics, Harvard Medical School Department of Neurology, Boston Children’s Hospital, Boston MA Department of Medicine, Division of Genetics and Genomics, Boston Children’s Hospital Boston, MA, USA

Allison Przekop, DO

Associate Professor Pediatrics, Division of Pediatric Neurology Loma Linda University Children’s Hospital Loma Linda, CA, USA Malcolm Rabie, MB BCh, FCP (SA) (Neurol.)

Staff Physician Institute of Neurology, Schneider Children’s Medical Center of Israel Tel Aviv University Tel Aviv, Israel Sampathkumar Rangasamy, PhD

Research Assistant Professor Neurogenomics Division and The Dorrance Center for Rare Childhood Disorders, The Translational Genomics Research Institute (TGen) Phoenix, AZ, USA Gerald V. Raymond, MD

Professor, Department of Neurology The University of Minnesota Minneapolis, MN, USA Alyssa T. Reddy, MD

Professor of Pediatrics; Director, Neuro-Oncology Program UAB Cancer Prevention and Control Training Program University of Alabama Birmingham, AL, USA Rebecca L. Rendleman, MD, CM

Assistant Professor of Clinical Psychiatry Weill Cornell Medical College; Assistant Attending Psychiatry NewYork-Presbyterian Hospital New York, NY, USA Jong M. Rho, MD

Professor, Departments of Paediatrics, Clinical Neurology; Division Head, Paediatric Neurology Alberta Children’s Hospital; Dr. Robert Haslam Chair in Child Neurology; Alberta Children’s Hospital Calgary, AB, USA

Sarah M. Roddy, MD

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Pedro Sanchez, MD, FAAP, MSCE, FACMG

Director of Craniofacial Genetics Children’s Hospital Los Angeles; Assistant Professor of Clinical Pediatrics University of Southern California; Assistant Professor of Clinical Pathology University of Southern California Los Angeles, CA, USA

Associate Professor of Pediatrics and Neurology; Associate Dean of Admissions Loma Linda University School of Medicine Loma Linda, CA, USA

Iván Sánchez Fernández, MD

Elizabeth E. Rogers

Tristan T. Sands, MD, PhD

Associate Professor of Pediatrics Director, Intensive Care Nursery Follow Up Program Associate Clinical Director, Intensive Care Nursery UCSF – Benioff Children’s Hospital San Francisco San Francisco, CA, USA

Assistant Professor of Neurology Columbia University Medical Center New York City, NY, USA

Stephen M. Rosenthal, MD

Professor of Pediatrics Division of Pediatric Endocrinology Medical Director, Child and Adolescent Gender Center University of California, San Francisco San Francisco, CA, USA N. Paul Rosman, MD

Professor of Pediatrics and Neurology Pediatrics, Neurology; Division of Pediatric Neurology Boston Medical Center Boston University School of Medicine Boston, MA, USA M. Elizabeth Ross, MD, PhD

Nathan Cummings Professor of Neurology and Neuroscience; Director, Center for Neurogenetics Brain and Mind Research Institute Weill Cornell Medical College New York, NY, USA Alexander Rotenberg, MD, PhD

Associate in Neurology; Research Associate in Neurology; Director, Neuromodulation Program F.M. Kirby Neurobiology Center Boston Children’s Hospital Boston, MA, USA Robert S. Rust, MA, MD

Professor Neurology University of Virginia Medical Center Charlottesville, VA, USA Cheryl P. Sanchez, MD

Associate Professor Department of Pediatrics Loma Linda University Children’s Hospital Loma Linda, CA, USA

Epilepsy Fellow Division of Epilepsy and Clinical Neurophysiology Boston Children’s Hospital Boston, MA, USA

Terence D. Sanger, MD PhD

Associate Professor University of Southern California Department Biomedical Engineering, Biokinesiology, Child Neurology Los Angeles, CA, USA Kumar Sannagowdara, MD DCH, MRCPCH (UK)

Assistant Professor of Pediatric Neurology and Epilepsy Medical College of Wisconsin Milwaukee, WI, USA Dustin Scheinost, MD

Associate Research Scientist Department of Radiology, Biomedical Imaging Yale School of Medicine New Haven, CT, USA Mark S. Scher, MD

Tenured Professor of Pediatrics and Neurology; Chief, Division of Pediatric Neurology; Director, Fetal and Neonatal Neurology Program Pediatrics, Rainbow Babies and Children’s Hospital Case Western Reserve University, School of Medicine Cleveland, OH, USA Nina F. Schor, MD, PhD

William H. Eilinger Professor and Chair Department of Pediatrics; Professor, Department of Neurology and Neuroscience; Pediatrician-in-Chief, Golisano Children’s Hospital University of Rochester School of Medicine and Dentistry Rochester, NY, USA

xxiv

Contributors

Isabelle Schrauwen, PhD

Rita D. Sheth, MD MPH

Katherine B. Sims, MD

Research Assistant Professor Neurogenomics Division The Translational Genomics Research Institute (TGen) Phoenix, AZ, USA

Assistant Professor of Pediatrics Pediatric Nephrology Department of Pediatrics Loma Linda University School of Medicine Loma Linda, CA, USA

Professor of Neurology Department of Neurology, Division of Child Neurology Massachusetts General Hospital and Harvard Medical School Boston, MA, USA

Michael I. Shevell, MDCM, FRCP(C), FCAHS

Harvey S. Singer, MD

Michael M. Segal, MD, PhD

Founder and Chief Scientist SimulConsult, Inc. Chestnut Hill, MA, USA Syndi Seinfeld, DO, MS

Assistant Professor Child Neurology Virginia Commonwealth University Richmond, VA, USA Duygu Selcen, MD

Associate Professor of Neurology and Pediatrics Department of Neurology Mayo Clinic College of Medicine Rochester, MN, USA Laurie E. Seltzer, DO

Senior Instructor of Child Neurology; Epilepsy Fellow University of Rochester Medical Center Rochester, NY, USA Margaret Semrud-Clikeman, PhD, LP ABPdN

Professor of Pediatrics University of Minnesota Medical School Minneapolis, MN, USA Dennis W. Shaw, MD

Professor of Radiology Department of Radiology University of Washington Seattle Children’s Hospital Seattle, WA, USA Bennett A. Shaywitz, MD

Charles and Helen Schwab Professor of Pediatrics (Neurology); Co-Director, Yale Center for Dyslexia and Creativity Yale School of Medicine New Haven, CT, USA Sally E. Shaywitz, MD

Audrey G. Ratner Professor of Learning Development; Co-Director, Yale Center for Dyslexia and Creativity Yale School of Medicine New Haven, CT, USA Renée A. Shellhaas, MD, MS

Clinical associate professor Department of pediatrics and communicable diseases (division of pediatric neurology) University of Michigan Ann Arbor, MI, USA Elliott H. Sherr, MD, PhD

Professor UCSF School of Medicine San Francisco, CA, USA

Professor, Departments of Pediatrics, Neurology and Neurosurgery; Chair, McGill Department of Pediatrics; Pediatrician-in-Chief, Montreal Children’s Hospital-McGill University Health Centre (MUHC); Harvey Guyda Professor Department of Pediatrics, Faculty of Medicine, McGill University Montreal, QC, Canada Shlomo Shinnar, MD, PhD

Professor Neurology, Pediatrics and Epidemiology and Population Health; Hyman Climenko Professor of Neuroscience Research; Director, Comprehensive Epilepsy Management Center Montefiore Medical Center, Albert Einstein College of Medicine Bronx, NY, USA Ben Shofty, MD

Resident Division of Neurosurgery Tel Aviv Medical Center Tel Aviv, Israel Stanford K. Shu, MD

Assistant Professor of Pediatrics Division of Child Neurology Department of Pediatrics Loma Linda University School of Medicine; Pediatric Neurologist Loma Linda University Children’s Hospital Loma Linda, CA, USA Michael E. Shy, MD

Professor of Neurology, Pediatrics and Physiology Carver College of Medicine University of Iowa Iowa City, IA, USA Laura Silveira Moriyama, MD

Professor, Department Posgraduate Program in Medicine Institute Ciências da Saúde Universidade Nove de Julho (Uninove) São Paulo, SP, Brazil Nicholas J. Silvestri, MD

Assistant Professor Department of Neurology University at Buffalo Jacobs School of Medicine and Biomedical Sciences Buffalo, New York, NY, USA

Professor Departments of Neurology and Pediatrics Johns Hopkins University School of Medicine Johns Hopkins Hospital Baltimore, MD, USA Nilika Shah Singhal, MD

Assistant Professor Department of Neurology, Pediatrics University of California San Francisco San Francisco, CA, USA Craig M. Smith, MD

Attending Physician, Critical Care; Instructor in Pediatrics Northwestern University Feinberg School of Medicine Ann & Robert H. Lurie Children’s Hospital of Chicago Chicago, IL, USA Edward Smith, MD

Director of Cerebrovascular Surgery; Associate Professor, Department of Neurosurgery Boston Children’s Hospital, Harvard Medical School Boston, MA, USA Stephen A. Smith, MD

Medical Director, Neuromuscular Program Gillette Children’s Specialty Healthcare Saint Paul, MN, USA Evan Y. Snyder, MD, PhD

Professor Department of Stem Cells and Regenerative Medicine Sanford-Burnham-Prebys Medical Discovery Institute La Jolla, CA, USA Janet Soul, MDCM, FRCPC

Associate Professor of Neurology Department of Neurology Harvard Medical School Boston, MA, USA Christy L. Spalink, RN, MSN, ACNP-BC

Complex Medical Care Coordinator Department of Neurology New York University School of Medicine New York, NY, USA



Contributors

Karen A. Spencer, MD, MS, MPH

Ingrid Tein, MD, FRCP (C)

Doris A. Trauner, MD

Instructor Department of Neurology Boston Children’s Hospital Boston, MA, USA

Director, Neurometabolic Clinic and Research Laboratory, Division of Neurology; Associate Professor, Department of Pediatrics, Laboratory Medicine and Pathobiology; Senior Associate Scientist, Genetics and Genome Biology Program The Hospital for Sick Children The University of Toronto Toronto, ON, Canada

Distinguished Professor Departments of Neurosciences and Pediatrics UCSD School of Medicine La Jolla, CA, USA

Carl E. Stafstrom, MD, PhD

Professor of Neurology and Pediatrics Lederer Chair in Pediatric Epilpesy Division of Pediatric Neurology Johns Hopkins University Cchool of Medicine Baltimore, MD, USA Robert Steinfeld, MD, PhD

Professor Department of Pediatrics University Medical Center Goettingen Goettingen, Germany Jonathan B. Strober, MD

Professor Departments of Neurology, Pediatrics UCSF Benioff Children’s Hospital San Francisco San Francisco, CA, USA Joseph Sullivan, MD

Associate Professor of Neurology, Pediatrics; Director, UCSF Pediatric Epilepsy Center University of California San Francisco San Francisco, CA, USA Kenneth F. Swaiman, MD

Director Emeritus, Division of Pediatric Neurology; Professor Emeritus of Neurology and Pediatrics University of Minnesota Medical School Minneapolis, MN, USA Kathryn J. Swoboda, MD

Director Neurogenetics Unit Center for Genomic Medicine Department of Neurology Massachusetts General Hospital Boston, MA, USA Elizabeth D. Tate, MN, ARNP, BC-FNP

Nurse Practitioner National Pediatric Neuroinflammation Organization, Inc. Orlando, FL, USA William O. Tatum IV, DO

Professor Department of Neurology Mayo Clinic College of Medicine Jacksonville, FL, USA

Kristyn Tekulve, MD

Assistant Professor of Child Neurology Department of Neurology, Division of Child Neurology Riley Hospital for Children at Indiana University School of Medicine Indianapolis, IN, USA Jeffrey R. Tenney, MD, PhD

Pediatric Epileptologist Division of Neurology; Assistant Professor UC Department of Pediatrics Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA Elizabeth A. Thiele, MD, PhD

Director, Pediatric Epilepsy Program; Director, Carol and James Herscot Center for Tuberous Sclerosis Complex; Professor of Neurology, Harvard Medical School Massachusetts General Hospital Boston, MA, USA Robert Thompson-Stone, MD

Assistant Professor Department of Neurology University of Rochester Rochester, NY, USA Laura Tochen, MD

Assistant Professor Department of Neurology Children’s National Medical Center Washington, DC, USA Laura M. Tormoehlen, MD

Associate Professor of Clinical Neurology and Emergency Medicine Indiana University School of Medicine Indianapolis, IN, USA Lily Tran, MD

Assistant Clinical Professor, Department of Pediatrics University of California- Irvine; CHOC Children’s Specialist, Pediatric Neurology Orange, CA, USA

xxv

Sinan O. Turnacioglu, MD

Assistant Professor Neurogenetics and Neurodevelopmental Pediatrics Children’s National Health System George Washington University Washington, DC, USA Nicole J. Ullrich, MD, PhD

Associate Professor of Neurology Department of Neurology Boston Children’s Hospital Harvard Medical School Boston, MA, USA David K. Urion, MD, FAAN

Director, Behavioral Neurology Clinics and Programs; Director of Education and Residency Training Programs in Child Neurology and Neurodevelopmental Disabilities; Charles F. Barlow Chair Boston Children’s Hospital; Associate Professor of Neurology Harvard Medical School Boston, MA, USA Guy Van Camp, PhD

Senior research scientist Centre of Medical Genetics University of Antwerp Antwerp, Belgium Michèle Van Hirtum-Das, MD

Neurologist Children’s Hospital Los Angeles; University of California Los Angeles Medical Center Los Angeles, CA, USA Clara D.M. van Karnebeek, MD, PhD

Associate Professor Department of Paediatrics Academic Medical Center Amsterdam, The Netherlands; Department of Pediatrics Centre for Molecular Medicine and Therapeutics University of British Columbia Vancouver, BC, Canada Lionel Van Maldergem, MD, PhD

Professor Centre for Human Genetics University of Franche-Comté Besançon, France

xxvi

Contributors

Adeline Vanderver, MD

Lauren C. Walters-Sen, MD

Jeffrey H. Wisoff, MD

Associate Professor Division of Neurology Program Director of the Leukodystrophy Center of Excellence Jacob A. Kamens Endowed Chair in Neurological Disorders and Translational NeuroTherapeutics Children’s Hospital of Philadelphia Philadelphia, PA, USA

Geneticist Center for Human Genetics, Inc. Cambridge, MA, USA

Professor of Neurosurgery and Pediatrics Director, Division of Pediatric Neurosurgery Department of Neurosurgery NYU Langone Medical Center New York, NY, USA

Nicholas A. Vitanza, MD

Acting Assistant Professor of Pediatrics University of Washington School of Medicine Seattle Children’s Hospital Seattle, WA, USA Michael von Rhein, MD

Head, Division of Developmental Pediatrics Department of Pediatrics Kantonal Hospital Winterthur; Child Development Center University Childrens Hospital Zurich, Switzerland Emily von Scheven, MD, MAS

Professor of Clinical Pediatrics Chief, Division of Pediatric Rheumatology University of California, San Francisco San Francisco, CA, USA Ann Wagner, PhD

Chief, Neurobehavioral Mechanisms of Mental Disorders Branch Division of Translational Research National Institute of Mental Health National Institutes of Health Bethesda, MD, USA Mark S. Wainwright, MD, PhD

Founders’ Board Chair in Neurocritical Care; Professor of Pediatrics and Neurology Ann, Robert H Lurie Children’s Hospital of Chicago Northwestern University Feinberg School of Medicine Chicago, IL, USA Melissa A. Walker, MD, PhD

Assistant in Neurology Massachusetts General Hospital Boston, MA, USA John T. Walkup, MD

Professor Department of Psychiatry Weill Cornell Medical College New York-Presbyterian Hospital New York, NY, USA Laurence Walsh, MD

Associate Professor of Clinical Neurology, Genetics and Pediatrics Departments of Neurology, Medical and Molecular Genetics and Pediatrics Indiana University School of Medicine Riley Hospital for Children at Indiana University Health Indianapolis, IN, USA

Raymond Y. Wang, MD

Director, Multidisciplinary Lysosomal Disorder Program Division of Metabolic Disorders CHOC Children’s Hospital; Assistant Clinical Professor Department of Pediatrics University of California-Irvine Orange, CA, USA Thomas T. Warner, BA, BM, BCh, PhD, FRCP

Professor and Director Reta Lila Weston Institute of Neurological Studies UCL Institute of Neurology National Hospital for Neurology and Neurosurgery London, UK Harry T. Whelan, MD

Bleser Professor, Neurology, Pediatrics and Hyperbaric Medicine; Director of Hyperbaric Medicine Medical College of Wisconsin Milwaukee, WI, USA Geoffrey A. Weinberg, MD

Professor of Pediatrics Director, Pediatric HIV Program Division of Pediatric Infectious Diseases Department of Pediatrics University of Rochester School of Medicine, Dentistry Rochester, NY, USA

Nicole I. Wolf, MD, PhD

Assistant Professor Child Neurology VU University Medical Center Amsterdam, The Netherlands Gil I. Wolfe, MD

Irvin and Rosemary Smith Professor and Chairman Department of Neurology University at Buffalo, State University of New York Jacobs School of Medicine and Biomedical Sciences Buffalo, NY, USA F. Virginia Wright, PT, PhD

Senior Scientist Bloorview Research Institute Holland Bloorview Kids Rehabilitation Hospital Bloorview Children’s Hospital Foundation Chair in Pediatric Rehabilitation. Toronto, ON, Canada Nathaniel D. Wycliffe, MD

Associate Professor of Radiology Loma Linda University School of Medicine Loma Linda, CA, USA

Elizabeth M. Wells, MD

Michele L. Yang, MD

Assistant Professor George Washington University; Medical Director Inpatient Neurology Center for Neuroscience and the Brain Tumor Institute Children’s National Health System Washington, DC, USA

Assistant Professor Department of Pediatrics; Section of Child Neurology Children’s Hospital Colorado Aurora, CO, USA

James W. Wheless, MD, FAAP, FAAN

Professor and Chief of Pediatric Neurology; Le Bonheur Chair in Pediatric Neurology University of Tennessee Health Science Center; Director, Le Bonheur Comprehensive Epilepsy Program, Neuroscience Institute Le Bonheur Children’s Hospital Memphis, TN, USA Elaine C. Wirrell, MD

Professor and Director of Pediatric Epilepsy Department of Neurology Mayo Clinic Rochester, MN, USA

Christopher J. Yuskaitis, MD, PhD

Department of Neurology, Boston Children’s Hospital Instructor in Neurology Harvard Medical School Boston, MA, USA Huda Y. Zoghbi, MD

Ralph D. Feigin Professor; Director, Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital; Investigator, Howard Hughes Medical Institute Pediatrics and Molecular and Human Genetics Baylor College of Medicine Houston, TX, USA Mary L. Zupanc, MD

Professor and Division Chief Department of Pediatrics and Neurology Children’s Hospital of Orange County University of California–Irvine Orange, CA, USA

PART I

1 

Clinical Evaluation

General Aspects of the Patient’s Neurologic History Kenneth F. Swaiman and John Phillips

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

When presented with a challenging patient in 1885, with students Josef Babinski, Sigmund Freud, and others looking on, Dr. Charcot used the most important tools he had at his disposal: a careful history and a detailed examination. If he were alive today, Dr. Charcot would use those same tools. There is no substitute for an accurate and thorough history. The patient or parent begins with an explanation of his or her concern. In most medical settings this opening statement lasts less than 60 seconds if not interrupted, as it unfortunately generally is, by the physician (Beckman and Frankel, 1984). More focused questions follow as a differential diagnosis is developed. In some cases language can be a barrier, particularly with the growing multiculturalism in the United States and other countries, and it is important that the interview be conducted in the native language of the patient. This may require the use of interpreters. Using a nonprofessional or poorly trained medical interpreter should be avoided because this has a much higher risk of causing clinically significant errors than using an experienced professional interpreter (Flores et al., 2012). In addition, an effective medical interview requires eye contact to help establish patient rapport (Cole and Bird, 2014), and the near-ubiquitous presence of computers in examination rooms, with an electronic medical record at the physician’s fingertips, can be a problem. Compared with using paper medical records, there is now significantly more time spent looking at the medical record (now on a computer screen) and less time looking at the patient (Asan et al., 2014). However, although there is no turning back on the electronic medical record, and the pressure to see more patients may be increasing, the balance of new technology is certainly favorable. Once adopted, the electronic medical record improves physician’s productivity and portable telemedicine equipment allows access to virtually any language needed in a medical setting (Cheriff et al., 2010). Arriving at an appropriate differential diagnosis is an active process. As information is obtained suggesting specific disease categories, further questioning helps narrow the possible diagnostic possibilities. This process is assisted by considering general groups of neurologic diseases. Memory aides are often used to recall differential diagnostic categories—VINDICATE and VITAMIN C are two common examples (Table 1-1). Overlap exists between categories, and within each disease category are multiple subcategories and then specific diseases that become more or less likely as the patient interview proceeds. For example, recurrent strokes from MELAS (a disorder of energy metabolism) could be considered both a vascular and a metabolic process. The important issue is that, if focal weakness is the presenting concern, then the patient interview continues in an effort to discern whether the weakness is recurrent or triggered by fever or dehydration (which might make

a metabolic disorder more likely). Further questioning may disclose a history of lactic acidosis that narrows the differential diagnosis further to a possible mitochondrial disorder such as MELAS, which can then be confirmed with genetic testing. The point is to begin broadly. Cast a wide net. Consider all disease categories until a more focused differential diagnosis is possible based on the detailed history. Part of clarifying the history of the current illness is to answer four basic questions: 1. Is the process acute or insidious? 2. Is it focal or generalized? 3. Is it progressive or static? 4. At what age did the problem begin? The order in which disease findings develop and the precise age of onset of symptoms and signs may be critical factors in the process of accurate diagnosis. Many degenerative disorders have specific ages of onset that can help narrow the differential diagnosis; cognitive regression in an 8-year-old may raise the question of adrenoleukodystrophy, whereas in a 2-year-old one might consider neuronal ceroid lipofuscinosis. The presence of repeated episodes or associated phenomena should also be determined. For example, although the clinical manifestations of cerebrovascular events such as an acute stroke normally develop over minutes to hours, the underlying process may be long-standing; therefore, acute onset of vascular symptoms may be the result of a subacute or chronic process. On the other hand, infections, electrolyte imbalances, and toxic processes (such as exposure to over-the-counter drugs, prescription medications, insecticides, and other toxins found around the home) usually progress over a day to several days before maximum symptoms occur. More chronic are degenerative diseases, inborn metabolic disorders, and neoplastic conditions that usually progress insidiously over weeks to months. Evaluation of whether a condition is focal or generalized is central to the diagnostic process. A focal neurologic lesion is not necessarily one that causes focal manifestations but is one that can be related to dysfunction in a circumscribed neuroanatomic location. For example, a focal lesion in the brainstem may cause ipsilateral cranial nerve and contralateral corticospinal tract involvement. If the problem is not focal, it usually results from a generalized process or from several lesions (i.e., multifocal). Neoplastic and vascular diseases frequently result in focal processes; occasionally, trauma results in such abnormalities. Generalized or multifocal conditions are usually associated with degenerative, congenital, metabolic, or toxic abnormalities. In child neurology, it is particularly important that the clinician always attempt to determine whether the condition

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PART I  Clinical Evaluation

TABLE 1-1  Disease Category Acronyms Vindicate V I N D I C A T E Vitamin C

Vascular Inflammatory Neoplastic Degenerative Infectious Congenital Allergy or autoimmune Trauma or toxin Endocrine

V I T A M I N C

Vascular Infectious Trauma Autoimmune Metabolic Idiopathic Neoplastic Congenital

is progressive or static. This is best accomplished by taking a detailed developmental history. Documenting the age of acquisition of major motor, language, and social milestones allows characterization of a child’s developmental progress compared with age-based norms. To address the critical issue of developmental regression, questions are posed that determine whether the child is no longer capable of motor or intellectual activities that were previously performed. This information is essential to the diagnosis of progressive disease, which is usually preceded by a period of normal development. Occasionally, prior formal neurologic and psychometric evaluations may be available that help enormously in providing objective documentation of prior developmental status. Reviewing family photographs, videos, baby books, or old Facebook postings can be helpful. In progressive conditions, such as those caused by metabolic or neoplastic disorders, documentation of increasing loss of normal function or an increase in any symptoms is essential. Static conditions can be the result of traumatic or anoxic injury, a congenital abnormality, or perhaps a resolving acute toxic ingestion. Reviewing the medical history is an essential part of any interview and often provides information that is critical in arriving at an appropriate diagnosis, extending information gleaned from the history of current illness. In child neurology, medical history begins with the moment of conception. Was conception achieved with reproductive technology, the longterm consequences of which are not clear? Was the mother older than 35 years at the time of conception, a possible risk factor for adverse outcome? During gestation, were there exposures to toxins such as alcohol, nicotine, or prescription or illicit drugs? Was the pregnancy planned and was the mother healthy throughout gestation? At what point was fetal movement first noted (i.e., quickening), which should be at approximately 4 to 5 months’ gestation, and did it continue throughout the entire pregnancy? Were there problems with poverty, nutrition, or exposure to violence and stress? Obtaining some of this important information could be difficult because of privacy concerns, and may require a confidential interview with mother. Details of the delivery are critical and may not be entirely recalled by parents; therefore, reviewing birth records if available is important. Information such as duration of labor, medications or assistive devices (forceps and vacuum extraction) used, presence of meconium at delivery, and gestational age may have direct relevance to later brain development. The

general status of the newborn immediately after delivery should also be understood. Objective information is important such as birth weight, Apgar scores, head circumference, and any neonatal complications encountered. Obtaining accurate information may require interviewing all caregivers, particularly with children whose mothers had pregnancyrelated health problems and may have been sick. An enormously important piece of information that needs to be confirmed and not just assumed is the status of neonatal screening. Depending on the state or country of birth, most children are screened as a public health measure for certain treatable metabolic conditions. In the United States (http:// www.babysfirsttest.org/newborn-screening/states) and Canada (http://raredisorders.ca/documents/CanadaNBSstatus updatedNov.112010.pdf), it varies by state and province, but all screen for at least some disorders of amino acid metabolism, fatty acid oxidation diseases, organic acid conditions, and hemoglobin and endocrine disorders. Family history is particularly important as many disorders encountered by the clinician may have a genetic basis. Begin by asking if any family members suffer from the same problems that affect the patient. Autosomal-dominant traits may be present in successive generations, although the degree of expressivity may vary. Autosomal-recessive traits often do not manifest in successive generations but may be present in siblings. Consanguinity must be considered when autosomalrecessive disease is part of the differential diagnosis, even if it is not forthcoming from interviewing parents (the incidence of false paternity has been reported to be from 1% to 30% depending on the population studied). Cognitive and behavioral development is influenced by the child’s home environment. A social history helps identify whether risk factors such as exposure to poverty, violence, parental depression, or bullying are present. Some clinics find the SEEK parent screening questionnaire helpful to identify potential challenges in the home environment (Fig. 1-2). Caregivers should be questioned carefully about the nature and results of previously performed tests, including electrodiagnostic tests, brain-imaging studies, biochemical studies (e.g., quantitative assays of amino acids, organic acids, lactic acid, and lysosomal enzymes), biopsies, and chromosomal or gene studies. It is particularly important to review the full report of prior comprehensive genetic tests such as microarray analysis, exome sequencing, or genome-wide association studies (GWAS). Even when these tests fail to establish a clear diagnosis, they usually identify abnormalities of unknown clinical significance, and what was once unclear may have over time been found to have clear clinical implications. Therefore it may be helpful to perform an updated review of abnormalities identified on prior genetic testing. Use of prior medication should also be documented, including those medications that may have been prescribed but not taken, with note made of results of such therapies. If prior imaging has been performed, reviewing the study and not simply relying on the report is helpful to confirm findings (this is particularly important if the radiology interpretation is by someone without pediatric experience, or whose experience is not known as may occur with an on-call teleradiology service). Thus, history taking is an active process. Beginning with a presenting complaint, the clinician broadly considers multiple diagnostic categories, which are narrowed as open-ended questions and followed by more specific queries. An exhaustive, all-encompassing neurologic history is impossible to obtain, particularly under the time constraints most clinicians face in today’s environment. Therefore a skilled clinician is able to focus the interview on relevant information, often following up details that are more important than the patient or caregiver is aware of, and likewise, gently steering the conversation



General Aspects of the Patient’s Neurologic History

SEEK Parent Questionnaire A Safe Environment for Every Kid

No. ___

Dear Parent or Caregiver: Being a parent is not easy. We want to help families have a safe environment for kids. We are asking everyone these questions. Please answer the questions about your child being seen today for a check-up. They are about issues that affect many families. If there’s a problem, we’ll try to help. Today’s Date: ____/____/200_ Child’s Date of Birth: ____/____/____  Male  Female Sex of Child: PLEASE CHECK Yes  No



Do you need the telephone number for Poison Control?



Yes



No

Do you need a smoke alarm for your home?



Yes



No

Does anyone smoke tobacco at home?



Yes



No

Is there a gun in your home?



Yes



No

In the last year, did you worry that your food would run out before you got money, or food stamps to buy more?



Yes



No

Do you worry that your child may have been physically abused?



Yes



No

Do you worry that your child may have been sexually abused?



Yes



No

Lately, do you often feel down, depressed, or hopeless?



Yes



No

Do you often feel lonely?



Yes



No

During the past month, have you felt little interest or pleasure in the things you used to enjoy?



Yes



No

Do you often feel your child is difficult to take care of?



Yes



No

Do you wish you had more help with your child?



Yes



No

Do you feel so stressed you can’t take another day?



Yes



No

Do you sometimes find you need to hit/spank your child?



Yes



No

In the past year, have you or your partner had a problem with drugs or alcohol?



Yes



No

In the past year, have you or your partner felt the need to cut back on drinking or drug use?



Yes



No

Have you ever been in a relationship in which you were physically hurt or threatened by a partner?



Yes



No

In the past year, have you been afraid of a partner?



Yes



No

In the past year have you thought of getting a court order for protection?



Yes



No

Are there any problems you’d like help with today?

Please give this form to the doctor or nurse you’re seeing today. Thank you ________________________________________________ ___________ Provider’s name, PRINTED Provider’s Signature Date Figure 1-2.  SEEK questionnaire. [With permission from Dubowitz et al. (2007).]

3

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4

PART I  Clinical Evaluation

away from trivial discussion. Carefully listening to what is stated and how it is stated is important. Directly questioning the child when possible provides unique information, particularly if done at the onset of the interview before the adults start talking. Documenting exact quotes, using the vocabulary of the child or caregiver, improves accuracy of the medical record and avoids relying on an observer’s interpretation of events when first-hand information is available. Bringing this information together is then the job of the clinician, who assembles all relevant facts into a cogent story that characterizes the neurologic process. A child’s developmental status is critically important in any neurologic assessment, and using a valid developmental screening test is helpful. Several assessment tools are available. These can be divided into provider-administered tools, such as the Denver developmental screening test-II (DDST-II) (see Fig. A-1ab in Appendix A), and parent questionnaires (Tervo, 2005), such as the ages and stages questionnaire and the parents’ evaluation of developmental status. Using the DDST-II, development is plotted over four broad domains of gross motor, fine motor, personal-social, and language skills from birth through 6 years of age. The age distribution for passing at the 25th, 50th, and 90th percentile is noted for each of 125 items. The DDST-II can be performed in a busy office setting; however, it is only a screening test, and any concerns should be followed up with more extensive developmental assessments. Also, adaptations must be made based on the cultural context. For example, the DDST-II items “using a spoon and fork” and “playing board games” are not relevant in cultures in which no one does these activities, and may need to be substituted by more appropriate developmental items. Concerns have been raised about the lack of validity of the DDST-II, and in the United States some states do not recommend using the DDST-II as a result of poor sensitivity and specificity (Minnesota Department of Health, http:// www.health.state.mn.us/divs/fh/mch/devscrn/). The ages and stages questionnaire is a preferred screening tool of many pediatric clinics and public health departments for children from 4 months to 5 years old, utilizing the insight that parents and caregivers offer regarding their child’s development (Thompson et al., 2010). It requires responses from parents and caregivers to answer questions regarding whether specific developmental skills are demonstrated (yes, sometimes, and not yet). Five broad developmental domains are covered: communication, gross motor, fine motor, problem solving, and personal-social. Similarly, the parents’ evaluation of developmental status is used for children from birth to 8 years old and relies on parent report through a 10-item standardized questionnaire covering expressive and receptive language, fine motor, gross motor, behavior, socialization, self-care, and learning, which identifies risk based on parental assessment. Both the ages and stages questionnaire and the parents’ evaluation of developmental status are appropriate screening tools for child development and can be completed in a busy office setting. Often it is not development but behavior that is of concern to parents. Clarifying as much as possible the nature of the behavioral concern helps. More helpful than hearing “He’s acting out” is knowing if there is a problem with attention, impulsivity, aggression, or mood swings. Is there social withdrawal? Are there compulsions? Is the maladaptive behavior triggered by something or does it occur without warning? Assessment tools are available that can help clarify problem behavior. For young children, one of the few available standardized measures is the infant toddler social emotional assessment or its abbreviated version, the brief infant toddler social emotional assessment, both of which are designed for children from 1 to 3 years old. The Brief Infant Toddler Social Emotional Assessment includes separate forms for parents and

for childcare providers, each of which can be completed in less than 10 minutes. Two general types of behavior are assessed: 1) social emotional problems, including aggression, anxiety, dysregulation, and atypical behavior, and 2) social emotional competence such as attention, motivation, empathy, and positive peer relationships. For older children, the child symptom inventory provides parent and teacher checklists to help screen for a broad number of behavioral concerns in children from 5 to 18 years of age such as anxiety, attention deficit hyperactivity disorder, depression, oppositional defiant disorder, and conduct disorder. Likewise, the Swanson, Nolan and Pelham qestionnaire (SNAP) for children from 6 to 18 years old has forms available for teachers or parents that help distinguish between attention deficit hyperactivity disorder and other childhood behavioral disorders. Other general behavior assessment tools commonly used are the Achenbach system of empirically based assessment for children from 6 to 18 years old (this includes the child behavior checklist, which is a parent-report questionnaire, and the youth self-report to be completed by the child), and the behavioral assessment system for children, second edition, for age 2 to 25 years (this also includes questionnaires for parents and teachers, as well as a self-report questionnaire). In all instances in which behavior is a concern, it is helpful to use assessment tools that characterize behavior across environments (i.e., home, school, and daycare). A common behavioral question is whether there is attention deficit hyperactivity disorder, in which case the revised Conners parent rating scale (age 3 to 17 years) or the Vanderbilt (age 6 to 12 years) is commonly used. Another common question that arises is whether a child has autistic spectrum disorder, which can be screened for using the modified checklist for autism in toddlers (Fig. 1-5) completed by a caregiver or via physician interview. Screening all children for autism is now recommended by the American Academy of Pediatrics at age 18 and 24 months. Developmental screening is an enormously important part of the neurologic evaluation, but it must be interpreted carefully. For example, language delay may be caused by a congenital brain malformation or could be entirely the result of an impoverished environment (Fernald et al., 2013). Also, a single developmental screening is not as accurate as repeated assessments over time, and any abnormal screening results should prompt an immediate referral for more complete developmental testing by an appropriate professional. Thus, a careful and informed history is at the core of the neurologic assessment of a child. The presenting complaint is explored in detail, followed by relevant aspects of the medical history, family history, and review of prior investigations or treatments. Assessment of the developmental status of the child is an essential component of this process, which eventually guides the examination to follow. Child neurology is a unique and inherently complex endeavor, and at times the initial history uncovers information requiring clarification through a follow-up literature search. Commonly used general medical search engines include PubMed (http://www.ncbi.nlm.nih.gov/pubmed) or Google Scholar (http://scholar.google.com/). Specific websites might be considered such as Treatable Intellectual Disorder (http:// www.treatable-id.org/) for metabolic conditions, or the Online Mendelian Inheritance in Man (http://www.omim.org/) for genetic disorders. As always, a tincture of humility is helpful for even the experienced clinician, knowing that a diagnosis can be frustratingly elusive at first. But what is initially confusing may be clarified as a child is followed over time and new information obtained, and through a partnership with the family and careful attention to neurologic detail, the correct diagnosis can be identified.



General Aspects of the Patient’s Neurologic History

5

M-CHAT

1

Please fill out the following about how your child usually is. Please try to answer every question. If the behavior is rare (e.g., you've seen it once or twice), please answer as if the child does not do it. 1.

Does your child enjoy being swung, bounced on your knee, etc.?

Yes No

2.

Does your child take an interest in other children?

Yes No

3.

Does your child like climbing on things, such as up stairs?

Yes No

4.

Does your child enjoy playing peek-a-boo/hide-and-seek?

Yes No

5.

Does your child ever pretend, for example, to talk on the phone or take care of a doll or pretend other things?

Yes No

6.

Does your child ever use his/her index finger to point, to ask for something?

Yes No

7.

Does your child ever use his/her index finger to point, to indicate interest in something?

Yes No

8.

Can your child play properly with small toys (e.g. cars or blocks) without just mouthing, fiddling, or dropping them?

Yes No

9.

Does your child ever bring objects over to you (parent) to show you something?

Yes No

10. Does your child look you in the eye for more than a second or two?

Yes No

11. Does your child ever seem oversensitive to noise? (e.g., plugging ears)

Yes No

12. Does your child smile in response to your face or your smile?

Yes No

13. Does your child imitate you? (e.g., you make a face-will your child imitate it?)

Yes No

14. Does your child respond to his/her name when you call?

Yes No

15. If you point at a toy across the room, does your child look at it?

Yes No

16. Does your child walk?

Yes No

17. Does your child look at things you are looking at?

Yes No

18. Does your child make unusual finger movements near his/her face?

Yes No

19. Does your child try to attract your attention to his/her own activity?

Yes No

20. Have you ever wondered if your child is deaf?

Yes No

21. Does your child understand what people say?

Yes No

22. Does your child sometimes stare at nothing or wander with no purpose?

Yes No

23. Does your child look at your face to check your reaction when faced with something unfamiliar?

Yes No

© 1999 Diana Robins, Deborah Fein, & Marianne Barton Figure 1-5.  Modified checklist for autism in toddlers. [With permission from Robins et al. (1999).]

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Asan, O., Smith, P., Montague, E., 2014. More screen time, less face time—implications for EHR design. J. Eval. Clin. Pract. 20, 896– 901.

Beckman, H.B., Frankel, R.M., 1984. The effect of physician behavior on the collection of data. Ann. Intern. Med. 101, 692–696. Cheriff, A.D., Kapur, A.G., Qui, M., et al., 2010. Physician productivity and the ambulatory EHR in a large academic multi-specialty physician group. Int. J. Med. Inform. 79, 492–500. Cole, S.A., Bird, J., 2014. The Medical Interview, third ed. Saunders, Philadelphia. Dubowitz, H., Felgelman, S., Lane, W., et al., 2007. Screening for depression in an urban pediatric primary care clinic. Pediatrics 119, 435–443.

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PART I  Clinical Evaluation

Fernald, A., Marchman, V.A., Weisleder, A., 2013. SES differences in language processing skill and vocabulary are evident at 18 months. Dev. Sci. 16, 234–248. Flores, G., Abreu, M., Barone, C.P., et al., 2012. Errors of medical interpretation and their potential clinical consequences: a comparison of professional versus ad hoc versus no interpreters. Ann. Intern. Med. 60, 545–553. Robins, D.L., Fein, D., Barton, M.L., 1999. Modified checklist for autism in toddlers (M-CHAT) follow-up interview. Self-published. Available at . Tervo, R.C., 2005. Parent’s reports predict their child’s developmental problems. Clin. Pediatr. 44, 601–611. Thompson, L.A., Tuli, S.Y., Saliba, H., et al., 2010. Improving developmental screening in pediatric resident education. Clin. Pediatr. 49, 737–742.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 1-1 Patterns of onset and courses of neurologic conditions. Fig. 1-3 Abbreviated Swanson, Nolan and Pelham Questionnaire (SNAP) rating scales. Fig. 1-4 Vanderbilt assessment scales. Table 1-2 Major available screening tools.

2 

Neurologic Examination of the Older Child Kenneth F. Swaiman and John Phillips

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

The neurologic examination provides critical and unique information that cannot be acquired otherwise (Campbell, 2013). Regardless of patient age, the essence of this information is the same: mental status, cranial nerves, motor, reflexes, sensory, and coordination/cerebellar testing. How this information is obtained is very age-dependent, however (Egan, 1990).

OBSERVATION/MENTAL STATUS Observation during history-taking is helpful, even when a child isn’t being directly questioned (Menkes et al., 2005). Abnormal movements might suggest epilepsy, motor tic disorder, or a behavioral diagnosis such as attention deficit hyperactivity disorder (Pina-Garza, 2013). Caregiver–child interactions during the interview may offer clues into what the home environment is like. During this period the examiner surreptitiously assesses mental status, making note of language, attention, affect, and general developmental status (see Table 2-1).

SCREENING GROSS MOTOR FUNCTION Consider beginning with a rapid screening examination in case the child later becomes uncooperative. Start with the child standing. Ask the child to hop in place on each foot, tandem-walk forward and backward, toe-walk, and heel-walk. Then, checking for Gowers’ maneuver, the child is asked to rise quickly from a squatting position, followed by asking the child to stand with the feet close together, eyes closed, and arms and hands outstretched. This maneuver allows simul­ taneous assessment of Romberg’s sign and adventitious movements. Finally, finger-nose-finger movements help assess cerebellar function.

PHYSICAL EXAMINATION Cranial Nerve Examination Examination of the cranial nerves in infants and younger children usually requires some modification of the sequence and may need some ingenious improvisation of the procedure, according to the degree of cooperation of the child (Volpe, 2008). As is the case with all examinations of infants and young children, the less threatening portions of the examination should be performed first.

Olfactory Nerve: Cranial Nerve I Cranial nerve I can be evaluated by having the child smell pleasant aromas (e.g., chocolate, vanilla, peppermint) through each nostril while the other is manually occluded. Anosmia may occur after head trauma, with a severe upper respiratory tract infection, or in the rare instance of a frontal lobe mass involving the cribriform plate region.

Optic Nerve: Cranial Nerve II Begin with formal visual acuity testing using a Snellen chart or a “near card” in older children. Younger children are more difficult and many times only gross vision can be evaluated. Beyond 4 years of age, the E test is useful. The child is taught to recognize the E, and to discern the direction in which the three “arms” are pointing and point a finger accordingly. Peripheral visual field testing is accomplished using a small (3-mm) white or red test object, a toy, or in a pinch, the examiner’s fingers can be used. The test object is moved from the temporal to the nasal fields and then from the superior and inferior portions of the temporal and nasal fields while the child looks directly at the examiner’s nose. Finger counting can be used if acuity is grossly distorted. In cases of extreme impairment, perception of a rapidly moving finger can be used. The optic disc (i.e., optic nerve head) of the older child is sharply defined and often salmon-colored, which differs from the pale gray color of the disc in an infant. In the presence of a deep cup in the optic disc, the color may appear pale, but the pallor is localized to the center of the disc. The pallor of optic atrophy occurs centrally and peripherally, and is accompanied by a decreased number of arterioles in the disc margins. Most commonly, papilledema is associated with elevation of the optic disc, distended veins, and lack of venous pulsations. Hemorrhages may surround the disc. Before papilledema is obvious, there may be blurring of the nasal disc margins and hyperemia of the nerve head. The presence or absence of the pupillary light reflex differentiates between peripheral and cortical blindness. Lesions of the anterior visual pathway (i.e., retina to lateral geniculate body) result in the interruption of the afferent limb of the pupillary light reflex, producing an absent or decreased reflex. Anterior visual pathway interruption can cause amblyopia in one eye. In this situation, the pupil fails to constrict when stimulated with direct light; however, the consensual pupillary response (i.e., response when the other eye is illuminated) is intact. The deficient pupillary reflex is revealed by alternately aiming a light source toward one eye and then the other. In the eye with decreased vision, consensual pupillary constriction is greater than the response to direct light stimulation (Marcus Gunn pupil); the pupil of the affected eye may dilate slightly during direct stimulation (Haymaker, 1969).

Oculomotor, Trochlear, and Abducens Nerves: Cranial Nerves III, IV, and VI The oculomotor, trochlear, and abducens cranial nerves control extraocular motor movements; these nerves must operate synchronously or diplopia ensues. Cranial nerve III innervates the superior, inferior, and medial recti; the inferior oblique; and the eyelid elevator (levator palpebrae superioris). Cranial nerves IV and VI innervate the superior oblique muscle and the lateral rectus muscle, respectively. Unfortunately for

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PART I  Clinical Evaluation

TABLE 2-1  Emerging Patterns of Behavior from 1 to 5 Years of Age 15 Months Motor: Adaptive: Language: Social:

Walks alone; crawls up stairs Makes tower of two cubes; makes line with crayon; inserts pellet into bottle Jargon; follows simple commands; may name familiar object (ball) Indicates some desires or needs by pointing; hugs parents

18 Months Motor: Adaptive: Language: Social:

Runs stiffly; sits on small chair; walks up stairs with one hand held; explores drawers and waste baskets Piles three cubes; initiates scribbling; imitates vertical stroke; dumps pellet from bottle Ten words (average); names pictures; identifies one or more parts of body Feeds self; seeks help when in trouble; may complain when wet or soiled; kisses parents with pucker

24 Months Motor: Adaptive: Language: Social:

Runs well; walks up and down stairs one step at a time; opens doors; climbs on furniture Makes tower of six cubes; circular scribbling; imitates horizontal strokes; folds paper once imitatively Puts three words together (subject, verb, object) Handles spoon well; tells immediate experiences; helps to undress; listens to stories with pictures

30 Months Motor: Adaptive:

Language: Social: 36 Months Motor: Adaptive: Language: Social:

purposes of understanding, the function of extraocular muscles depends somewhat on the direction of gaze. The lateral and medial recti are abductors and adductors of the globe, respectively. The superior rectus and inferior oblique are elevators, and the inferior rectus and superior oblique are depressors. The oblique muscles act in the vertical plane while an eye is adducted. The recti muscles serve this function when an eye is abducted (Figure 2-2). When directed forward (i.e., primary position), the oblique muscles effect torsion around the anteroposterior axis (rotation) of the globes. In heterophorias, also called phorias, both globes are directed normally on near or far objects during fixation; however, one or both deviate when one eye is occluded while the other eye fixes. Forcing fixation of the uncovered eye by alternately covering each eye confirms the diagnosis of heterophorias. Exophoria is a predisposition to divergence, whereas esophoria is a predisposition to convergence. Eye deviations detectable during binocular vision are heterotropias, also called tropias. Adduction tropias are esotropias; abduction tropias are exotropias. Tropias are most often caused by compromised extraocular muscle innervation. Extraocular palsies can frequently be detected by observation of eye movements. A red glass is placed in front of an eye, and a focused, relatively intense white light is aimed at the eyes from various visual fields while the child fixes on the light. A merged, solitary, red–white image is perceived when extraocular movements are normal; however, when muscle paresis is present, the child reports a separation of the red and white images when looking in the direction of action of the affected

Jumps Makes tower of eight cubes; makes vertical and horizontal strokes but generally will not join them to make a cross; imitates circular stroke, forming closed figure Refers to self by pronoun “I”; knows full name Helps put things away; pretends in play

ELEVATION Superior rectus Inferior oblique

Goes up stairs alternating feet; rides tricycle; stands momentarily on one foot Makes tower of nine cubes; imitates construction of “bridge” of three cubes; copies circle; imitates cross Knows age and gender; counts three objects correctly; repeats three numbers or sentence of six syllables Plays simple games (in “parallel” with other children); helps in dressing (unbuttons clothing and puts on shoes); washes hands

A

DEPRESSION Inferior rectus Superior oblique

48 Months Motor: Adaptive:

Language: Social:

Hops on one foot; throws ball overhand; uses scissors to cut out pictures; climbs well Copies bridge from model; imitates construction of “gate” of five cubes; copies cross and square; draws man with 2–4 parts besides head; names longer of two lines Counts four pennies accurately; tells a story Plays with several children with beginning of social interaction and role playing; goes to toilet alone

60 Months Motor: Adaptive: Language: Social:

Skips Draws triangle from copy; names heavier of two weights Names four colors; repeats sentences of ten syllables; counts ten pennies correctly Dresses and undresses; asks questions about meanings of words; domestic role playing

(Adapted with permission from Behrman RE, et al. Nelson Textbook of Pediatrics, 14th edn. Philadelphia: WB Saunders, 1992.)

Superior rectus

Inferior oblique

A b d u c Lateral rectus

B

t i o n

Inferior rectus

A b d u c

A d d u c Medial rectus

t i o n

Superior rectus

Medial rectus

Superior oblique

t i o n

Lateral rectus

Inferior rectus

Figure 2-2.  Extraocular muscle movement. A, In primary position. B, In abduction and adduction. (Courtesy of the Division of Pediatric Neurology, University of Minnesota Medical School.)



muscle. The farthest peripheral image is the one perceived by the abnormal eye; this eye can be identified by the color of the image. Volitional turning of the head accompanies paresis of the lateral rectus muscle to forestall diplopia; the head is deviated toward the paretic muscle, and the eyes are directed ahead. In superior oblique or superior rectus muscle palsies, tilting of the head toward the shoulder opposite the side of the paretic eye muscle occurs. Extraocular muscle dysfunction is associated with many conditions that affect the brainstem, cranial nerves, neuromuscular junction, or muscles. Cranial nerve VI function may be impaired by increased intracranial pressure, irrespective of cause. Squint, usually esotropia, often accompanies decreased visual acuity in infants and young children. Ptosis and extraocular muscle paralysis accompany dysfunction of cranial nerve III. Ptosis resulting from oculomotor nerve compromise is usually more pronounced than is the malposition of the lid associated with Horner syndrome. Complete oculomotor nerve paralysis, although uncommon, causes the eye to position downward and outward. Poor adduction and elevation are also evident. Eye deviation is often the harbinger of a serious neurologic problem. Destructive lesions of the brainstem nuclei cause conjugate eye deviation toward the opposite side. Destructive cerebral hemispheral lesions cause eye deviation toward the side of the lesion; conversely, an irritative cerebral hemispheral lesion (such as a seizure focus) causes the eyes to turn away from the side of the lesion. Hence for a cortical lesion, “the patient looks at their stroke but away from their seizure.” Vertical gaze paresis results from dysfunction of the tectal area of the midbrain. Patients with a pineal tumor or hydrocephalus may be unable to elevate the eyes for upward gaze. Brainstem lesions, especially those in the midbrain or pons, may disrupt the medial longitudinal fasciculus. The resultant impairment of conjugate eye movement is referred to as an internuclear ophthalmoplegia. There is weakness of medial rectus muscle contraction of the adducting eye, which is accompanied by a monocular nystagmus in the abducting eye. Occasionally, paresis of lateral rectus muscle movement in the abducting eye may occur. Medial longitudinal fasciculus involvement may be unilateral or bilateral. Internal ophthalmoplegia consists of a fully dilated pupil that is unreactive to light or accommodation. Extraocular muscle function is normal when each muscle is tested separately. The oculomotor nerve, nucleus, or the parasympathetic ciliary ganglion may be a site of involvement. External ophthalmoplegia results in ptosis and paralysis of all extraocular muscles. Pupillary reactivity is normal. Opticokinetic nystagmus is a useful test in evaluating the eye movements of children. A drum or tape with stripes or figures is slowly rotated or drawn before the child’s eyes in horizontal and vertical directions. With fixation, the child should visually track the object in the direction the tape is being drawn, with a rapid, rhythmic movement (refixation) of the eyes in the reverse direction to enable fixation on the next figure or stripe. Absence of such a response may result from failure of fixation, amaurosis, or disturbed saccadic eye movements. The child who appears clinically blind because of a conversion reaction usually exhibits a normal opticokinetic nystagmus response. Children who manifest congenital nystagmus and have an opticokinetic nystagmus response in the vertical plane likely have adequate functional sight. Spontaneous nystagmus (i.e., involuntary oscillatory movements of the eye) may be horizontal, vertical, or rotary; a patient can exhibit all three types. The movements may consist of a slow and a fast phase, giving rise to the term jerk nystag-

Neurologic Examination of the Older Child

9

mus. However, the phases may be of equal duration and amplitude, appearing pendular. In general, vertical nystagmus is associated with either medication or brainstem dysfunction. While a few beats of horizontal nystagmus with extreme lateral gaze are normal, persistent horizontal nystagmus indicates dysfunction of the cerebellum or brainstem vestibular system components; the nystagmus is coarser (i.e., the amplitude of movements are greater) when the direction of gaze is toward the side of the lesion. Seesaw nystagmus is characterized by disconjugate (alternating) movement of the eyes, which move upward and downward in a seesaw motion. This type of nystagmus may accompany lesions in the region of the optic chiasm (see Chapter 6).

Trigeminal Nerve: Cranial Nerve V Cranial nerve V, the trigeminal nerve, has motor and sensory functions. The motor division of the trigeminal nerve innervates the masticatory muscles: masseter, pterygoid, and temporalis. Temporalis muscle atrophy manifests as scalloping of the temporal fossa. The masseter muscle bulk may be assessed by palpation while the patient firmly closes the jaw. Pterygoid muscle strength is evaluated by having the patient open the mouth and “slide” the jaw from one side to the other while the examiner resists movements with the hand to assess muscle strength. The jaw reflex is elicited when the examiner places a finger on the patient’s chin while the mouth is slightly open and taps the finger to stretch the masticatory muscles. A rapid muscle contraction with closure of the mouth is the reflex response. This stretch reflex receives its afferent and efferent nerve control from cranial nerve V; the segmental level is located in the midpons. The expected reflex reaction is absent with motor nucleus and peripheral trigeminal nerve compromise. Conversely, this reflex is overactive in the presence of supranuclear lesions; rarely, jaw clonus may be evident. Because of weakness of the ipsilateral pterygoid muscles, unilateral impairment of the trigeminal nerve causes deviation of the jaw toward the side of the lesion. Cranial nerve V is also responsible for sensation involving the face, including eye and the anterior half of the scalp.

Facial Nerve: Cranial Nerve VII Taste sensation over the anterior two-thirds of the tongue, secretory fibers (parasympathetic) innervating the lacrimal and salivary glands, and innervation of all facial muscles are accomplished by cranial nerve VII. Complete motor dysfunction on one side of the face ensues when the cranial nerve VII pathway is disrupted in the nucleus, pons, or peripheral nerve. The patient is unable to move the forehead upward, close the eye forcefully, or elevate the corner of the mouth on the side of the affected nerve. Central (supranuclear) facial nerve impairment produces only paresis of the muscles involving the lower face, with resultant drooping of the angle of the mouth, disappearance or diminution of the nasal labial fold, and widened palpebral fissure. The muscles of the forehead, which are innervated bilaterally, are unaffected. Taste sensation in the anterior two-thirds of the tongue is in part provided by the chorda tympani nerve, which traverses the path of the facial nerve for a short distance. Testing of taste sensation is difficult. Evaluation of taste requires that the patient extend the tongue and that the examiner hold the tip of the tongue with a piece of gauze and place salty, sweet, acidic, and sour and bitter materials, usually represented by salt, sugar, vinegar, and quinine, on the anterior portion of the tongue. The patient’s tongue must remain outside of the mouth until the test is completed. An older patient should be able to identify each substance.

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10

PART I  Clinical Evaluation

Auditory Nerve: Cranial Nerve VIII Function and evaluation of cranial nerve VIII are discussed in detail in Chapters 7 and 8. Although cranial nerve VIII is known as the auditory nerve, it has auditory and vestibular functions. Patients who fail to develop speech or who have slow speech development, as well as those who have difficulty with fluency and articulation, may have hearing impairment. Older children can cooperate with formal audiometric testing. Such testing may not be possible in younger infants, but brainstem auditory-evoked potentials may provide the necessary information concerning hearing impairment and the level of dysfunction within the nervous system. Clinical evaluation and caloric testing can be used for gross assessment of vestibular function. To perform caloric testing, the patient is in the supine position, with head flexed at 30 degrees. Ice water (10 mL) is injected over 30 seconds into one external auditory canal at a time. The conscious patient develops coarse nystagmus toward the ipsilateral ear; no eye deviation occurs. If the patient has some degree of obtundation, there is a modification of the response. The eyes become tonically deviated ipsilaterally, with accompanying nystagmus occurring contralaterally. If the patient is comatose, cold water stimulation usually causes tonic deviation ipsilaterally and no nystagmus; if the coma is profound or the patient is braindead, no eye changes occur.

Glossopharyngeal and Vagus Nerves: Cranial Nerves IX and X Examination of the larynx, pharynx, and palate provides most of the desired information concerning the function of cranial nerves IX and X. Unilateral paresis of the soft palate causes an ipsilateral droop, even when the patient is expelling air through the open mouth or gagging in response to a tongue blade. Bilateral involvement causes a flaccid soft palate bilaterally. The gag reflex is mediated through cranial nerve IX and is elicited by touching the posterior pharyngeal mucosa with a tongue blade. Normal individuals may have absence or a seemingly disproportionately violent response; assessing the importance of changes in the gag reflex is difficult in the absence of other findings. The integrity of cranial nerves IX and X is necessary for a gag response; sensation of the soft palate and uvula travels via cranial nerve IX, and motor function is carried by cranial nerve X. Thus unilateral weakness causes deviation of the uvula away from the weak side (unlike unilateral weakness of cranial nerve XII, discussed later, which causes deviation of the tongue toward the weak side).

Spinal Accessory Nerve: Cranial Nerve XI Cranial nerve XI provides innervation for the trapezius and sternocleidomastoid muscles. Cranial nerve XI comprises some fibers from C1 and C2, and some from the motor nucleus in the brainstem, and is unique in combining brainstem and cervical cord origins. The trapezius muscles are assessed when the patient is asked to shrug the shoulders against resistance while the sternocleidomastoid muscle is tested by asking the child to rotate their head to one side against resistance. Weakness of the sternocleidomastoid muscle results in an inability to rotate the head to the contralateral side.

Hypoglossal Nerve: Cranial Nerve XII The tongue muscle is the primary responsibility of cranial nerve XII. Atrophy and fasciculation of the tongue occur when

the ipsilateral hypoglossal nucleus or hypoglossal nerve is involved. The protruded tongue deviates toward the involved side because contraction of the normally innervated tongue muscle causes protrusion and is unopposed.

Skeletal Muscles Tone, bulk, and strength of the skeletal muscles should be determined during this portion of the examination. Motor functions of the spinal nerves are described in Table 2-3. The strength of limb muscles is assessed, when possible, by testing the child’s ability to counteract resistance imposed by the examiner on proximal and distal muscle groups or individual muscles.

Muscle Testing The following scoring system is useful for recording muscle power: 5: normal power 4: inability to maintain position against moderate resistance 3: inability to maintain position against slight resistance or gravity 2: active movement with gravity eliminated 1: trace of contraction 0: no contraction. Arm and shoulder strength can also be assessed by asking the child to lean against a wall with legs placed a foot or two from the wall edge and arms outstretched with the palms against the wall. Testing lower extremity strength can be assessed by asking the child to sit on the floor then rapidly stand; the normal child will spring erect. With weakness of the hip extensors, however, Gowers’ maneuver will be engaged, and the patient climbs up their own legs, pushing themselves into the erect position. Muscle bulk is evaluated by gentle palpation and observation. Muscle tenderness, nerve tenderness, and nerve hypertrophy can also be assessed by palpation. Myotonia can be elicited by tapping over the thenar eminence and deltoid muscles. Muscle tone is evaluated when the child is relaxed so that resistance to passive movement can be monitored. Aside from passive movement of limbs at joints, the examiner also assesses the extensibility of muscles by shaking the limbs and determining the range of motion. Tone may be decreased in the presence of cerebellar disease and anterior horn cell disease. Tone may be increased because of the rigidity associated with basal ganglia disease and spasticity associated with corticospinal tract dysfunction.

Deep Tendon Reflexes Standard deep tendon reflexes (i.e., muscle stretch reflexes) are elicited: biceps, triceps, brachioradialis, patellar, and Achilles reflexes. The response to elicitation of deep tendon reflexes can be characterized as follows: 0: 1: 2: 3: 4: 5:

absent hyporeflexic (trace, or only seen with reinforcement) normal hyperreflexic unsustained clonus sustained clonus.

Enhancement of tendon reflex responses when reflexes are seemingly absent can be promoted by having the child squeeze an object such as a block or ball or perform the more



Neurologic Examination of the Older Child

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TABLE 2-3  Extraocular Muscle Paralysis Nerves

Muscles*

2

Function

Cervical Plexus (C1–C4) Cervical Phrenic

Deep cervical Scalene Diaphragm Brachial Plexus (C5–T1)

Flexion, extension, and rotation of neck Elevation of ribs (inspiration) Inspiration

Anterior Long thoracic Dorsal scapular

Adduction and depression of arm downward and medially Fixation of scapula on raising arm Elevation of scapula Drawing scapula upward and inward Outward rotation of arm Elevation and outward rotation of arm

Suprascapular Subscapular Axillary Musculocutaneous Median

Ulnar

Radial

Pectorales major and minor Serratus anterior Levator scapulae Rhomboid Supraspinatus Infraspinatus Latissimus dorsi Teres major Subscapularis Deltoid Teres minor Biceps brachii Coracobrachialis Brachialis Flexor carpi radialis Palmaris longus Flexor digitorum sublimis Flexor pollicis longus Flexor digitorum profundus (radial half ) Pronator quadratus Pronator teres Abductor pollicis brevis Flexor pollicis brevis Lumbricals I, II, III Opponens pollicis brevis Flexor carpi ulnaris Flexor digitorum profundus (ulnar half ) Adductor pollicis Hypothenar Lumbricals III, IV Interossei Triceps brachii Brachioradialis Extensor carpi radialis Extensor digitorum communis Extensor digiti quinti proprius Extensor carpi ulnaris Supinator Abductor pollicis longus Extensor pollicis brevis Extensor pollicis longus Extensor indicis proprius

Inward rotation and abduction of arm toward the back Inward rotation of arm Raising of arm to horizontal Outward rotation of arm Flexion and supination of forearm Elevation and adduction of arm Flexion of forearm Flexion and radial deviation of hand Flexion of hand Flexion of middle phalanges of second through fifth fingers Flexion of distal phalanx of thumb Flexion of distal phalanges of second and third fingers Pronation Pronation Abduction of metacarpus I at right angles to palm Flexion of proximal phalanx of thumb Flexion of proximal phalanges and extension of other phalanges of first, second, and third fingers Opposition of metacarpus I Flexion and ulnar deviation of hand Flexion of distal phalanges of fourth and fifth fingers Adduction of metacarpus I Abduction, opposition, and flexion of little finger Flexion of first phalanx and extension of other phalanges of fourth and fifth fingers Same action as preceding. Also spreading apart and bringing together of fingers Extension of forearm Flexion of forearm Extension and radial flexion of hand Extension of proximal phalanges of second through fifth fingers Extension of proximal phalanx of little finger Extension and ulnar deviation of hand Supination of forearm Abduction of metacarpus I Extension of proximal phalanx of thumb Abduction of metacarpus I and extension of distal phalanges of thumb Extension of proximal phalanx of index finger

Thoracic Nerves Thoracic Thoracic and abdominal Lumbar Plexus (T12–L4)

Elevation of ribs, expiration, abdominal compression, etc.

Femoral

Flexion of leg at hip Inward rotation of leg together with flexion of upper and lower leg Extension of lower leg

Obturator

Iliopsoas Sartorius Quadriceps femoris Pectineus Adductor longus Adductor brevis Adductor magnus Gracilis Obturator externis

Adduction of leg Adduction and outward rotation of leg Continued on following page

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PART I  Clinical Evaluation

TABLE 2-3  Extraocular Muscle Paralysis (Continued) Sacral Plexus (L5–S5) Superior gluteal

Inferior gluteal Sciatic

Peroneal Deep Superficial Tibialis

Pudendal

Gluteus medius Gluteus minimus Tensor fasciae latae Piriformis Gluteus maximus Obturator internus Gemelli Quadratus femoris Biceps femoris Semitendinosus Semimembranosus Tibialis anterior Extensor digitorum longus Extensor hallucis brevis Peroneus Gastrocnemius Soleus Tibialis posterior Flexor digitorum longus Flexor hallucis longus Flexor digitorum brevis Flexor hallucis brevis Plantar Perineal anal sphincters

Abduction and inward rotation of leg; also, under certain circumstances, outward rotation Flexion of leg at hip Outward rotation of leg Extension of leg at hip Outward rotation of leg Flexion of leg at hip

Dorsiflexion and supination of foot Extension of toes Extension of great toe Pronation of foot Plantar flexion of foot Adduction of foot Flexion of distal phalanges II–V Flexion of distal phalanx I Flexion of middle phalanges II–V Flexion of middle phalanx I Spreading, bringing together, and flexion of proximal phalanges of toes Closure of sphincters of pelvic organs; participation in sexual act; contraction of pelvic floor

*Various muscles may receive still other nerve supplies than those mentioned. The following are the principal accessory nerve supplies: the brachial muscle receives fibers from the radial nerve; the flexor digitorum sublimis, from the ulnar; the adductor pollicis, from the median; the pectineus, from the femoral; the adductor magnus, from the tibial. (With permission from Haymaker W. Bing’s Local Diagnosis in Neurological Diseases, 15th edn. St. Louis: Mosby, 1969.)

traditional Jendrassik maneuver (i.e., hooking the fingers together while flexed and then attempting to pull them apart). Hyperreflexia may be indicated by an abnormal “spread” of responses, which includes contraction of muscle groups that usually do not contract when a specific reflex is being elicited (i.e., crossed thigh adductor or finger flexor reflexes).

Other Reflexes A flexor (plantar) toe sign response is normal in children. The Babinski reflex is elicited by firm, steady, slow stroking from posterior to anterior of the lateral margin of the sole with an object such as a key or a tongue blade. The stimulus should not be painful. A positive response is a slow, tonic hyperextension of the great toe. A similar response is elicited using maneuvers such as the Chaddock (firmly stroking the lateral aspect of the foot) or Oppenheim (downward pressure on the medial aspect of the tibia). Flicking the patient’s nail (second or third finger) downward with the examiner’s nail (i.e., the Hoffmann reflex) results in flexion of the distal phalanx of the thumb. No response or a muted response occurs in normal children; a brisk or asymmetric response occurs in the presence of corticospinal tract involvement. Abdominal reflexes are obtained by stroking the abdomen from lateral to medial with strokes beginning just above the umbilicus, lateral to the umbilicus, and just below the umbilicus directed toward the umbilicus. Unilateral absence of the reflex can be associated with acquired corticospinal tract dysfunction. The cremasteric reflex is elicited in males by stroking the inner aspects of the thigh in a caudal–rostral direction and observing the contraction of the scrotum. The reflex is normally present and symmetric. Absence or asymmetry may indicate corticospinal tract involvement.

Sensory System Cooperation is necessary for a successful sensory examination. Vibration and proprioception can be assessed in all four limbs. Touch may be assessed by a single stimulus or by double simultaneous stimulation of two skin areas, which involves touching two parts of the body simultaneously (i.e., double simultaneous stimulation test). Extinction is the term used to denote failure of the child to perceive both stimuli. The contralateral parietal lobe to the side on which the unidentified stimulus was applied is the site of dysfunction. Pain, as tested with a pinprick, must be assessed gently, rapidly, and in a nonthreatening and playful manner. Segmental sensory innervations of the arm and leg should be noted. For example, the nipples are at approximately the T5 level and the umbilicus at the T10 level. Cortical sensory function can be tested in the older child. Stereognosis is the recognition of familiar objects by touch. After the patient closes the eyes, objects are placed by the examiner in one of the child’s hands and then the other. The patient should recognize the objects by size, texture, and form. Objects may include a button, coins, safety pin, or key. Absence of stereognosis is astereognosis. Astereognosis usually results from lesions of the parietal lobe. Graphesthesia is the ability to recognize numbers, letters, or other readily identifiable symbols traced on the skin. This ability can be determined best by tracing the symbols in a preliminary trial while the child’s eyes are open. When the patient’s eyes are closed, the figures are traced over the palm or forearm. Failure to identify the symbols is dysgraphesthesia. By 8 years of age, most children are able to identify all single digits correctly. The ability to distinguish between closely approximated stimulation at two points is two-point discrimination. Normal findings have been reported for children 2 to 12 years old.



Testing of this modality is frequently performed over the fingertips. Absence or impairment of two-point discrimination results from parietal lobe dysfunction.

Cerebellar Function Cerebellar function is assessed in a number of ways. Hand patting (i.e., alternating pronation and supination of the hand on the thigh while the other hand remains stationary on the other thigh) is a good method for assessing dysdiadochokinesis. The maneuver is repeated with each hand separately to assess the presence of mirror movements (i.e., synkinesis). Other cerebellar tests include repetitive finger tapping (thumb to forefinger), foot tapping, and finger-to-nose, finger-to-finger (examiner’s)-to-nose, and heel-to-knee-to-shin stroking. Several signs of cerebellar disease include head tilt, tremor when approaching a target (intention tremor), overshooting or undershooting a target (dysmetria), speech with an unusual cadence or prosody (cerebellar speech), or gait ataxia.

GAIT EVALUATION The evaluation of gait is discussed in detail in Chapter 5. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Campbell, W.W., 2013. DeJong’s The Neurologic Examination, seventh ed. Lippincott, Philadelphia. Egan, D.F., 1990. Developmental examination of infants and preschool children. Clinics in developmental medicine, vol. 112. MacKeith Press, Oxford. Haymaker, W., 1969. Bing’s local diagnosis in neurological diseases, fifteenth ed. CV Mosby, St. Louis.

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Menkes, J.H., Sarnat, H.B., Maria, B., 2005. Textbook of Child Neurology, seventh ed. Williams & Wilkins, Baltimore. Pina-Garza, J.E., 2013. Fenichel’s Clinical Pediatric Neurology: a Signs and Symptoms Approach, seventh ed. WB Saunders, Philadelphia. Volpe, J.J., 2008. The neurological examination: normal and abnormal features. In: Volpe, J.J. (Ed.), Neurology of the Newborn, fifth ed. WB Saunders, Philadelphia.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig 2-1 Bilateral oculomotor nerve paralysis. Fig 2-3 Facial sensation supplied by the trigeminal nerve. Fig 2-4 Right facial paralysis of the peripheral type. Fig 2-5 Möbius’ syndrome is manifested by bilateral palsy of cranial nerves VI and VII. Fig 2-6 Fasciculation of the tongue, especially of the right lateral border, in a patient with group 2 Werdnig– Hoffmann disease. Fig 2-7 Position of the limbs for muscle strength (see Table 2-6). Fig 2-8 Gowers’ maneuver indicates weakness of truncal and proximal lower extremity muscles. Fig 2-9 Radicular cutaneous fields. Fig 2-10 Segmental sensory innervation of the leg. Fig 2-11 Segmental sensory innervation of the arm. Table 2-2 Extraocular Muscle Paralysis Table 2-4 Segmental Innervation of Muscles of Extremities Table 2-5 Segmental Innervation of Trunk Muscles Table 2-6 Muscle Testing Table 2-7 Muscle Stretch (Tendon) Reflexes

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3 

Neurologic Examination after the Newborn Period Until 2 Years of Age Kenneth F. Swaiman and John Phillips

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. There is no one way to organize the examination of an infant. Experienced examiners develop individual techniques and sequences that are flexible depending on the child’s level of cooperation (Jan, 2007). The technique presented here, which has worked for many clinicians, is a four-stage examination sequence, beginning with the least intrusive maneuvers. Developmental assessment is an integral part of this examination; norms are well established (Box 3-1), and when development lags, referral for more detailed testing may be considered. The first stage of the examination is observation. In the second stage, the head, muscle tone, superficial and deep sensation, gross response to sound, and visual fields can be evaluated while the child remains on the caregiver’s lap. The third stage becomes more invasive, and may require help from a caregiver or assistant. At this point, a general examination is performed, including measurement of the occipitofrontal circumference and optic fundi. In the fourth stage of the examination, the child is placed on the floor and encouraged to crawl, walk, and run, if possible.

EVALUATION OF THE PATIENT Stage 1 Because many children at this age need a few minutes to feel comfortable with a stranger, it is preferable not to rush into the examination. It is often helpful to have the child sit on the caregiver’s lap facing the examiner during this history-taking session to encourage familiarity. The point is to try to help the child become comfortable with the examination room and the examiner. The sequence of examination should be flexible and determined by the child’s comfort level and temperament, although eventually a complete examination must be conducted (Campbell, 2013). Most importantly, it is imperative that the clinician comprehensively conduct that aspect of the examination related to the chief complaint. Observations done at this stage include an assessment of the child’s level of alertness, awareness of surroundings, and affect. Communication skills can be noted and compared with age-appropriate expectations (Egan, 1990). Movement should be evident as well, particularly of the face, eyes, and extremities, and the examiner should look specifically for any asymmetry or abnormalities of control or posture.

Head Examination of the head is done systematically, looking for asymmetry, indentations, and protuberances. Evaluation of the fontanels and cranial sutures should be performed with gentle palpation. Hair color, distribution, texture, and pattern, including unusual whorl patterns, also should be assessed. The occipitofrontal circumference should always be measured. If the child becomes agitated, this can be deferred until later in the examination (stage 3), but it must be taken at some

14

point. Change over time, rather than a single measurement, provides the most useful information. In addition, the size of the anterior fontanel, which is typically closed by 12 months of age, should be recorded, along with any tenseness when the child is sitting comfortably in an upright position. Other fontanels are usually difficult to palpate, except in pathologic states. Finally, the head should be auscultated for the presence of unusual intracranial bruits.

Cranial Nerves Most of the examination of cranial nerve function of the infant and toddler can be completed by observation with minimal invasive procedures. Details concerning examination of each cranial nerve can be found in Chapter 2. Toys or colorful objects can facilitate the assessment of extraocular movements in young children. If the child appears uninterested in bright objects, the possibility of a visual defect or an underlying intellectual defect must be considered. Double simultaneous stimulation (i.e., simultaneously bringing two bright objects into both temporal fields) normally causes the child to look from one object to the other; failure to take notice of one object may indicate homonymous hemianopsia. An opticokinetic tape (with repetitive bars or objects) should be drawn horizontally and then vertically across the child’s field of vision. An absent response may result from lack of visual fixation or from gross impairment of vision. A beam from a small flashlight directed at each eye allows evaluation of pupil size, pupillary responses, and the red retinal reflex. Eye features to be noted include symmetry of the palpebral fissures, relative size of the two globes, angulation of the eyes compared with other facial components (i.e., mongoloid or antimongoloid slant) and with the ears, cataracts, conjunctival telangiectases, colobomas of the iris, ptosis, proptosis, and malformed or eccentrically placed pupils. Observing the child’s facial movements throughout the entire examination is helpful (Nelson and Eng, 1972). Widening of the ipsilateral palpebral fissure or inability to bury the limbus when crying is indicative of facial nerve weakness. In the younger infant, sucking and rooting reflexes should be obtained. Sometimes, the child can be induced to protrude the tongue if the examiner urges the child to imitate the examiner’s tongue movements. Deformity, atrophy, or abnormal positioning of the tongue can be observed. Tongue fasciculations should be evaluated with the tongue in the resting position, and by gently elevating the tongue with a depressor and examining the undersurface. Basic responses to the sound made by a tuning fork, rubbing fingers together, ringing a bell, or using a toy noisemaker that generates noise at a modest volume may provide much information. The examiner must be careful not to confuse response to a visual cue (e.g., the movement needed to elicit noise from a toy) with response to the sound.



Neurologic Examination after the Newborn Period Until 2 Years of Age

15

BOX 3-1  Child Development from 2 Months through 2 Years 2 MONTHS • Keeps hands predominantly fisted • Lifts head up for several seconds while prone • Startles in response to loud noise • Follows with eyes and head over 90-degree arc • Smiles responsively • Begins to vocalize single sounds 3 MONTHS • Occasionally holds hands fisted • Lifts head up above body plane and holds position • Holds an object briefly when placed in hand • Turns head toward object, fixes and follows fully in all directions with eyes • Smiles and vocalizes when talked to • Watches own hands, stares at faces • Laughs 4 MONTHS • Holds head steady while in sitting position • Reaches for an object, grasps it, brings it to mouth • Turns head in direction of sound • Smiles spontaneously 5–6 MONTHS • Lifts head while supine • Rolls from prone to supine • Lifts head and chest up in prone position • Exhibits no head lag • Transfers object from hand to hand • Babbles • Sits with support • Localizes direction of sound 7–8 MONTHS • Sits in tripod fashion without support • Stands briefly with support • Bangs object on table • Reaches out for people

3 • Mouths all objects • Says “da-da,” “ba-ba” 9–10 MONTHS • Sits well without support, pulls self to sit • Stands holding on • Waves “bye-bye” • Drinks from cup with assistance • Uses pincer grasp 11–12 MONTHS • Walks with assistance • Uses two to four words with meaning • Creeps well • Assists in dressing • Understands a few simple commands 13–15 MONTHS • Walks by self, falls easily • Says several words, uses jargon • Scribbles with crayon • Points to things wanted 18 MONTHS • Climbs stairs with assistance, climbs up on chair • Throws ball • Builds two to four-block tower • Feeds self • Takes off clothes • Points to two or three body parts • Uses many intelligible words 24 MONTHS • Runs, walks up and down stairs alone (both feet per step) • Speaks in two- to three-word sentences • Turns single pages of book • Builds four- to six-block tower • Kicks ball • Uses pronouns “you,” “me,” and “I”

(Data from Frankenburg WK, Dodds J, Archer P, et al. Pediatrics. 1992;89:91; Illingsworth RS. The development of the infant and young child. 9th ed. Baltimore: Williams & Wilkins; 1987; and Knobloch H, Stevens F, Malone A. The revised developmental screening inventory. Houston, Texas: Gesell Developmental Test Materials; 1980.)

Motor Evaluation As with all other parts of the evaluation, the motor examination begins with observation. Even before touching the child, general posture and the symmetry of movements of the arms and legs are observed, with note made of any gross discrepancies in muscle bulk or limb length. Definite hand preference (such as reaching across the midline to avoid using the contralateral hand) before 24 months is abnormal. Decreased muscle bulk may not be appreciated because of the large amount of subcutaneous fat at this age, and muscle atrophy may be undetected. Careful palpation helps distinguish between fat and muscle. The next step is evaluation of muscle tone, which is defined as resistance of muscle to passive stretch. This also requires palpation. Muscle tone and range of motion of the arms and legs are best assessed when the child is in the relaxed state by gently shaking and moving the hands and feet in flexion and extension. Pronation and supination of the hands and forearms provide further information about range of motion and the presence of spasticity or rigidity. Greater-than-normal resistance to passive movement indicates hypertonia, whereas

less-than-normal resistance indicates hypotonia. It is important to distinguish increased tone from limitation of movement due to joint contracture. It is also important to note when the child is actively resisting the examiner, which is a reflection of strength. Spontaneous muscle movements, particularly those against gravity, provide the most information concerning muscle strength. Further assessment of strength is provided by judging the degree of resistance that occurs when active movement is attempted against the examiner. Experience helps in this part of the examination, particularly in cases of mild abnormalities, but even a novice should be able to make a reasonable judgment about both tone and strength in most instances. Upper motor neuron unit involvement may cause decreased movement of an entire extremity or more focal abnormalities, such as limited flexion of the arm at the elbow, persistent fisting, or adduction of the thumb against the palm. Erb’s brachial plexus injury is a lower motor neuron disorder commonly causing internal rotation and adduction at the shoulder, often with the “waiter’s tip” posture (Pina-Garza, 2013). Interacting with the infant using toys and other interesting objects may facilitate the evaluation of limb strength, range

16

PART I  Clinical Evaluation

of motion, and coordination. In the older cooperative child, individual muscle testing should be carried out when appropriate. There is a normal developmental sequence of fine motor control as the child becomes more adept at reaching for objects. Grasping things with both hands and holding the object before the face or immediately placing it in the mouth is later superseded by transferring the object from hand to hand and manipulating the toy. The infant’s grasping skills are best demonstrated in response to small objects. The 4- to 5-month-old infant is able to grasp an object with the entire hand, at 7 months the thumb and the neighboring two fingers are used, and the pincer grasp (using only the thumb and forefinger) should be present by 9 to 11 months. The palmar grasp reflex (i.e., obligate grasp reflex) should gradually diminish from 3 to 6 months of age. The persistence of the obligate grasp reflex beyond 6 months of age may signal corticospinal tract dysfunction. Observation of the child’s ability to raise the arms while reaching for an object helps assess proximal muscle strength. Congenital malformations of the fingers and hands from webbing to clinodactyly can be readily determined during this portion of the examination. Direct examination of the hips should include assessment of the range of motion; decreased excursion may signify spasticity or subluxation of the hip joints. Galeazzi’s sign is performed in a supine child by flexing the hips 90 degrees with feet on the examination table, noting any asymmetry of femur length. Hip disease such as subluxation often results in a shorter leg and may exist separately or as a result of spasticity. Conversely, increased excursion may represent hypotonia or ligamental laxity. Initial examination of the legs consists of assessment of muscle symmetry and mass. Spontaneous motor movements are also evaluated, making note of the quality and symmetry of any movement. Assessment of tone is similar to that done with the arms and hands; one should gently shake the feet and passively move the joints of the lower extremities from hip to knee to ankle.

C4 13 5 C5

7 9

T1

11 C7

L1 L2

C4 4 T2 6

Deep tendon reflexes that are excessively brisk may indicate upper motor neuron unit disease, especially when associated with clonus. Asymmetry is particularly worrisome because of the association with pathologic conditions. Absent deep tendon reflexes are seen with anterior horn cell disease or peripheral neuropathy. The crossed adductor reflex is elicited when the patellar reflex is stimulated and resultant contraction of the adductor muscles occurs in the opposite leg. This response can be normal until approximately 1 year of age. However, persistence of the response, particularly unilaterally, suggests the presence of corticospinal tract involvement. The plantar response can be as important in infants as in adults. There is no consensus about when an extensor response is a normal finding, although an asymmetric extensor toe sign is always abnormal, as is an extensor toe sign that persists beyond 12 months of age (Hogan and Milligan, 1971). A pathologic extensor plantar sign is indicative of upper motor neuron unit disease. Several beats of ankle clonus are often present in the neonatal period and should disappear by 2 months of age. The persistence of ankle clonus and extensor plantar responses in an older child suggests upper motor neuron unit disease even in the absence of hyperreflexia. Cerebellar function is difficult to assess in infants; it is easiest when a cooperative child can be observed sitting, standing, walking, or reaching for objects. The examiner can also observe the child during play to see resting or intention tremor, dysmetria, titubation or truncal sway while sitting, and fine motor coordination. Decreased tone may accompany other signs of cerebellar dysfunction.

Sensory Testing and Cutaneous Examination Light touch can be tested by gently stroking the extremities; this should lead to a reaction, with signs of recognition ranging from eye deviation and facial response to anxious withdrawal of the limbs (Figure 3-4). Application of a tuning fork often causes arrest of motion and a wide-eyed look of wonder in the child who cannot otherwise describe the feeling.

C4 T2 C6

8 10

C6

12

4 6 8 10 12

L2

C8

L1

C8

L2

C3 C4 C5 T3 5 7 T1 9 11 L1

C7

L2 S2

L3

C7 S4 S5

L4

L3 L4

S3 L3 L2 L5

L5 L5

S1

S1

S1

Figure 3-4.  Segmental distribution of the cutaneous nerves of an infant. (Modified from Fanaroff AA, Martin RJ. Neonatal-perinatal medicine: diseases of the fetus and infant, 5th ed. St. Louis: Mosby, 1992.)



Neurologic Examination after the Newborn Period Until 2 Years of Age

Proprioception cannot be directly evaluated at this age, but observations of sitting positions, gait, and posture may provide some clues. Pain response from light application of a pin or gentle pinching should be reserved until late in the examination, lest causing pain confirms a child’s suspicions about the examiner, and upsets an already worried parent. During the sensory examination, careful observation of the child’s skin is important to rule out a neurocutaneous disorder. Are there hypopigmented macules of tuberous sclerosis present, café au lait spots as seen in neurofibromatosis, or a port wine stain in the area of the first division of the trigeminal nerve that might suggest Sturge-Weber syndrome? Particular examination of the spine is necessary to check for scoliosis, sinus tracts, scars, dimples, and hemangiomas. Unusual skin lesions or hair growth over the spine suggest the presence of an underlying mesodermal defect, such as diastematomyelia or spina bifida occulta. The spine should be palpated along its entire course for defects. Abdominal and cremasteric reflexes are present at birth. The abdominal reflex is elicited by stroking the skin of the upper, middle, and lower portions of the abdomen laterally from the midline. Each stroke elicits a muscle contraction mediated by a different group of thoracic nerves from T8 to T12. The response results in the retraction of the umbilicus toward the stimulated side. The cremasteric reflex is elicited by upwardly stroking the inner thigh, beginning 3 to 5 cm below the inguinal crease. The cremasteric reflex results in an elevation of the testicles due to contraction of the overlying smooth muscles. Cremasteric reflexes are mediated by spinal nerves L1 to L2.

Stage 2 For stage 2 of the evaluation the child should be placed on an examination table with the caregiver close by to provide reassurance to the child and assistance to the examiner, if necessary. Motor evaluation of the older child can also be carried out on a larger, carpeted surface. By 3 months of age, an infant in the prone position should be able to hold the head and chest off the table. Good head control when held in the sitting position should be evident by 4 months of age. The child should be able to sit unsupported and maintain adequate balance by 8 to 9 months of age. Independent achievement of the sitting position should occur by 10 months of age. The child should crawl by 10 months, pull to a standing position by 10 months, and creep by 11 months. The child should walk with support by 12 months and without support by 13 to 14 months. Trunk, shoulder, and pelvic girdle tone and strength are directly evaluated. The child is observed while held in vertical and horizontal suspension. A hypotonic infant often droops over the examiner’s arm when held in horizontal suspension. In vertical suspension, the hypotonic child may slide through the examiner’s hands (Volpe, 2008). The child may be unable to maintain a standing posture when the feet are placed on the table surface; this must be distinguished from active withdrawal of the legs that may also prevent successful standing. If spasticity is present, there may be arching of the extended head, neck, and back while in horizontal suspension. Spasticity may also cause extension of the lower extremities with “scissoring” (excessive abduction) and toe walking.

Motor Performance Instruments Through the years, several instruments have been devised that are useful for evaluating motor performance in relation to chronologic age. These instruments have provided norms for

17

evaluating the expected rate of motor development for a number of different assessments and maneuvers.

Developmental Reflexes Developmental reflexes represent maturational stages of the developing nervous system (Prechtl, 1997). Occasionally, developmental reflexes can have localizing value, but usually they are nonspecific. Abnormal findings include the absence or poor manifestation of the expected response, persistence of a reflex that should have disappeared, or an asymmetric response (Table 3-1). Correctly eliciting the Moro reflex requires holding the infant in the supine position, lifting the head, and then allowing the head to fall approximately 30 degrees while cradling the head in the examiner’s hands. The expected response is initial extension and abduction of the arms with extension of the fingers, followed by adduction of the arms at the shoulder. Asymmetry at any age, or persistence beyond 5 to 6 months, is always abnormal. The asymmetric tonic neck reflex (ATNR) may be detected in the neonatal period but reaches its peak at 2 months and is absent by 6 months of age. To elicit the reflex, the head is turned to one side while the infant is lying in the supine position. There is extension of the arm and leg on the side toward which the face is turned, while the contralateral extremities flex (“fencer’s posture”). A normal infant should not maintain the position beyond a few seconds (i.e., obligate ATNR). The palmar grasp reflex is elicited by placing an object or the examiner’s finger in the palm of the infant’s hand; this leads to an involuntary flexion response. This reflex subsides by 3 to 6 months of age and is replaced by voluntary grasping, which is necessary to allow transfer of objects from hand to hand. In slightly older infants, the Landau reflex can first be elicited between 5 and 10 months of age, and can usually be seen up to 2 years of age. With one hand supporting the abdomen in the prone position, the examiner flexes the infant’s head with his or her other hand. The normal response is flexion of the legs and trunk. The placing reflex response can be demonstrated by holding the upright infant in a manner that causes the dorsal surface of the infant’s feet to touch the underside of a tabletop. The infant flexes the legs at the hips and knees so that contact with the underside of the surface ceases. One of the most useful maneuvers is the traction response (Zafeiriou, 2004). This is elicited with the infant in the supine position; the examiner grasps both hands and pulls the infant gently and slowly upward, to a sitting position. Marked head lag with little resistance to the examiner’s pulling efforts characterizes the newborn response. By 1 month, the infant’s head shows transient neck flexion followed by extension as the infant is pulled forward. Usually, by 3 to 5 months of age at the latest, the infant is able to participate actively with arm flexion at the elbow, and by holding the head and trunk in a straight line as the examiner pulls the child to the upright position. At this point there should be no head lag, and little or no forward motion of the head as the child reaches the upright position. A valuable measure of vestibular function in the newborn can be obtained by holding the infant in a supine position with the feet closest to the examiner. As the examiner rotates the infant laterally in each direction, the eyes of the infant deviate in the direction of rotation, accompanied by intermittent nystagmus to the opposite side. This maneuver also allows extraocular movements to be assessed.

3

18

PART I  Clinical Evaluation

TABLE 3-1  Eliciting Primitive Reflexes Reflex

Position

Method

Response

Age at Disappearance

Palmar grip

Supine

Placing the index finger in the palm of the infant

Flexion of fingers, fist making

6 months

Plantar grip

Supine

Pressing a thumb against the sole just behind the toes

Flexion of toes

15 months

Galant

Prone

Scratching the skin of the infant’s back from the shoulder downward, 2–3 cm lateral to the spinous processes

Incurvation of the trunk, with the concavity on the stimulated side

4 months

Asymmetric tonic neck

Supine

Rotation of the infant’s head to one side for 15 seconds

Extension of the extremities on the chin side and flexion of those on the occipital side

3 months

Suprapubic extensor

Supine

Pressing the skin over the pubic bone with the fingers

Reflex extension of both lower extremities, with adduction and internal rotation into talipes equinus

4 weeks

Crossed extensor

Supine

Passive total flexion of one lower extremity

Extension of the other lower limb, with adduction and internal rotation into talipes equinus

6 weeks

Rossolimo

Supine

Light tapping of toes 2–4 at their plantar surfaces

Tonic flexion of the toes at the first metacarpophalangeal joint

4 weeks

Heel

Supine

Tapping on the heel with a hammer, with the infant’s hip and knee joints flexed and the ankle joint in neutral position

Rapid reflex extension of the lower extremity in question

3 weeks

Moro

Supine

Sudden head extension produced by a light drop of the head

Abduction followed by adduction and flexion of upper extremities

6 months

Babinski

Supine

Striking along the lateral aspect of the sole, extending from the heel to the head of the fifth metatarsal

Combined extensor response: simultaneous dorsiflexion of the great toe and fanning of the remaining toes

Presence always abnormal

(Data from multiple sources: Futagi Y, Tagawa T, Otani K. Brain Dev. 1992;14:294; Vojta V. Die cerebralen Bewegungstoerungen im Kindesalter, 4te Auflage. Stuttgart: Ferdinand Enke Verlag; 1988; Zafeiriou DI, Tsikoulas IG, Kremenopoulos GM. Pediatr Neurol. 1995;13:148; Zafeiriou DI, Tsikoulas I, Kremenopoulos G, et al. Brain Dev. 1999a;21:216; Zafeiriou DI, Tsikoulas I, Kremenopoulos G, et al. J Child Neurol. 1999b;14:514; Zafeiriou DI, Tsikoulas I, Kremenopoulos G, et al. Brain and Development. 1998;20:307; and Zafeiriou DI. Pediatr Neurol. 2000;22:75.)

There are other developmental reflexes, but those discussed here appear to be the most often evaluated and the most useful.

Stage 3 Examination of the optic fundi should be performed with the infant supine, possibly lying in the caregiver’s lap or held over the caregiver’s shoulder with the infant’s head held tightly against the caregiver’s head. Abnormalities of the fundi, including vascular changes, elevation of the optic disc, and retinal changes, along with abnormalities of the lens and media, should be assessed. Mydriatic agents and sedation are rarely employed in the office evaluation, although they are both occasionally necessary. During the first few months of life, the optic discs may be somewhat gray. This normal finding should not be confused with optic atrophy. The general portion of the examination follows. A heart murmur may signify congenital structural anomalies more widespread than just in the heart. Stridor heard on auscultation may accompany weakness of the upper respiratory musculature. The presence of hepatosplenomegaly should be determined because many storage diseases, which also affect the brain, may be the cause of organ enlargement. When spinal lesions are suspected, the anal sphincter should be examined for tone and the presence of an anal cutaneous

reflex (the so-called “anal wink”). Congenital anomalies of the genitalia should be noted. The remainder of the general examination, particularly the intrusive aspects, such as evaluation of the auditory meati, tympanic membranes, mouth, and teeth, can be done at this time.

Stage 4 Spontaneous motor abilities are assessed in this stage of the examination. The crawling child can be put on a carpeted floor or a suitable pad; if the child stands, or walks, he or she should be placed on the floor. The child should be allowed to ambulate or encouraged by rolling a ball across the room or having the child follow a parent across the room. Spastic diparesis, hemiplegia, waddling, footdrop, limp, or ataxia may be evident. The manner in which the child stoops and bends to retrieve a ball or block may show premature hand dominance, athetosis, tremor, or weakness of the legs. Whenever there is a question of proximal weakness, the child should be observed when arising from the floor to a standing position to determine the presence of Gowers’ maneuver. Unlike in the examination of older children, the testing of individual muscle groups in infants is usually impracticable. Nevertheless, evaluation of spontaneous movements and use of some specific maneuvers (e.g., traction response, wheelbarrow maneuver, standing from the floor or a seated position)



Neurologic Examination after the Newborn Period Until 2 Years of Age

can provide information about spasticity, weakness, and incoordination. As always, a comparison of the examination findings must be made with expected age-related norms. Further examination of muscle strength can be accomplished by using the parachute response; the examiner holds the child in the prone position over an examination table and gently thrusts the patient toward the table surface. A fully developed response (expected at 8 months) consists of arm and wrist extension, allowing the outstretched palms to make contact with the table as the infant supports his or her body weight with the arms and shoulders. Formal individual muscle testing can be used in the older child whenever necessary. The sensory examination can be difficult. Begin with examination of touch, position sense, and vibration sense. A tuning fork placed on the appropriate bony prominence may elicit a look of surprise or bemusement. Evaluation of pain should be done last and only after the examiner demonstrates to the child the method that will be used. During this phase of the examination, the Romberg maneuver can be performed. The older child is asked to stand in one place with the feet together and close the eyes; a positive Romberg’s sign occurs when the child sways or falls with the eyes closed. The examiner should also observe the child for titubation, nystagmus, and dysmetria while reaching for objects. Cooperative children older than 3 years should be able to perform finger-to-nose testing with the eyes closed. The heel-shin test is frequently not possible in children younger than 4 years. Assessment of the deep tendon reflexes is best carried out with the infant or toddler in the caregiver’s lap. The biceps response in most infants can be difficult to elicit, but the triceps and brachioradialis reflexes are usually readily detected. The patellar and Achilles responses are typically present and easy to elicit. Toe signs can be evaluated as in older children.

GENERAL CONSIDERATIONS Throughout the examination, the clinician should evaluate the child’s alertness, interest in the surroundings, and ability to learn during the examination. The child’s speech pattern should also be assessed. By 15 months of age, the child should have a consistent vocabulary of 2 to 6 words, and by 18 months, up to 20 words. Short phrases consisting of two or three words are usually part of the child’s repertoire by 21 to 24 months. By 2 years of age, most children have a vocabulary of up to 50 words. Using specific scales to evaluate intelligence and development levels is of some help, but a single office assessment may not be reliable. It is therefore important that the examiner become proficient in informal means of evaluating these characteristics (Maria and English, 1993). Young children are not always easy to examine. However, taking a staged approach as suggested here, and being sensitive to the child’s temperament, often results in a successful examination.

19

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Campbell, W.W., 2013. DeJong’s The Neurologic Examination, seventh ed. Lippincott, Philadelphia. Egan, D.F., 1990. Developmental examination of infants and preschool children. Clinical Developmental Medicine, vol. 112. MacKeith Press, Oxford. Hogan, G.R., Milligan, J.E., 1971. The plantar reflex of the newborn. N. Engl. J. Med. 285, 502. Jan, M.M., 2007. Neurological examination of difficult and poorly cooperative children. J. Child Neurol. 22, 1209. Maria, B.L., English, W., 1993. Do pediatricians independently manage common neurological problems? J. Child Neurol. 8, 73. Nelson, K.B., Eng, G.D., 1972. Congenital hypoplasia of depressor anguli oris muscle: differentiation from congenital facial palsy. J. Pediatr. 81, 16. Pina-Garza, J.E., 2013. Fenichel’s Clinical Pediatric Neurology: A Signs and Symptoms Approach, seventh ed. WB Saunders, Philadelphia. Prechtl, H.F., 1997. State of the art of a new functional assessment of the young nervous system. An early predictor of cerebral palsy. Early Hum. Dev. 24, 1. Volpe, J.J., 2008. The neurological examination: normal and abnormal features. In: Volpe, J.J. (Ed.), Neurology of the Newborn, fifth ed. WB Saunders, Philadelphia. Zafeiriou, D.I., 2004. Primitive reflexes and postural reactions in the neurodevelopmental examination. Pediatr. Neurol. 31, 1.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 3-1 Entire hand grasp of a 4-month-old infant. Fig. 3-2 Use of two fingers and thumb in the grasp of a 7-month-old infant. Fig. 3-3 Pincer grasp with the thumb and forefinger of an 11-month-old infant. Fig. 3-5 Extended legs, scissoring, toe stance, and fisting in an infant with spastic quadriplegia. Fig. 3-6 The Moro response to rapid extension of the neck in a 2-day-old infant. The abduction phase of arm movement is illustrated. A cry usually accompanies the response, and the leg position varies. Fig. 3-7 The traction maneuver causes little response in a 2-day-old infant. There is little or no perceptible flexion of the neck or the arms at the elbows. Fig. 3-8 Abnormal parachute response. Box 3-2 Most Commonly Used Motor Performance Tools Box 3-3 Tips for Examining Noncooperative Children Table 3-2 Eliciting Postural Reactions

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4 

Neurologic Examination of the Term and Preterm Infant Kenneth F. Swaiman and John Phillips

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

THE TERM INFANT The essence of the newborn neurologic examination, whether for a premature or a term-born child, remains exactly the same as with older children. It begins with observation, followed by an examination that may need to be done “out of order” depending on circumstances. Several examinations done over time may be required to most accurately characterize an infant’s neurologic status.

Observation Careful observation begins the examination, noting any congenital abnormalities that are present and the general level of alertness. Cranial nerve assessment can be largely obtained via observation, making note of spontaneous eye movement, facial symmetry, and response to sounds and light. Observation also provides much information regarding the motor system. For example, term infants have predominantly flexor tone with frequent flexion at the knees and elbows. Intermittent fisting of the hands, including adduction and infolding of the thumbs (i.e., cortical thumbs), is often present. Limb position and posturing should be roughly symmetric. While supine, a healthy infant may have spontaneous limb movements that are asymmetric with a jerking quality—this is normal. Excessive jitteriness or tremulousness, however, particularly of the hands or jaw may suggest hyperexcitability of the central nervous system (CNS).

Cranial Vault Evaluation The occipitofrontal circumference should be plotted on a graph standardized for gender, race, and gestational age to determine whether the measurement falls within the normal range (i.e., two standard deviations above or below the mean). Variances within two standard deviations may be due in part to head shape; for example, the same volume will require a larger circumference in an oblong head compared with a round head. Significant deviation from normal always requires further evaluation. Some deformities of the cranium are related to the birthing process. Vaginal deliveries may be associated with scalp and subcutaneous edema causing caput succedaneum, particularly if vacuum extraction is used. Cephalohematomas are hemorrhages within the periosteum of individual cranial bones and therefore do not cross suture lines. Subgaleal hematomas result from bleeding under the scalp aponeurosis and are often preceded by forceps or vacuum-assisted delivery space. The scalp may be edematous and boggy because of underlying blood. Although most subgaleal hematomas are benign, if large enough they can cause hypovolemic shock. Infants delivered by cesarean section usually have relatively round heads. The anterior fontanel, readily palpable at birth and often pulsating with the infants heart rate, is concave or flat in relation to the surrounding cranium. The fontanel should be assessed with the child held in the sitting position if there is

20

any question of increased pressure. A bulging fontanel without the child crying raises a concern regarding increased intracranial pressure. The anterior fontanel varies in size but usually ranges from 1 to 3 cm in its longest dimension (Popich and Smith, 1972). The posterior fontanel in the neonate usually is open but admits only a fingertip. Cranial sutures (e.g., sagittal, metopic, lambdoidal, and squamosal) are readily palpable in the newborn. Overriding sutures, often the sagittal and lambdoidal, are sometimes seen in the first week of life. Gentle palpation should demonstrate that sutures readily separate from one another unless premature closure has occurred, which may cause asymmetric skull growth. Auscultation over the infant skull, particularly the anterior fontanel and neck vessels, usually reveals a venous hum in a number of locations. Rarely, systolic-diastolic bruits, particularly those that are focal and asymmetric, indicate the presence of an arteriovenous malformation; however, at times these bruits may be heard in normal infants.

Developmental Reflexes Developmental reflexes are primitive reflexes with complex responses, and largely reflect the integrity of the brainstem and spinal cord; the role of higher centers, although of importance, is not fully known. This includes the Moro, rooting, grasping, tonic neck, stepping, and placing reflexes. Many of these reflexes are present at birth and undergo modification during the first 6 months of life. Detailed discussion of these reflexes is presented in Chapter 3.

Motor Function Gentle manipulation of the infant’s limbs allows for assessment of muscle tone and strength. Tone is resistance to passive movement and should be evaluated while the infant is awake but at rest. Strength is resistance to active movement, which can be assessed in an infant by noting resistance to spontaneous movements. The optimal position to assess tone and strength is supine with the head in the midposition so that the tonic neck reflex does not augment tone unilaterally. Horizontal and vertical suspensions are helpful maneuvers when assessing infant motor function. When held in the vertical position, the hypotonic and weak infant tends to slide through the examiner’s hands. In the horizontal position, the hypotonic infant droops over the examiner’s arms without raising head or legs. Conversely, increased tone may cause opisthotonus, with persistent extension in both vertical and horizontal positions. Scissoring (i.e., crossing of the legs because of excessive, involuntary adductor magnus contraction) may also be evident with increased tone, but usually does not occur until after the neonatal period. The most common cause of generalized decreased tone is depression of CNS function, congenital malformations, or neuromuscular disorders. Increased muscle tone may be seen in a variety of conditions that cause neonatal encephalopathy. Indeed, there



are myriad causes of abnormalities of tone and strength, and careful serial examinations over time are often required to arrive at the correct diagnosis. While the infant is being handled, stimulation may cause jittery or tremulous movements of the jaw or limbs. The movements usually terminate when stimulation ends, although noises or abrupt changes in light may trigger them. Brief and mild tremulousness can be normal; however, when increased, these movements may indicate metabolic abnormalities (e.g., electrolyte imbalance), bleeding, congenital CNS defects (structural or functional), infections, or drug withdrawal syndromes. Deep tendon reflexes are assessed just as with older children. Although they may be brisk or absent in the newborn (Critchley, 1968), asymmetry is always abnormal. Typically, the plantar response is extensor for at least the first month of life and usually through the first year of life. Persistence of extensor toe-sign responses beyond infancy or any asymmetry suggests corticospinal tract impairment and may be associated with alterations in tone and other deep tendon reflex abnormalities. Several beats of ankle clonus are frequently elicited in the newborn, often enhanced by crying. Increased clonus, however, often with other examination abnormalities, may be the harbinger of serious CNS disease.

Cranial Nerve Examination A more detailed discussion of the cranial nerve examination is found in Chapter 2. Cranial nerve I, the olfactory nerve, is infrequently tested but may be evaluated by the use of pleasant but definitive aromatic substances; virtually, all neonates born after 32 weeks’ gestation respond. Evaluation of cranial nerves II, III, IV, and VI involves assessment of the eyes. Pupils should be symmetric, with equal response to light. A bright light causes the infant to blink or hold the lids closed. The presence of ptosis or increased height of the palpebral fissure should be evaluated. Examination of the optic fundi may be difficult but is necessary. Numerous changes, including chorioretinitis (i.e., salt-and-pepper pigmentary changes), may be observed. Hemorrhages are commonly detected after vaginal delivery, even in the absence of traumatic delivery. The optic nerve may be hypoplastic, as manifested by a small, pearl-colored optic disc. The color of the optic disc in the newborn infant is grayish white. Retinal hemorrhages may be found in a large percentage of otherwise normal infants who have no history of abnormal delivery and who later prove to be neurologically normal. The newborn infant turns toward a light of moderate intensity and fixes on a bright object or the examiner’s face. Most often, the newborn’s eyes are symmetrically open or closed. If one eye is open and the other closed, there should be a shifting from one side to the other. Width of palpebral fissures should be equal; if not, the presence of ptosis may suggest an abnormality of cranial nerve III function, sympathetic innervation dysfunction, neuromuscular junction difficulty, weakness of the levator muscle of the lid, or abnormality of the lid connective tissue. Occasionally, central or peripheral seventh nerve paresis may result in asymmetry of the palpebral fissure. Extraocular movements are monitored while a child is lying quietly. Slight lapses of conjugate gaze are common in the newborn period. Newborn visual acuity is difficult to assess, but black and white–patterned objects can be used. The examiner’s face is often the best “target.” The intended object of focus is moved slowly in the infant’s field of vision, less than a foot from the infant’s eyes. The infant slowly follows

Neurologic Examination of the Term and Preterm Infant

21

with eye movement, particularly in lateral directions. Prolonged gaze may occur in the newborn period (Brazelton et al., 1976). Opticokinetic nystagmus may be elicited by using a striped, rotating drum or striped cloth strip, which is slowly pulled across the infant’s visual field in the vertical and horizontal directions. The response is the same as in older children (Chapter 2). Although small-excursion, lateral-gaze nystagmus may be present in the newborn, the coarser to-and-fro pattern of congenital nystagmus, which is oscillatory in nature, is usually unmistakable. Although unusual, nystagmus associated with mild esotropia or exotropia may be evident in the newborn. Wild, jerky nystagmus of congenital opsoclonus is a startling and readily discernible finding suggesting midbrain involvement. Doll’s-eye movement is elicited by the examiner by gently rotating the infant’s head from one side to the other. The eyes move conjugately in the direction opposite to the rotation of the head. Movement of the head in the vertical position (upward and downward) causes similar movements in the vertical plane. Failure of the eyes to move in the expected manner may suggest abnormalities of cranial nerves or brainstem nuclei. To gain further information, the infant may be held supine on the examiner’s arm as the examiner rotates and watches the infant’s eyes. This oculovestibular maneuver causes movement so that there is lateral conjugate deviation in the direction of the rotation. When the rotational movement is terminated abruptly, the eye movements reverse. It is possible to assess the integrity of cranial nerves III and VI with this maneuver. Facial movements are readily observed during crying. Asymmetry should be carefully assessed to determine whether it is related to an upper motor neuron lesion (such as the so-called central seventh nerve palsy causing contralateral lower face weakness), a peripheral nerve lesion (causing unilateral weakness of both the upper and lower face), or a muscle problem such as hypoplasia of the depressor anguli oris that causes weakness of a lower lip and is also referred to as asymmetric crying facies (Nelson and Eng, 1972). This syndrome is a congenital abnormality that does not involve cranial nerve VII, but may be associated with somatic atrophy, vertebral and rib abnormalities, renal dysgenesis, or cardiac defects. Thus, careful observation makes an enormous difference in helping localize abnormalities of facial movement. Meaningful hearing evaluation during routine neurologic examination is difficult because of simultaneous visual cues and variable responses. Crying should not be intentionally elicited by the examiner; however, when it does occur, as it often the case, there is an opportunity to assess cranial nerves IX, X, and XII. During the lusty segments of crying, the infant’s tongue and palate may be readily inspected. Asymmetry or loss of tongue bulk may indicate abnormalities of cranial nerve XII or its nucleus. Tongue fasciculations are best identified when the child is quiet and not crying and often occur along the lateral margins and underside of the tongue. Furthermore, the quality of crying may reflect general neurologic status. An infant with generally depressed CNS function often cries infrequently, and the cry is weak and may be high-pitched. An irritable child with a hyperexcitable nervous system may have a high-pitched shriek. Cranial nerves V, VII, IX, X, and XII are involved in sucking and swallowing. Swallowing dysfunction requires close scrutiny to determine which cranial nerve or nerves are involved. The gag reflex is present in term newborns and requires normal function of cranial nerves IX and X. Tests for pain and sensation are imprecise at this age, and the gross response of infants to stroking and pinprick with

4

22

PART I  Clinical Evaluation

withdrawal, crying, and change in sucking rates may be the only information possible. More sophisticated testing can be devised during which heart and respiratory rates are monitored. If necessary, in the presence of olfactory, gustatory, visual, tactile, or auditory stimuli, sophisticated monitoring and scoring of body activity may be performed. All such sensory stimuli produce habituation in the newborn.

THE PRETERM INFANT The designation of an infant as preterm is related primarily to length of gestation. Term gestation is 38 to 42 weeks from conception. Late prematurity is used to describe infants born between 34 and 37 weeks’ gestation. Gestational age must be estimated to appropriately interpret the neurologic examination (Mercuri et al., 2003). Normally, birth weight reflects gestational age; infants born before 28 weeks’ gestation usually weigh less than 1000 g (so-called extremely low birth weight), and infants born after 31 to 32 weeks’ gestation often weigh between 1000 and 1500 g (low birth weight).

General Examination It is sometimes difficult (as well as inaccurate) to estimate gestational age from the date of the first day of the mother’s last menstrual period. Examination findings can be helpful when determining gestational age such as skin texture and color, quantity of breast tissue and ear cartilage, and the stage of development of the external genitalia (Table 4-3) (Dubowitz et al., 1970).

stimulation is usually unnecessary to provoke wakefulness. In those born after 37 weeks’ gestation, crying is commonly present during wakefulness. By 40 weeks’ gestational age, the preterm infant continues to be alert for reasonable periods and responds to visual, auditory, and tactile stimulation. Sleep and wakeful periods are easily identified.

Formal Scale of Gestational Assessment Using a systematic evaluation of body and neurologic characteristics, Dubowitz et al. (1970) were able to achieve a high correlation with gestational age (Fig. 4-3).

Deep Tendon Reflex Assessment Deep tendon reflexes vary with maturity (Kuban et al., 1986). In a study of preterm infants of more than 27 weeks’ postconceptional age, the pectoralis major reflex was elicited in all, and by 33 weeks’ gestation, essentially all demonstrated the Achilles, patellar, biceps, thigh adductor, and brachioradialis reflexes. Infants of less than 33 weeks’ gestation had decreased elicitation rates for patellar and biceps reflexes and had overall decreases in reflex intensity compared with their older counterparts. Contrary to conventional wisdom, head position had no effect on the reflexes.

Body Attitude During maturation, preterm infants adopt typical postures that correspond to gestational age. These postures have been charted and are useful for evaluation of gestational age (Dubowitz et al., 1970).

Muscle Tone

Neurologic Examination Although estimation of gestational age should be made as soon after birth as possible, the neurologic examination may be postponed for 1 to 2 days, depending on the condition of the infant and the need for physiologic support. The examination should be performed while the infant is awake and approximately 1 hour before the next scheduled feeding. Otherwise the child may seem fussy if examined when hungry, or hypotonic and lethargic if examined shortly after a feeding.

Environmental Interaction Responsiveness increases with CNS maturation. Periods of apparent wakefulness are rare before 28 weeks’ gestation. By 31 weeks’ gestation, a readily recognizable level of alertness during wakeful stages occurs and by 32 weeks, external

At 26 to 28 weeks’ gestation, the infant is extremely hypotonic. When held by the examiner in vertical suspension, the infant does not extend the head, limbs, or trunk. The change from the hypotonia of the preterm infant to the flexion posture of the term infant manifests first in the legs and then in the arms and head. At 34 weeks’ gestation, the infant lies in the frogleg position while supine; the legs are flexed at the hip and knee, but the arms remain extended and relatively hypotonic. Measurement of various limb angles offers some objective evidence for the degree of tone. The popliteal angle, measured by maximum extension of the leg at the knee with the hip fully flexed, decreases from 180 degrees at 28 weeks’ gestation to less than 90 degrees at term, and further decreases through the first year of life. During the traction maneuver, the head lags considerably, with little resistance until after 30 weeks’ gestation. The head

TABLE 4-3  External Characteristics Useful for Estimation of Gestational Age Gestational Age

External Characteristics

28 Weeks

32 Weeks

36 Weeks

40 Weeks

Ear cartilage

Pinna soft, remains folded

Pinna slightly harder but remains folded

Pinna harder, springs back

Pinna firm, stands erect from head

Breast tissue

None

None

1- to 2-mm nodule

6- to 7-mm nodule

Male external genitalia

Testes undescended; smooth scrotum

Testes in inguinal canal; few scrotal rugae

Testes high in scrotum; more scrotal rugae

Testes descended; pendulous scrotum covered with rugae

Female external genitalia

Prominent clitoris; small, widely separated labia

Prominent clitoris; larger separated labia

Clitoris less prominent; labia majora cover labia minora

Clitoris covered by labia majora

Plantar surface

Smooth

1–2 anterior creases

2–3 anterior creases

Creases cover sole

(With permission from Volpe JJ. Neurology of the newborn, 4th edn. Philadelphia: WB Saunders, 2001.)



23

Neurologic Examination of the Term and Preterm Infant

extensors develop gradually, followed by the flexors. By 38 weeks, the head follows the trunk, is maintained briefly, and then falls forward when the infant is pulled from a supine to a sitting position during the traction maneuver. In small preterm infants, the scarf sign, which is elicited by folding the arm across the chest toward the opposite shoulder, is present if the elbow reaches the opposite shoulder. In term infants, the elbow cannot be brought beyond the midline. The extreme hypotonia of preterm infants permits the legs to be flexed at the hip so that the heel can be passively brought to the side of the face (i.e., heel-to-ear maneuver). Understandably, this positioning is restricted in the older infant because of increasing tone. Tone may also be monitored while postural and righting reflexes are assessed. During the stepping maneuver, the 28-week preterm infant will not support weight. However,

over the next few weeks, there is gradual support of weight, and by 34 weeks, a good supporting response is present. Tremors and even clonic movements may occur in the small preterm infant but are not normally present after 32 weeks’ gestation. Stretching movements of the limbs are common in small preterm infants while they are awake but somewhat less common during sleep. These movements may spread to include the trunk and head.

Cranial Nerves Some features of the preterm infant examination are different from features of the older infant’s examination. Head position is unpredictable in the small preterm infant, but by 35 weeks’ gestation, there is a preference for the head to be held to the right, which is normal.

Neuromuscular Maturity -1

1

0

4

3

2

5

Posture Square Window (wrist)

< 90°

90°

60°

30°

45°

0°

Arm Recoil 180° 140° - 180° 110° - 140° Popliteal Angle

180°

160°

140°

< 90°

90-110°

120°

100°

90°

< 90°

Scarf Sign

Heel to Ear

Physical Maturity Skin

Lanugo

Plantar Surface

Breast

sticky friable transparent

gelatinous red, translucent

smooth pink, visible veins

superficial peeling &/or rash, few veins

cracking pale areas rare veins

none

sparse

abundant

thinning

bald areas

mostly bald

heel-toe 40–50 mm: -1 50 mm no crease

faint red marks

anterior transverse crease only

creases ant. 2/3

creases over entire sole

barely perceptible

flat areola no bud

stippled areola 1–2 mm bud

raised areola 3–4 mm bud

full areola 5–10 mm bud

15

30

20

32

lids open pinna flat stays folded

sl. curved pinna; soft: slow recoil

well-curved pinna; soft but ready recoil

formed & firm instant recoil

thick cartilage ear stiff

25

34

30

36

scrotum empty faint rugae

testes in upper canal rare rugae

testes descending few rugae

testes down good rugae

testes pendulous deep rugae

35

38

40

40

prominent clitoris small labia minora

prominent clitoris enlarging minora

majora & minora equally prominent

majora large minora small

majora cover clitoris & minora

45

42

50

44

Figure 4-3.  A, Scoring system for neurologic criteria.

Continued

4

24

PART I  Clinical Evaluation

SOME NOTES ON TECHNIQUES OF ASSESSMENT OF NEUROLOGIC CRITERIA POSTURE: Observed with infant quiet and in supine position. Score 0: Arms and legs extended; 1: Beginning of flexion of hips and knees, arms extended; 2: Stronger flexion of legs, arms extended; 3: Arms slightly flexed, legs flexed and abducted; 4: Full flexion of arms and legs. SQUARE WINDOW: The hand is flexed on the forearm between the thumb and index finger of the examiner. Enough pressure is applied to get as full a flexion as possible, and the angle between the hypothenar eminence and the ventral aspect of the forearm is measured and graded according to diagram. (Care is taken not to rotate the infant’s wrist while doing this maneuver.) ARM RECOIL: With the infant in the supine position the forearms are first flexed for 5 seconds, then fully extended by pulling on the hands, and then released. The sign is fully positive if the arms return briskly to full flexion (Score 2). If the arms return to incomplete flexion or the response is sluggish it is graded as Score 1. If they remain extended or are only followed by random movements the score is 0. LEG RECOIL: With the infant supine, the hips and knees are fully flexed for 5 seconds, then extended by traction on the feet, and released. A maximal response is one of full flexion of the hips and knees (Score 2). A partial flexion scores 1, and minimal or no movement scores 0. POPLITEAL ANGLE: With the infant supine and the pelvis flat on the examining couch, the thigh is held in the knee−chest position by the examiner’s left index finger and thumb supporting the knee. The leg is then extended by gentle pressure from the examiner’s right index finger behind the ankle and the popliteal angle is measured. SCARF SIGN: With the infant supine, take the infant’s hand and try to put it around the neck and as far posteriorly as possible around the opposite shoulder. Assist this maneuver by lifting the elbow across the body. See how far the elbow will go across and grade according to illustrations. Score 0: Elbow reaches opposite axillary line; 1: Elbow between midline and opposite axillary line; 2: Elbow reaches midline; 3: Elbow will not reach midline.

B

HEEL TO EAR MANEUVER: With the infant supine, draw the infant’s foot as near to the head as it will go without forcing it. Observe the distance between the foot and the head as well as the degree of extension at the knee. Grade according to diagram. Note that the knee is left free and may draw down alongside the abdomen.

Figure 4-3, cont’d  B, Description of techniques used to assess neurologic signs.

The small preterm infant may cry in response to provocation (Fenichel, 1978), but crying often occurs when the infant is unprovoked. By 36 to 37 weeks’ gestation, the cry is more vigorous, frequent, and persistent, and it is easily elicited by noxious stimuli. The pupillary light reflex is not fully mature before 29 to 30 weeks’ gestation, and in the resting state, the infant’s pupils are usually miotic. The reflex becomes progressively evident and is mature by 32 weeks. Although they may forcefully close their eyes when a bright light is directed toward them, infants of 28 weeks’ gestation or less do not turn in the direction of the light. By using a large target (e.g., large, red ball; hoop; and handful of yarn), visual fixation and even rudimentary scanning and tracking may be evident in infants of 31 to 32 weeks’ gestation (Hack et al., 1976). Associated with this response, there may be widening of the palpebral fissure. By 36 to 38 weeks’ gestation, the infant rotates the head toward a light and closes the eyes forcefully when a strong light stimulus is presented. The doll’s-eye reflex is elicited in the 28- to 32-week preterm infant who has no compromise of consciousness. The ease of eliciting a response is enhanced because infants do not visually fixate. By 36 weeks’ gestation, this response is not elicited in the normal infant.

Developmental Reflexes Observation and description of the major reflex changes peculiar to the preterm infant have been undertaken by many investigators (Table 4-7).

The rooting and sucking reflexes in small preterm infants are perfunctory but become vigorous in infants of 34 weeks’ gestation. The Moro reflex, first present in fragmentary form at 24 weeks, is well developed by 28 weeks, although it fatigues easily and lacks a complete adduction phase. Not until 38 weeks’ gestation is the entire response characteristic of the term infant observed. At 28 weeks’ gestation, the grasp reflex is evident just in the fingers, and by 32 weeks, the palm and fingers participate. Slightly later, contraction of the muscles of the shoulder girdle and elbows occurs during the traction maneuver when the infant is pulled from a supine to a sitting position. The tonic reflex is elicited by turning of the head to one side. The arm on the side to which the head is turned extends, and the other arm flexes. The legs may follow suit, but the response is often absent or subtle. This “fencing” position often can be elicited in the 35-week preterm infant. The crossed-extensor reflex is obtained by stroking the sole of one foot while holding the leg firmly in extension. The response occurs in the opposite leg and comprises rapid flexion at the hips and knees with attendant withdrawal, followed by extension, adduction, and fanning of the toes. The complete response, elicited in infants of about 36 weeks’ gestation, is informative when asymmetric. Otherwise, it only establishes that some degree of primitive function is present. The stepping response (i.e., automatic walking) is usually present by 37 weeks’ gestation and can be induced by resting the infant’s soles on a mattress and rocking the infant gently from one foot to the other. This procedure usually initiates



Neurologic Examination of the Term and Preterm Infant

25

TABLE 4-7  Neurologic Maturation Function

26 Weeks

30 Weeks

34 Weeks

38 Weeks

Resting posture

Flexion of arms Flexion or extension of legs

Flexion of arms Flexion or extension of legs

Flexion of all limbs

Flexion of all limbs

Arousal

Unable to maintain

Maintain briefly

Remain awake

Remain awake

Rooting

Absent

Long latency

Present

Present

Sucking

Absent

Long latency

Weak

Vigorous

Pupillary reflex

Absent

Variable

Present

Present

Traction

No response

No response

Head lag

Mild head lag

Moro

No response

Extension; no adduction

Adduction variable

Complete

Withdrawal

Absent

Withdrawal only

Crossed extension

Crossed extension

(With permission from Fenichel GM. The neurological consultation. In: Fenichel GM, ed. Neonatal neurology, 4th edn. New York: WB Saunders, 2001.)

GROWTH RECORD FOR INFANTS in relation to GESTATIONAL AGE AND FETAL AND INFANT NORMS (Combined sexes) 46

46 cm

44

44

42

42

40

cm 80

38

76

36

72

34

68

32

kg 64 11 60 10 56 9.0 52 8.0 48 7.0 44 6.0

30 28 26 24

Weight

Length

cm

22 40 36

32 kg 2.5 2.0 1.5 1.0

Mean ± 1 S.D.

Length

Head circumference

cm

5.0 4.5 4.0 3.5 3.0 2.5

± 2 S.D. 26 28

30

32

34 36

40 1 mo.

2

3

6

9

1 year

Figure 4-15.  A fetal-infant growth graph for infants of various gestational ages. This can be used for plotting growth from birth until 1 year of age after term status has been reached. (With permission from Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational age. J Pediatr 1976;89:814.)

a walking sequence, which is facilitated by the examiner supporting the infant’s weight and tilting the infant forward and begins at approximately 32 to 34 weeks’ gestation. The preterm infant usually walks on the toes, whereas a term infant typically uses a heel-to-toe gait pattern. Ongoing neurologic examinations of the preterm infant are most important for the assessment of development and neurologic status. When the preterm infant reaches the equivalent

of 40 weeks’ gestation, the neurologic examination results are not the same as those of a term newborn. After reaching 40 weeks’ gestation the preterm infant lies with relatively less elevation of the pelvis, and so the prone body profile is flatter than that of the term newborn. The preterm infant continues toe-walking and, even at 40 weeks, often has hypotonia, incomplete dorsiflexion of the foot, and a greater popliteal angle compared with the term newborn.

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PART I  Clinical Evaluation

Assessment of Head Growth Patterns There are expected changes in head growth. Naturally, size should increase with age, but the shape also changes, becoming more elongated during the first few months of life. Abnormalities of head growth such as microcephaly or hydrocephalus often develop over time, and therefore serial measurements are required to make such diagnoses. A standard plotting curve is necessary to monitor head growth in the preterm infant such as depicted in Fig. 4-15 (Babson and Benda, 1976). Thus with flexibility and persistence, a newborn neurologic examination is accomplished. As always, it is helpful to be aware of the range of normal variation among children, and any abnormal findings need to be carefully replicated. Involving the family when possible during the examination provides an opportunity to build trust and establish rapport. This is essential to the job of the child neurologist, who not only characterizes the neurologic status and helps guide a diagnostic and therapeutic plan, but must also engage in that most human of endeavors, providing support and empathy to a family facing an unexpected and often frightening future. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Babson, S.G., Benda, G.I., 1976. Growth graphs for the clinical assessment of infants of varying gestational age. J. Pediatr. 89, 814. Brazelton, T.B., Parker, W.B., Zuckerman, B., 1976. Importance of behavioral assessment of the neonate. Curr. Probl. Pediatr. 2, 49. Critchley, E.M., 1968. The neurological examination of neonates. J. Neurol. Sci. 7, 427. Dubowitz, L., Dubowitz, V., Goldberg, C., 1970. Clinical assessment of gestational age in the newborn infant. J. Pediatr. 77, 1. Fenichel, G.M., 1978. Neurological assessment of the 25 to 30 week premature infant. Ann. Neurol. 4, 92. Hack, M., Mostow, A., Miranda, S.B., 1976. Development of attention in preterm infants. Pediatrics 58, 669. Kuban, K.C.K., Skouteli, H.N., Urion, D.K., et al., 1986. Deep tendon reflexes in premature infants. Pediatr. Neurol. 2, 266. Mercuri, E., Guzzetta, A., Laroche, S., et al., 2003. Neurologic examination of preterm infants at term age: comparison with term infants. Pediatrics 142, 647.

Nelson, K.B., Eng, G.D., 1972. Congenital hypoplasia of depressor anguli oris muscle: differentiation from congenital facial palsy. J. Pediatr. 81, 16. Popich, G.A., Smith, D.W., 1972. Fontanels: range of normal size. J. Pediatr. 80, 749.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 4-1 Head circumference charts. Fig. 4-2 Horner syndrome (left eye). Fig. 4-4 Graph for reading gestational age from total score obtained from scores derived from Figure 4-3. Fig. 4-5 Elicitation of deep tendon reflexes in a preterm infant of 32 weeks’ gestation. Fig. 4-6 Preterm baby, 26 to 28 weeks’ gestation. Fig. 4-7 Two weeks after birth. Fig. 4-8 The popliteal angle is 180 degrees in a preterm infant of 28 weeks’ gestation. Fig. 4-9 The adductor angle of the thighs is almost 180 degrees in a preterm infant of 30 weeks’ gestation. Fig. 4-10 An infant of 32 weeks’ gestation demonstrates the scarf sign, with the elbow approximating the opposite shoulder. Fig. 4-11 Diminished tone in the very small preterm infant of 30 weeks’ gestation allows the heels to reach the head easily. Fig. 4-12 A preterm infant of 28 weeks’ gestation supports his or her weight briefly. Fig. 4-13 The hips are abducted and the pelvis is low in a prone preterm infant of 32 weeks’ gestation. Fig. 4-14 Measurement of the popliteal angle in an infant who was 8 months old (corrected age). Fig. 4-16 Head circumference growth record for preterm infants. Table 4-1 Apgar Scoring Table 4-2 Encephalopathy Scoring System in Term Neonates with Hypoxic-ischemic Brain Injury Table 4-3 External Characteristics Useful for Estimation of Gestational Age

5 

Muscular Tone and Gait Disturbances Kenneth F. Swaiman and John Phillips

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

TONE Muscle tone is defined as resistance to passive stretch (Sanger et al., 2003). It is conventionally separated into postural and phasic types. Postural tone is the result of a steady, restrained stretch on tendons and attached muscles, resulting in protracted muscle contraction. Gravity is the most common stimulus for this response. The axial muscles are primarily involved with postural tone. Phasic tone is the result of rapid stretching of a tendon, attached muscle, and most importantly, the muscle spindle. Muscles of the extremities are primarily involved in phasic tone. The response is rapid and short-lived. Phasic tone is the topic primarily discussed in this chapter, and it is referred to simply as tone. Abnormalities of tone can be broadly defined as hypertonia (increased tone) or hypotonia (decreased tone). Common forms of hypertonia are spasticity, dystonia, and rigidity. Spasticity is velocity-dependent resistance to passive stretch. Dystonia includes velocity-independent resistance to passive stretch, often with simultaneous contraction of agonist and antagonistic muscles and fluctuating involuntary extremity movement or postures. With dystonia, tone may increase if another body part is moved or touched. Rigidity is also velocity-independent resistance to passive stretch in all directions of joint movement, but unlike dystonia there is no involuntary movement or extremity postures (Sanger et al., 2003).

PATHOLOGY The final common pathway of upper or lower motor unit modification of tone is through the gamma loop (fusimotor) system. Intimately involved with monitoring and effecting tone are the two stretch-sensitive muscle receptors—the muscle spindles and the Golgi tendon organs (Figure 5-1). Spinal cord reflex responses depend on ongoing activity in interneurons. Stationed in all areas of the skeletal muscle is the muscle spindle, a fusiform-shaped receptor structure. Sensory endings wrap around the central sections of the intrafusal fibers and monitor the stretch of these fibers. Through efferent axons, gamma neurons within the anterior horn of the spinal cord innervate the contractile muscle portions on each end of the intrafusal fiber and enhance the sensitivity of the sensory endings to stretch. The intrafusal muscle fibers are divided into three types: nuclear chain fibers, dynamic nuclear bag fibers, and static nuclear bag fibers. A solitary Ia afferent fiber provides primary sensory innervation for all three types of intrafusal fibers. A group II afferent fiber innervates chain and static bag fibers, providing secondary sensory endings. The various sensory endings on the different types of intrafusal fibers have different sensitivities to the rate of the change of length. This intricate system of muscle spindle innervation allows the muscle stretch receptors to monitor muscle tension, length, and velocity of stretch, and provide input for maintenance of tone.

It is through their effect on the gamma motor neuron that portions of the central nervous system (CNS) (i.e., motor cortex, thalamus, basal ganglia, vestibular nuclei, reticular formation, and cerebellum) modify tone, with ensuing hypotonia or hypertonia (i.e., spasticity). The Golgi tendon organs, unlike the muscle spindles, are found in series with the skeletal muscle fibers and are attached at one end to the muscle and at the other to the tendon. Tendon organs are much more sensitive to muscle contraction than muscle spindles. Conversely, tendon organs are much less sensitive to stretch than muscle spindles. Each of these relative sensitivities plays a specific role during the performance of various motor tasks.

EVALUATION OF THE PATIENT History It is critical to establish when an abnormality first became evident, and what changes, if any, have occurred over time.

Examination Preterm infants, even when healthy, are normally hypotonic relative to a term newborn; therefore, corrected ages must be considered when assessing preterm infants during the first months of life. The infant’s tendency to assume unusual postures may indicate the presence of hypotonia—especially the “frogleg” position, in which the supine infant lies with the lower limbs externally rotated and abducted. Hypotonia is often associated with generalized weakness, with resultant poor suck, cry, and respiratory effort in addition to a paucity of spontaneous limb movements. Observation of the chest may disclose pectus excavatum and a bell-shaped chest, indicating relative weakness of intercostal muscles compared with the better-preserved strength of the diaphragm during respiratory efforts. Tone should be assessed both when the neonate is active and also when at rest. Passive pronation, supination, flexion, and extension of the limbs and gently shaking the hands and feet is required. The scarf sign (wrapping the infant’s arm across the chest) and the traction can be helpful as well. The hypotonic infant will slip through the hands of the examiner when held under the axillae (i.e., vertical suspension maneuver). If the hypotonic infant is supported by the trunk in an outstretched prone position (i.e., horizontal suspension maneuver), gravity causes flexion, or droop of the head and extremities (“inverted comma”). The infant with hypertonia responds differently to these maneuvers. In vertical suspension the infant with spasticity may demonstrate extension and scissoring of the legs with fisting, and in horizontal suspension there can be persistent hyperextension of the legs and neck. Weakness is often readily diagnosed in the infant and younger child by observation; in the older child, more formal

27

28

PART I  Clinical Evaluation Alpha motor axon

Spindle afferents and efferents Tendon organ afferent

Extrafusal muscle fiber Muscle spindle

Golgi tendon organ Figure 5-1.  Muscle spindles and Golgi tendon organs are encapsulated structures found in skeletal muscle. The main skeletal muscle fibers, or extrafusal fibers, are innervated by large-diameter alpha motor axons. The muscle spindle has a fusiform shape and is arranged in parallel with extrafusal fibers. It is innervated by afferent and efferent fibers. The Golgi tendon organ is found at the junction between a group of extrafusal fibers and the tendon; it is therefore in series with extrafusal fibers. Each tendon organ is innervated by a single afferent axon. (Adapted from Granit R., 1975. The functional role of the muscle spindles–facts and hypotheses. Brain 98, 531.)

and discrete muscle testing is possible, as described in Chapter 2. Deep tendon reflexes should always be elicited. When the lower motor unit is involved, the deep tendon reflexes range from hypoactive to absent. Whereas hypotonia may occur due to pathology in either the peripheral or CNS, increased tone always involves the CNS. In general terms, dystonia and rigidity are usually related to involvement of the basal ganglia or their output tracts and are associated with normal or decreased deep tendon reflexes. Spasticity can be conceptualized as involving the pyramidal tract system and is associated with hyperreflexia, the sometimes abnormal spread of the reflex (crossed adductor response or Hoffman sign) and extensor plantar responses. An exception is in the acute phase of traumatic injury when transient hypotonia and decreased reflexes can occur (for example, as seen in the so-called “spinal shock”). Specific laboratory studies may be essential in establishing the diagnosis. There is increasing reliance for specific diagnosis on genetic analysis, which has been replacing the need for biopsy in most cases. When upper motor unit diseases are involved, a careful history, electroencephalography, evoked potentials, brain imaging, specific endocrine evaluations, and specific enzyme determinations may be required.

DIAGNOSIS For didactic purposes and simplification, the motor pathway from the motor neuron in the motor strip to the skeletal muscle fiber can be divided into upper and lower motor neuron units. The upper motor neuron (unit) includes the pyramidal neuron in the motor cortex and the myelinated nerve fiber, which traverses the corticospinal tract and eventually terminates in the internuncial pool in the spinal cord adjacent to the anterior horn cell. The lower motor neuron (unit) consists of the anterior horn cell, peripheral nerve, neuromuscular junction, and muscle. Upper motor unit disease may result in increased or diminished muscle tone in infants and young children, whereas lower motor unit disease generally results in decreased tone.

When assessing a child with hypotonia, it is important to distinguish whether there is a central or peripheral etiology. Impairment of the lower motor unit causes hypotonia and weakness. Hyporeflexia, fasciculations, and muscle atrophy also result. Inadequate brain control of the motor pathways, or central hypotonia, is the most common cause of decreased tone. The presence of normoactive or brisk deep tendon reflexes suggests that the child is probably not suffering from lower motor unit impairment. The examiner should be alert for other signs of brain dysfunction, such as lethargy, unresponsiveness to the environment (i.e., visual and auditory stimuli), lack of development of social skills in the early months of life, and delayed development of language and reasoning skills in older children. Diseases of the upper motor unit may be classified according to pathophysiologic causes (i.e., metabolic, degenerative, traumatic, congenital–structural, infectious, or toxic). A similar classification may be used for lower motor unit diseases; such diseases also may be categorized by the anatomic site of involvement. Increased muscle tone needs to be characterized as spasticity, dystonia, or rigidity. The Hypertonia Assessment Tool provides a convenient approach to patient evaluation, particularly when mixed tone exists (Figure 5-4) (Jethwa et al., 2010). More detailed evaluation of spasticity is possible using the Modified Ashworth Scale (Bohannon and Smith, 1987) and the Tardieu assessment (Patrick and Ada, 2006).

CLINICAL LABORATORY STUDIES Conventional laboratory studies are rarely helpful, although creatine kinase and thyroid studies should be performed in the presence of hypotonia. Abnormalities of increased or decreased tone may require specific enzyme testing or genetic analysis. Magnetic resonance imaging (MRI) is the standard imaging modality for the diagnosis of structural CNS abnormalities. Cerebrospinal fluid studies may demonstrate pleocytosis, increased levels of protein, or abnormal proteins, and specific patterns may point to demyelinating conditions or peripheral neuropathy. Spinal fluid neurotransmitter metabolite assessment may be helpful in the evaluation of dystonia. Assessment for leukocyte enzyme activities associated with certain lipid storage diseases may provide definitive diagnoses for conditions that affect the brain alone, the brain and anterior horn cells, or the brain and peripheral nerves. Some neuromuscular and mitochondrial diseases are associated with cardiomyopathies, and electrocardiography or echocardiography may be of assistance in establishing a diagnosis. Electromyography differentiates neurogenic from myopathic conditions. The diagnosis of peripheral neuropathy, particularly in conditions that involve the central and peripheral nervous systems, may be readily overlooked without the determination of nerve conduction velocities. Normative data are available for all age groups.

GAIT IMPAIRMENT Physiologic Considerations Conventionally, the period from one heel–ground contact to the next heel–ground contact of one foot is one gait cycle; walking can be divided into stance and swing phases. The instant from which heel–ground contact occurs until the instant when contact terminates is the stance phase. The period beginning immediately after the toe leaves the ground



Muscular Tone and Gait Disturbances

29

5

HYPERTONIA ASSESSMENT TOOL (HAT) - SCORING CHART Name:

Chart/File #:

Clinical Diagnosis:

Date of Birth:

Limb Assessed:

Gender:

Male

Arm

Left

Right

HAT Assessor:

Leg

Left

Right

Date of Assessment:

Female

HYPERTONIA ASSESSMENT TOOL (HAT) SCORING GUIDELINES (0=negative or 1=positive)

HAT ITEM 1. Increased involuntary movements/postures of the designated limb with tactile stimulus of another body part 2. Increased involuntary movements/postures with purposeful movements of another body part 3. Velocity-dependent resistance to stretch 4. Presence of a spastic catch 5. Equal resistance to passive stretch during bidirectional movement of a joint 6. Increased tone with movement of another body part 7. Maintenance of limb position after passive movement

0= No involuntary movements or postures observed

SCORE 0=negative 1=positive (circle score)

0

1= Involuntary movements or postures observed

1

0= No involuntary movements or postures observed 1= Involuntary movements or postures observed 0= No increased resistance noticed during fast stretch compared to slow stretch 1= Increased resistance noticed during fast stretch compared to slow stretch

0 DYSTONIA

0 1 0

1= Spastic catch noted

1

SPASTICITY SPASTICITY

0 RIGIDITY

1 0

DYSTONIA

1 0

RIGIDITY

1

SUMMARY SCORE – HAT DIAGNOSIS DYSTONIA → SPASTICITY → RIGIDITY → MIXED TONE →

DYSTONIA

1

0= No spastic catch noted 0= Equal resistance not noted with bi-directional movement 1= Equal resistance noted with bi-directional movement 0= No increased tone noted with purposeful movement 1= Greater tone noted with purposeful movement 0= Limb returns (partially or fully) to original position 1= Limb remains in final position of stretch

TYPE OF HYPERTONIA

Positive score (1) on at least one of the Items #1, 2, or 6 Positive score (1) on either one or both of the Items #3 or 4 Positive score (1) on either one or both of the Items #5 or 7 Presence of 1 or more subgroups (e.g. dystonia, spasticity, rigidity)

Check box:

Yes Yes Yes Yes

No No No No

HAT DIAGNOSIS:

(Fill in all that apply)

HAT Manual can be accessed at http://www.hollandbloorview.ca/research/scientistprofiles/fehlings.php © (2010) Fehlings D, Switzer L, Jethwa A, Mink J, Macarthur C, Knights S, & Fehlings T Development of the Hypertonia Assessment Tool (HAT): Dev Med & Child Neurol 2010;52(5):e83-e87. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-8749.2009.03483.x/full

Figure 5-4.  Hypertonia Assessment Scale. (From: Jethwa, A., Mink, J., Macarthur, C., Knights, S., Fehlings, T., Fehlings, D., 2010. Development of the Hypertonia Assessment Tool (HAT): a discriminative tool for hypertonia in children. Dev. Med. Child Neurol. 52, e83–e87.)

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PART I  Clinical Evaluation

until the heel contacts the ground is the swing phase. Normally, the stance phase occupies 60% of the duration of the cycle, and the swing phase occupies 40%.

Evaluation of the Patient Specific aspects of the neurologic examination are particularly relevant to gait. It is important to determine whether abnormalities are focal or diffuse and to note whether there is abnormal muscle tone, weakness, extrapyramidal movements, extensor toe signs, or abnormalities of deep tendon reflexes. To evaluate gait fully, it is important that the examiner be able to see the entire picture, so the patient should be unencumbered by clothing and is best tested wearing only underwear (or, for more modest older children, short pants and an undershirt). The child’s back should be carefully examined with special attention to the lower spine, looking for cutaneous lesions or scoliosis. The hip, knee, and ankle joints should be moved through their entire range of motion, and the presence of contractures determined. Any pain associated with joint movement should be evaluated. In infants, congenital dislocation or subluxation of the hip is often associated with skin fold asymmetry along the medial thigh. Before the patient’s walk is observed, the Romberg test should be performed. Walking should be assessed while the patient is barefoot and also while the patient is wearing shoes. Patients who wear braces should be examined both with and without braces. Among the important characteristics are symmetry of gait from leg to leg; whether walking occurs on the balls of the feet, flat-footed, or on the heels; and the relative stability of the pelvis. Fluctuating upper extremity postures triggered by walking may suggest a dystonic component. Reduced arm swing is often seen in hemiparesis. The arms should move so that the contralateral arm swings forward synchronously with the swing phase of each leg (see Figure 5-5). When the child runs, abnormal arm and hand postures and movements are frequently accentuated. An older child should be asked to tandem-walk forward and backward (heel-to-toe); the examiner can facilitate compliance by demonstration. The child should be asked to pivot quickly when changing direction. The backward heel-to-toe walk should also be executed. The child should walk on the toes and reverse direction, remaining on the toes. This process needs to be repeated on the heels. The clinician should ask the child to circle the examiner, first in one direction and then in the other. If the child has hemispheric cerebellar disease, the child will tend to depart from the circular path toward the examiner or away from the examiner, depending on the side of the lesion. It is advantageous to have the child climb steps to observe pelvic strength and stamina. Hip girdle strength can be

Initial contact

Loading response

Midstance

Terminal stance

assessed when the child is asked to squat and then stand rapidly. Evidence of hip girdle weakness may also be gained by asking the child to lie down in the supine position and sit up by flexing at the hip. Gowers’ maneuver can help identify proximal leg weakness. While the child walks and runs with shoes on, the examiner should listen and observe for evidence of scraping, scuffing, and slapping sounds. Formal gait analysis may be obtained, which assesses various facets of gait in children.

DIFFERENTIAL DIAGNOSIS Spastic Hemiplegic Gait Hemiplegia typically results from disruption of the corticospinal tract above the medulla. Tone is often increased, and posture is characterized by leg extension or slight knee flexion. Hemiplegic gait includes impaired natural swing at the hip and knee with leg circumduction. The pelvis is often tilted upward on the involved side to permit adequate circumduction. With ambulation, the leg moves forward and then swings back toward the midline in a circular movement. The heelwalking exercise is impaired as the patient scuffs the lateral sole and the toe of the shoe while dragging the foot. The affected leg bears weight for less time than the normal leg during ambulation. The expected rhythmic reciprocal swing of the arm with the stance phase of the opposite leg is absent. Dystonia rather than spasticity should be considered if the arm is held behind the plane of the body on a routine basis. The etiology of hemiplegic gait cannot always be determined, but one should look for focal brain lesions such as porencephalic cysts, subdural hematomas, cerebral masses, and cerebrovascular accidents.

Spastic Diplegic Gait Spastic diplegia implies bilateral corticospinal tract dysfunction involving both legs out of proportion to arms. Sutherland and Davids (1993) provided the classic description of four types of pathologic gait patterns seen with spastic diplegia. Jump gait is characterized by excessive flexion throughout the gait cycle of the hip and knee with plantar flexion of the ankle, resulting in a jumping quality to each step. Crouch gait has excessive hip and knee flexion with the ankle in excessive dorsiflexion through the gait cycle and is often seen in patients with severe spastic diplegia or quadriplegia. In the stiff knee gait pattern, the knee is stiff with insufficient flexion in the swing phase, causing difficulty with foot clearance, resulting in compensatory hip circumduction and external rotation of the affected leg and a vaulting quality to the contralateral leg during stance. Recurvatum gait is less common and occurs

Preswing

Initial swing

Midswing

Terminal swing

Figure 5-5.  Schematic representation of various phases of a child walking. (Adapted from Õunpuu, S., Gage, J.R., Davis, R.B, 1991. Three-dimensional lower extremity joint kinetics in normal pediatric gait. J Pediatr Orthop. 11, 341.)



with excessive knee extension in the stance phase of the gait cycle with or without an equinus ankle contracture.

Cerebellar Gait An unsteady, wide-based, often lurching gait signifies cerebellar pathway dysfunction. Cerebellar hemispheric lesions result in veering to the ipsilateral side. For example, if a child with a right cerebellar lesion is asked to circle the examiner in a clockwise direction, he or she will collide with the examiner within a few circles. In order for cerebellar impairment to be better observed, the child should be asked to rise from a chair, walk a straight line, and suddenly reverse direction while walking in a tight circle. The child should be asked to tandem-walk along a straight line to facilitate observation of ataxia. The child should be asked to stand with feet close together, first with eyes open and then with eyes closed. This is the Romberg test, and the child with cerebellar difficulties will maintain a stable or mildly unsteady stance with eyes open, but sway or fall toward the involved cerebellar hemisphere with eyes closed. Compromise of the cerebellar hemisphere is associated with abnormal movement of the ipsilateral limbs. If the anterior lobe of the cerebellum or midline cerebellar structures are compromised, only gait may be involved, without abnormalities of the upper extremities. The clinical presentation of sensory ataxia can be similar to ataxia due to a midline cerebellar lesion. With sensory ataxia, the cerebellum lacks normal sensory input from various portions of the sensory system, including peripheral nerves, posterior roots, posterior columns, or connections leading from the posterior columns to the parietal lobes through the medial lemnisci. This results in marked instability during standing, and when walking there is a wide-based gait. Muscle power remains unaffected. The patient with sensory ataxia lacks position sense and avoids obstacles by raising the legs inordinately and stepping sharply downward, the heel striking the ground first (“steppage gait”). A fraction of a second later the toe makes contact and produces the second part of a split sound. The child often compensates for loss of sensory awareness by looking at the ground during walking. The child usually has no complaint of sensory abnormality unless ataxia is caused by a global peripheral neuropathy (i.e., one severely affecting all sensory modalities). However, examination will reveal abnormal position and vibratory sense primarily in the lower extremities. The Romberg test is positive as well, just as it is with lesions of the cerebellum. The differential diagnosis of a cerebellar gait depends on time course. Chronic or slowly progressive ataxia may be caused by congenital malformations, inherited cerebellar atrophies, aminoacidurias, mitochondrial diseases, lipid storage diseases, anoxic encephalopathy, demyelinating diseases, posterior fossa tumors, or hydrocephalus. Whole exome sequencing may provide a diagnosis in more than half of patients without a clear etiology for their ataxia (Pyle et al., 2015). Some causes of sensory ataxia include subacute combined degeneration, polyneuritis, demyelinating disease, and Friedreich’s ataxia. Acute onset of ataxia can be frightening for parents as well as clinicians. Although the process is most often benign and self-limited, the differential diagnosis is broad and includes a number of serious conditions. A careful, systematic, neurologic evaluation helps ensure dangerous processes are not missed. Evaluation of acute ataxia requires neuroimaging to rule out a growing structural lesion such as a posterior fossa tumor. MRI is required for best visualization of the posterior fossa

Muscular Tone and Gait Disturbances

31

structures. Obtaining urine for catecholamine metabolites might be considered to rule out neuroblastoma, which can present with opsoclonus and myoclonus or “dancing eyes, dancing feet.” Urine should also be obtained for toxicology screening (Onders et al., 2015; Monte et al., 2015). Episodic ataxia might be see with inborn errors of metabolism such as Hartnup disease or maple syrup urine disease; therefore, serum amino acid testing might be considered in the appropriate setting. Epileptic seizures may also appear as episodic clumsiness or ataxia, therefore an electroencephalogram (EEG) might be considered as part of the workup. The extensive differential diagnosis of ataxia is found in Chapter 67. Acute cerebellar ataxia of childhood is a diagnosis of exclusion, generally felt to be an autoimmune disorder involving the cerebellum. The patient is usually between 1 and 4 years old with a peak in the second year of life (Connolly et al., 1994). The attacks may be so severe that the patient is bedridden, but more often present with unsteadiness and truncal ataxia. Lumbar puncture usually includes normal opening pressure, mild pleocytosis, and normal glucose and protein, although a slight increase in protein content may be evident after several weeks. There is no standard therapy for acute cerebellar ataxia of childhood. Full recovery without treatment typically occurs within several weeks. Acyclovir does not appear beneficial; although, there are several case reports of using steroids and intravenous immunoglobulin. Long-term neurologic sequelae can occur.

Extrapyramidal Gait Extrapyramidal gait disturbance is identified by decreased automatic movements, rigidity, and bradykinesia. The patient often leans forward, with a subsequent anterior shift of the center of gravity; this results in propulsion or festinating gait. The child may lose control and fall if the steps become more rapid and the center of gravity shifts unduly forward. Characteristically, the affected child may have difficulty with the initial step and may take a few short steps or actually hop and shuffle forward before the walking sequence is established. In addition to the gait difficulties, children with extrapyramidal involvement may have reduced blinking, be devoid of normal facial expression (“mask facies”), and seldom fold their arms or cross their legs.

Other Dyskinetic Gaits A number of other movement disorders cause unusual gait patterns. Athetosis, when profound, may be associated with overall stiffness and bizarre body postures. The walk may have an associated dance-like or prancing appearance and may be incorrectly diagnosed as a form of conversion reaction. Arms, hands, wrists, and fingers frequently move in deliberate, writhing movements about the long axis of the limb and then slowly reverse the rotational movement with irregular pace. Other uncommon gait manifestations may accompany torsion dystonia. The foot may be held in plantar flexion or inversion. Manifestations may fluctuate in intensity; therefore, the clinician should be careful not to diagnose a con­ version reaction. Children with this condition walk better backward than forward, including during the tandem-walk examination. This pattern of walking better backward than forward also may be found in patients who have quadriceps muscle weakness. Chorea may also impair proximal hip muscle and trunk muscle action. The result is a rapidly shifting positioning of

5

32

PART I  Clinical Evaluation

the trunk and body. The head may also move quickly along, with associated grimacing of the facial muscles, choreiform movements of the trunk and limbs, and irregular breathing patterns and sounds.

Steppage Gait Weakness of dorsiflexion of the feet and toes and fixed contracture in plantar flexion result in a steppage gait. The contracture most often accompanies weakness of the peroneal and anterior tibial muscles. To avoid stumbling, the child lifts the foot disproportionately high at the start of each stride. Flexion at the hip and knee is exaggerated, followed by a forward flinging of the foot. The toe precedes the heel or ball of the foot in hitting the ground, emitting the first portion of a split sound.

Hip Weakness Gait Severe weakness of the abductors and extensors of the hip leads to a pathologic “waddling” gait caused when the child walks with a marked lordosis of the thoracolumbar spine with a forward center of gravity to compensate for pelvic instability and a wide-based gait. The pelvis markedly pivots and rotates sharply from side to side as weight shifts. This unusual movement pattern allows balance to be maintained despite hip muscle weakness.

Gait Apraxia Severe frontal lobe disease can result in gait disturbance despite absence of any direct motor or sensory impairment. Although the child may successfully complete certain simple and automatic movements with the legs, he or she is unable to implement more complex activities, such as tracing a circle with the feet, kicking an object, or attempting to walk in a prescribed pattern. The patient may have difficulty initiating the walking process when already standing and have further problems with execution of the serial acts of rising, standing, or walking. Other frontal lobe manifestations, such as dementia and reappearance of primitive grasp reflexes, rooting, and palmomental reflexes, may be present.

Antalgic Gait (Painful Gait) Pain can arise from any leg and foot structure, including nails, skin, joints, bone, and muscles. The associated limp is caused by a decreased weight support on the painful leg and increased duration of weight support on the unaffected leg.

Conversion Disorder Various terms have been used for nonneurologic gait abnormalities such as psychogenic gait disorder, functional gait disorder, hysterical paralysis, and conversion disorder. Presentations are diverse. Characteristic of the gait pattern with conversion disorder is that it may vary from one moment to the next, and there is often a distractible component to the movement disorder. Usually the clinician will find no associated abnormalities of coordination, tone, or strength when the patient is sitting or lying down. Pediatric patients with conversion reaction gait difficulties are almost never malingerers. Rather, they have physical manifestations of underlying psychological disorders and require supportive and empathetic intervention. Confronting the patient and family with a diagnosis that appears to trivialize

their pain and fear is never helpful. Accurate, prompt diagnosis leading to early treatment in a multidisciplinary setting offers the best chance of a successful outcome in pediatric conversion disorders (Schwingenschuh et al., 2008). It is therefore with careful observation and a systematic approach that abnormalities of tone and gait are appropriately addressed. A thoughtful examination can often avoid the need for extensive diagnostic testing, or can identify patients in whom an expedient workup is required because of serious pathology. Addressing such problems requires an understanding of basic neuroanatomy and neurophysiology, as well as possessing the compassion required to calm a nervous child or listen carefully to a worried parent. This is indeed part of the challenge and satisfaction that comes from the practice of child neurology. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bohannon, R.W., Smith, M.B., 1987. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys. Ther. 67 (2), 206–207. Connolly, A.M., Dodson, W.E., Prensky, A.L., et al., 1994. Course and outcome of acute cerebellar ataxia. Ann. Neurol. 35 (6), 673–679. Jethwa, A., Mink, J., Macarthur, C., et al., 2010. Development of the Hypertonia Assessment Tool (HAT): a discriminative tool for hypertonia in children. Dev. Med. Child Neurol. 52 (5), e83–e87. Monte, A.A., Zane, R.D., Heard, K.J., 2015. The implications of marijuana legalization in Colorado. JAMA. 313 (3), 241–242. Onders, B., Casavant, M.J., Spiller, H.A., et al., 2015. Marijuana exposure among children younger than six years in the United States. Clin. Pediatr. (Phila) 0009922815589912. Patrick, E., Ada, L., 2006. The Tardieu Scale differentiates contracture from spasticity whereas the Ashworth Scale is confounded by it. Clin. Rehabil. 20 (2), 173–182. Pyle, A., Smertenko, T., Bargiela, D., et al., 2015. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 138 (2), 276–283. Sanger, T.D., Delgado, M.R., Gaebler-Spira, D., et al., 2003. Classification and definition of disorders causing hypertonia in childhood. Pediatrics. 111 (1), e89–e97. Schwingenschuh, P., Pont-Sunyer, C., Surtees, R., et al., 2008. Psychogenic movement disorders in children: a report of 15 cases and a review of the literature. Mov. Disord. 23 (13), 1882–1888. Sutherland, D.H., Davids, J.R., 1993. Common gait abnormalities of the knee in cerebral palsy. Clin. Orthop. Relat. Res. 288, 139–147.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 5-2 The main components of the muscle spindle. Fig. 5-3 Golgi tendon organs. Fig. 5-6 Graphic representation of the phases of gait and their duration. Fig. 5-7 Graphic representation of the involvement of various muscles during the phases of gait. Table 5-1 Differentiation of Central versus Peripheral Causes of Congenital Hypotonia Table 5-2 Modified Ashworth Scale Box 5-1 Selected Conditions Associated with Hypotonia

6 

Vision Loss Douglas R. Fredrick

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. In children, the complaint of blurred vision or vision loss is often nonspecific and may be difficult to elicit. Although most causes of vision loss in children result from ocular problems, neurologic disorders may have vision loss as a characteristic and early manifesting feature. The ability to determine the cause of vision loss frequently aids in the diagnosis of the underlying neurologic disorder, may help determine prognosis, and can be used to monitor treatment efficacy.

VISUAL DEVELOPMENT Of all the sensory systems, the visual system is perhaps the most immature at birth. Postnatal developmental reorganization of the retina takes place during the first several months of life, with intercellular connections forming between the photoreceptors and inner retinal cells. Myelination of the optic radiations through the temporal, parietal, and occipital lobes occurs in the first year of life. The most dramatic structural reorganization occurs in the striate cortex, where cortical cells responsible for the first stages of visual processing require normal focused visual input to develop in the correct orientation and to achieve maximum visual acuity. As described by Hubel and Wiesel in 1962, visual deprivation occurring in an immature brain causes abnormal formation of the striate cortical cells and decreased synaptic connections and leads to amblyopia. For vision to develop normally, all of the anatomic components of the visual system must be properly formed during development. A structurally intact neurologic substrate must receive properly focused visual information consistently over the first several years of life if normal, maximal visual acuity is to be achieved.

ASSESSMENT AND QUANTIFICATION   OF VISUAL ACUITY Vision Assessment in Infancy At term, healthy infants display a wide range of visual behaviors, with some infants lying awake and alert and tracking faces from the first day of life, whereas others are seemingly disinterested in their visual world for the first several weeks. Most infants can visually fix on a face and follow by 2 months of age. It is possible to assess vision before this time in the office with no special tools or techniques. The most important requisite for assessing visual acuity is that the infant is fully awake (Huo et al., 1999). For infants, light is usually an aversive stimulus, and turning on the lights or shining a light in the eye causes the infant to wince. This response is an indication that the child is experiencing some light stimuli. The best stimulus to elicit visual behavior is the face of a parent or caretaker. Positional changes can also be used to the examiner’s advantage, because an infant who keeps his or her eyes closed often opens the eyes when held in the supine position and rotated gently about the observer. Another method is to grasp the infant under the arms and lift her or him above the observer’s head. The infant

reflexively opens the eyes, allowing the observer to attract the infant’s attention. As most infants fix and follow by 2 months of age, those who do not should be referred to an ophthalmologist. Although fixation behavior allows the clinician to determine whether the infant can see, it does not quantify visual acuity. Two techniques have been devised for this purpose. The visual evoked potential is an electrophysiologic test in which visual stimuli are presented to an alert and focused infant, and the cortical response to the visual stimulus is measured in a repeatable and quantifiable fashion (see Chapter 12) (Fulton et al., 1981). The pattern may be an alternating checkerboard, or horizontally or vertically aligned black-and-white stripes. The size of the stripes or checkerboard is described as cycles per degree or cycles per centimeter, which can be correlated to standard methods of visual or decimal visual acuity. Large targets are initially used to confirm that a cortical signal is recorded by occipitally placed scalp electrodes. The stimulus pattern is then slowly decreased in size until a recordable response can no longer be elicited. A second test used to quantify visual acuity is the forcedchoice preferential looking test (PLT) (see Figure 6-1). Instead of using a cortically recorded electrical response, visual stimuli are presented and the child’s ability to see is determined by the ability to move the eyes toward the visual stimulus. Vertically or horizontally aligned black-and-white stripes are presented to the child on a test card. When given a choice between a pattern background and a homogeneous background, infants instinctively are interested in the pattern background and make an eye movement or saccade toward the black and white stripes. An observer who is watching through a peephole in the middle of the card records in a masked fashion whether he or she sees the infant make the saccade. Limitations of this test include the need for an infant who is not irritable and a trained observer. Both techniques have been validated in older children and are reliable and accurate methods to assess visual acuity. Using these techniques, it can be estimated that a neonate’s visual acuity is approximately 20/2000. By 2 months of age, acuity has improved to 20/200, and by 1 year of age, it is approximately 20/60. By 4 years of age, infants should see 20/25. At this age, more reliable tests of visual acuity can be used.

Vision Assessment in Children Once a child becomes verbal but is still preliterate, matching tests can be used to quantify visual acuity (Figure 6-2). In the past, the tumbling E has been used; the examiner asks the child to show the direction of the letter E as it is presented in numerous different positions. These tests have been replaced by matching games such as HOTV cards and child recognition symbols or Lea symbols that ask a child to match test optotypes that are presented in progressively smaller sizes (Figure 6-2). These tests have been validated and are consistent with Snellen visual acuity, which is the gold standard for measurement of visual acuity in children and adults. Snellen visual

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PART I  Clinical Evaluation

acuity can be recorded in numerous forms using notations such as 20/20, decimal notation, or logmar notation, a method of quantification that allows more useful statistical analysis when conducting studies of visual acuity in children and adults.

ASSESSMENT OF COLOR VISION Assessment of color vision can be useful in determining the cause of vision loss. Optic nerve injury often causes decreased color vision as its first presenting sign, even before distance visual acuity or the size of the visual field has been affected. The most useful tests for this purpose are the Hardy-RandRittler (HRR) test plates and the Ishihara color plates. The combination of these techniques can separate those children who simply have red–green color deficiency from those with impaired color vision caused by optic nerve injury.

ASSESSMENT OF VISUAL FIELDS It is not possible to quantify small visual-field deficits in young children. It is possible to diagnose significant hemianopias in small infants using a two-person examination technique. With this technique, one examiner sits in front of the child, maintaining fixation through use of a toy or verbal stimulus. A second tester stands behind the child and introduces a toy or colored object silently in the periphery of the child’s vision. When the child sees the toy, he or she generates a saccade or a head movement toward the toy. In this fashion, hemianopias can be detected, aiding in the diagnosis of underlying neurologic problems and determining rehabilitation strategies for children with vision impairment associated with neurologic disease. Older patients can be tested with kinetic perimetry using the Goldmann perimeter or automated visual fields. These tests are particularly useful for patients who are being monitored for visual-field changes associated with benign intracranial hypertension, low-grade gliomas, or midline tumors that, before treatment, may induce ocular or central nervous system (CNS) injury.

ASSESSMENT OF OCULAR MOTILITY Assessment of ocular motility allows the examiner to assess function of cranial nerves III, IV, and VI (see Chapters 2–4). Ductions and versions can be tested using brightly colored toys and objects. It is important to check the child binocularly first before patching the infant’s eye because patching may be distracting and preclude acquiring useful information. Alignment should be checked using the alternate cover test where fixation is maintained and the visual axis of each eye is occluded alternately. Refixation of the eyes during alternate occlusion may indicate the presence of strabismus such as esotropia, exotropia, or hypertropia (Figure 6-3).

Assessment of Optic Nerve and Retinal Nerve Fiber Layer Integrity Assessment of the health of the optic nerve is an essential task when evaluating a child with vision loss. Either the direct ophthalmoscope or the indirect ophthalmoscope can be used, and when examining a cooperative child through a dilated pupil, this can be simple. However, when examining an unhappy infant with nystagmus and an undilated pupil, this can be a challenge even for experienced ophthalmologists, let alone the pediatric neurologist. The color, contour, and clarity of the peripapillary vessels should be evaluated. If the nerve is pale and flat, that may indicate optic atrophy; if the optic

cup is enlarged, that may indicate glaucoma or transynaptic degeneration; if the nerve is elevated and disc margins are blurred, that may indicate papilledema or nerve head drusen. In the past, the description of the nerve was qualitative, or could be documented by photographs, which could be compared in a longitudinal serial fashion. In recent years, spectral domain ocular coherence tomography (sd-OCT) has been used to objectively quantify the contour of the optic nerve and the thickness of the retinal nerve fiber layer (Avery et al., 2015). This technology will be standard of care for following children with demyelinating disorders and children with compressive optic neuropathy and degenerative neurometabolic disorders.

CLINICAL FEATURES ASSOCIATED   WITH VISION LOSS The three features that must be characterized in assessing vision loss are laterality of vision impairment, temporal nature of vision loss, and associated ocular and neurologic abnormalities. Children with unilateral vision loss are frequently asymptomatic. When a child does realize that there is unilateral decreased visual acuity, it is usually because of the sudden discovery of this problem rather than its sudden onset. Mild degrees of vision loss are not usually recognized by the child but are detected by a teacher or healthcare provider at the time of a vision-screening examination. The rapidity of onset of the vision loss also depends on whether the loss is unilateral or bilateral; long-standing unilateral vision loss may not be noticed until the unaffected eye is covered. In contrast, bilateral sudden vision impairment, as can occur with compressive or rapidly demyelinating lesions, may be noticed by the child or caretaker immediately. Associated neurologic signs and symptoms often allow the clinician to localize the disease process before neuroimaging and help the neuroradiologist determine the best type of study to perform. Because symptoms are inconsistently reported, clinicians must be familiar with the physical signs of unilateral vision loss. During the newborn’s physical examination, pediatricians must look for the presence of a red pupillary reflex in each eye. The presence of a white pupil is called leukocoria, and it is associated with poorly developed vision in one or both affected eyes in the infant (Figure 6-4). The causes of leukocoria are variable, and at a minimum, the condition can cause loss of vision; in more serious situations, leukocoria can be associated with life-threatening conditions such as retinoblastoma. Poor vision in one eye from birth often leads to strabismus that is noticed by the caretaker. Nystagmus is common when there is decreased visual acuity in one or both eyes resulting from a structural anomaly or to a functional deficit preventing visual information from being transmitted from the eye to the cortex. In an infant, bilateral vision loss is manifested by strabismus or nystagmus and visual inattention with poor fixation after 2 months of age. Older children with mild vision loss are usually asymptomatic and their problems are not detected until vision is screened by their pediatrician or family practitioner. Children who have progressive loss of visual acuity exhibit behaviors such as sitting extremely close to the television, being disinterested in distant objects or activities, and having difficulty with tasks that require fine visual acuity. Associated ocular features of vision loss are important to confirm. Infants with poor vision often develop nystagmus by 2 months of age. They are visually inattentive and do not fix and follow well by this age, and they frequently manifest strabismus or a “wandering eye.” Older children usually do not complain of vision problems but have strabismus. They



often close one eye or squint the eye in different lighting conditions, rub their eyes frequently, and occasionally complain of double vision when strabismus occurs suddenly. Children with significant vision loss have disrupted circadian rhythms and disturbed sleep–wake cycles. Other associated neurologic symptoms include headache, nausea, and vomiting.

EXAMINATION OF CHILDREN WITH VISION LOSS It is the role of the neurologist or the primary care physician to document decreased visual acuity in children who are suspected of having vision loss or found to have vision loss during a screening examination. Infants should have their visual acuity assessed by their fixation behavior. Extraocular movements should be tested to evaluate cranial nerve function, and pupils should be tested to determine the response to light and presence or absence of an afferent pupillary defect. A direct ophthalmoscope should be used to check for a red reflex, because absence of the red reflex indicates a corneal or lenticular opacity or an intraocular tumor such as retinoblastoma. If the patient has any of these abnormalities, she or he should be seen by an ophthalmologist to assess for structural abnormalities and to recommend additional diagnostic tests. Older children can have their acuity assessed as described earlier. They should have a full motility examination, and an attempt should be made to examine the fundus. The neurologist should feel comfortable using dilating eye drops such as tropicamide. This procedure facilitates examination of the optic nerve head and macula. Any child with abnormal visual acuity, motility, pupillary reflexes, or retinal examination should be referred to an ophthalmologist for further examination.

VISION LOSS IN INFANTS Clinical Manifestations Whereas most adults and older children with neurologic disease involving the visual pathways have alterations in visual acuity or visual function, infants usually have problems resulting from failure of vision to develop normally after birth. Parents are concerned that their children fail to use their vision appropriately or never develop normal visual fixation behaviors. These children have no symptoms because they cannot articulate their complaints, but they manifest many signs that can be useful in diagnosing and localizing the cause of the decreased visual acuity. Signs of decreased visual acuity in an infant include failure to fix and follow an object by 2 months of age or visual inattention manifested by the complaint that the infant looks through the caretaker or indirectly at the caretaker’s face. Strabismus is another common complaint in children and infants who have poor visual acuity. Strabismus early in life is not rare. Up to 30% of infants manifest intermittent deviations in the first 2 months of life, with exotropia occurring more commonly than esotropia. The deviation is usually intermittent and decreases in frequency over the first few months of life. Any child who has a strabismus lasting longer than a few months should be assessed for an underlying ocular anomaly. Nystagmus is commonly seen in children who have bilateral structural anomalies, leading to abnormal visual development. Nystagmus rarely exists at birth. At birth, there may be other movements such as ocular flutter, square wave jerks, or saccadic intrusions that are short-lived and become infrequent over time. In contrast, when a child has a structural anomaly such as bilateral optic nerve hypoplasia, lack of visual stimulation of the striate cortex leads to a sensory nystagmus. The

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amplitude of the nystagmus can be quite large between the ages of 2 and 6 months, with the amplitude decreasing and the frequency increasing with time. Infants with visual problems also often demonstrate behavioral mannerisms that help suggest the cause of the vision loss. Children with retinal dysfunction from congenital dysfunction of the photoreceptors or from retinopathy of prematurity often press their eyes to generate some sort of photic stimulation. Children with cortical visual impairment may demonstrate overlooking behavior, an eccentric fixation, to maximize visual function in the visual fields that are least damaged from the underlying cortical injury. Patients with achromatopsia or congenital glaucoma may be quite photosensitive and demonstrate behaviors to shield their eyes from the light to minimize the dysphoric sensation they receive from visual stimulation.

Differential Diagnosis of Vision Loss in Infants As with every physical sign and symptom, the history and general physical examination often determine the diagnosis, even before ophthalmologic and neurologic examination. If vision loss is suspected by the pediatrician or family practitioner, the child should be seen by an ophthalmologist before being referred to a neurologist. Most infants with vision loss have underlying ocular anomalies that can be diagnosed and obviate the need for expensive neuroimaging or genetic and metabolic testing. The ophthalmologist can direct the neurologist and geneticist toward the most likely diagnosis to minimize the inconvenience, cost, and morbidity associated with diagnostic evaluation in children with vision loss resulting from neurologic disease.

Structural Anomalies Retinopathy of Prematurity.  Retinopathy of prematurity remains a common cause of vision impairment in infants, causing blindness in more than 500 infants each year in the United States. These patients develop cicatricial changes in the retina leading to vision impairment. Premature infants who do not develop retinopathy of prematurity are still at risk for cerebral vision impairment because of periventricular leukomalacia. Prematurity is the most common cause of pediatric vision impairment in developed countries and the vision loss can be caused by damage to the retina or injury to gray or white matter involving the visual pathways (Dutton and Jacobson, 2001). Children with periventricular leukomalacia can sometimes have enlargement of the optic cup, mimicking glaucoma, but representing loss of nerve fiber layer because of transynaptic degeneration. Congenital Cataracts.  All infants should be screened for cataracts at birth by their pediatrician or family practitioner. The presence of a clear red reflex makes it unlikely that cataracts are present. An abnormal red reflex should prompt ophthalmologic evaluation to determine the location of the optical opacity. Treatment involves prompt recognition, removal of visually significant cataracts, and visual rehabilitation with intraocular lens implantation, extended-wear soft contact lenses, or aphakic spectacles. Corneal Opacity.  Corneal opacities usually are easily detected by pediatricians or parents at birth when a white spot, or leukoma, is detected within the cornea (see Figure 6-5). These opacities are associated with other structural anomalies, such as microphthalmos, or small eye, and anterior segment dysgenesis, which may also be associated with glaucoma or birth trauma. These corneal opacities can cause significant vision

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impairment and are difficult to correct, because the success rate of corneal transplantation is poor in infants. Ocular Coloboma.  Coloboma, or absence of tissue, can affect vision profoundly. If the coloboma involves the iris but not deeper tissues, visual acuity can be normal (Figure 6-6). However, when the coloboma involves the central retina, macula, or the optic nerve, vision can be severely impaired. Children with bilateral colobomata are at high risk for underlying neurologic problems. Any child with bilateral colobomata should be evaluated for chromosomal trisomies and the CHARGE association (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies). Aicardi syndrome should be considered in any female with a seizure disorder and ocular colobomata (Figure 6-7). Patients with Aicardi syndrome have ectopic gray matter and other CNS malformations; the disorder is X-linked and lethal for males. Coloboma of the optic nerve can also be associated with underlying renal disease, known as the papillorenal syndrome; this diagnosis is made by genetic testing for mutations in the PAX6 gene. Retinal Dysplasia.  Structural anomalies of the retina not associated with retinopathy of prematurity can lead to significant vision impairment. These forms of retinal dysplasia are frequently associated with a variety of neurologic malformations. An example is Walker–Warburg syndrome, in which congenital retinal dysplasia is associated with cerebral structural abnormalities such as hydrocephalus, agyria, and occasionally encephalocele (see Chapters 25–30) (Liu, 2001). Muscle–eye–brain disease is another example of neurologic and retinal dysplasia resulting from abnormal glial development caused by defective glycosylation of α-dystroglycan. This results in profound CNS involvement and significant vision loss. Norrie disease is an X-linked condition in which retinal dysplasia is associated with mental retardation and deafness. Optic Nerve Hypoplasia.  Failure of the optic nerves to form properly leads to a small dysfunctional optic nerve. In optic nerve hypoplasia, the nerve is small and its morphology abnormal (Figure 6-8). Frequently, there is a double-ring sign; the scleral canal of the optic nerve is present, but the optic nerve tissues comprise only a small portion of the canal, leading to two distinct rings. Children with optic nerve hypoplasia frequently have nystagmus. Children with optic nerve hypoplasia may have de Morsier syndrome, or septo-optic dysplasia, characterized by midline structural defects of the CNS (e.g., absence of the septum pellucidum and agenesis of the corpus callosum) in addition to neuroendocrine dysfunction (see Chapter 97). All children with optic nerve hypoplasia should undergo neuroimaging, with particular attention to the septum pellucidum, corpus callosum, and pituitary body. The presence of an ectopic bright spot places the child at higher risk for neuroendocrine dysfunction. The absence of cerebral developmental anomalies does not mean that endocrine abnormalities will not occur, and children require continued endocrinologic follow-up. There have been numerous cases of sudden death associated with septo-optic dysplasia, in which affected children develop a febrile illness that leads to rapid decompensation and death as a result of adrenal insufficiency. Parents should be advised concerning these potential risks and treat all illnesses seriously. Ocular or Oculocutaneous Albinism.  Normal pigment formation is essential for normal ocular development and normal function of the retinal pigment epithelium. Albinism may involve the eye and skin (oculocutaneous albinism), or only the eye (ocular albinism); both forms are associated with decreased visual acuity. Patients with oculocutaneous albinism are more severely affected, with visual acuity in the

20/200 range, whereas those with ocular albinism have acuity in the range of 20/60 to 20/80. Both conditions manifest with nystagmus early in life. The diagnosis of ocular albinism is made by documenting transillumination defects in the iris during slit-lamp examination. This test can be performed in infants, and it obviates the need for further evaluation. Leber Congenital Amaurosis.  Leber congenital amaurosis is a disorder of the photoreceptors and the retinal pigment epithelium in which photoreceptor function is extinguished. Infants have large-amplitude, slow-frequency, roving nystagmus. They frequently begin to press on their eyes by 2 to 3 months of age, and they may have a completely normal ophthalmoscopic examination with normal-appearing optic nerve and retina. The diagnosis is established by electroretinography. In this test, the electrical amplitude of the retina is measured using a contact lens placed on the eye that is stimulated by bright lights to elicit a cone response and dim lights to stimulate a rod response (Figure 6-9). In congenital amaurosis, both rod and cone responses are extinguished.

Vision Loss Caused by Cortical Visual Impairment In developed countries, decreased vision caused by cortical or cerebral visual impairment is the leading cause of vision impairment in infants. Damage to the visually immature brain impedes normal visual development and leads to lifelong subnormal vision. The most common causes of cortical visual impairment in developed countries are neonatal encephalopathies (see Chapter 17). The second most common cause of cortical visual impairment is periventricular leukomalacia (see Chapter 19). Injury and ischemia lead to damage in the periventricular white matter and frequently affect visual development. Clinical features of cortical visual impairment are those of an infant who fails to develop visual fixation behavior after 2 to 3 months of age. These children are often neurologically impaired and have delayed motor milestones and abnormal findings for the neurologic examination. Magnetic resonance imaging (MRI) in affected children usually provides evidence of leukoencephalopathy. Infants with cortical visual impairment do not fix or follow, and appear to be visually disinterested in the environment. Infants commonly demonstrate off and on visual behavior, during which there are moments of what appears to be normal visual fixation interspersed with longer periods of visual inattention. Infants respond well to high-contrast targets such as black-and-white toys and large pattern images. Children with profound cortical visual impairment early in infancy can demonstrate a progressive increase in visual function over several years and may become quite visually proficient. It is important to refer children with cortical visual impairment for low-vision services that can provide sensory stimulation exercises, which improve the visual performance of infants and provide emotional, social, and educational support for parents.

Structural Cerebral Anomalies Causing Cortical Visual Impairment Hydrocephalus.  Ophthalmic signs of hydrocephalus and increased intracranial pressure include the setting sun sign, which describes the infant’s gaze held in a downward fixed position, with the eyelids retracted and the infant unable to elevate the eyes willfully. Because the cranial sutures are not closed, papilledema usually does not occur early in infancy. After the cranial vault is closed, papilledema can occur as with any child with increased intracranial pressure (see Chapter 77). Children with hydrocephalus require surgical relief of their obstruction by ventriculostomy or ventriculoperitoneal



shunt placement. An ophthalmologic examination should be obtained to document the presence of normal optic nerves or the absence of optic atrophy. Many older children with chronic hydrocephalus have optic atrophy that precludes future useful information about the presence of intracranial pressure because atrophic optic nerves do not swell and cannot reflect increased intracranial pressure. Other ocular signs of increased intracranial pressure include cranial nerve VI paresis, often manifesting as new-onset esotropia. Structural Brain Anomalies.  Children with schizencephaly frequently have decreased visual acuity as a result of damage to the optic radiations and pathways. Contralateral hemianopias and epilepsy are common clinical manifestations. Visual function in children with large schizencephalic clefts, as well as those with porencephaly or hydrocephalus, may improve despite a very abnormal appearance on neuroimaging once the patient is shunted and the cortex re-expands. There are numerous congenital disorders associated with brain malformations, such as the Walker–Warburg syndrome, Dandy–Walker syndrome, and muscle–eye–brain disease, in which structural brain anomalies (see Chapters 22–27) are accompanied by decreased visual function because of striate cortex involvement or associated ocular anomalies such as retinal dysplasia. Vision Loss Caused by Epilepsy.  Children with epilepsy frequently have poor visual function. When the seizure disorder results from a structural abnormality, there is often concomitant strabismus, nystagmus, and developmental delay. Patients with seizures may develop visual auras before the seizure (see Chapter 54), and functional blindness during the postictal period. Children with frequent seizures throughout the day often have poor visual fixation development. The use of antiepileptic drugs may sedate the child to the point where general development is delayed, and this can affect development of visual acuity. Optimizing antiepileptic drug therapy should be encouraged, because visual acuity can markedly improve when seizures are well controlled. Certain antiepileptic drugs such as vigabatrin may be associated with specific retinal or ophthalmic abnormalities (see Chapter 59). Delayed Visual Maturation.  Occasionally, a healthy infant older than 2 months is referred because of failure of development of visual fixation behaviors. Results of ophthalmologic and neurologic examinations may be completely normal. Such infants may have the condition of delayed visual maturation, a diagnosis of exclusion in which visual development is delayed but eventually becomes normal. Often, the onset of visual fixation is dramatic and usually occurs by 6 months of age.

Diagnostic Evaluation of Infants with   Poor Vision An infant who fails to develop visual fixation should first be referred to an ophthalmologist. Examination by an ophthalmologist most often uncovers the causes of decreased vision, which may be caused by any of the congenital structural anomalies described previously. If examination findings are completely normal, the next considerations are a neurologic examination and possibly neuroimaging.. Neurometabolic testing should be performed to exclude reversible and potentially treatable inborn errors of metabolism involving carbohydrate or urea cycle metabolism or mitochondrial disorders. These conditions are described in detail in various chapters in this textbook. In an infant with poor visual function but normal neurologic examination results and normal neuroimaging findings,

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electroretinography may be used to determine the presence of photoreceptor dysfunction. Such patients usually demonstrate signs of retinal disease, including nystagmus and eye-pressing behavior. Depending on the response to different light stimuli, determination can be made whether there is rod-related (affecting night vision) or cone-related dysfunction that affects central vision or color, or both (Figure 6-9).

VISION LOSS IN CHILDREN The disease processes leading to vision loss in children are quite different from those affecting infants. Children often demonstrate different signs of vision loss and are frequently able to complain of symptoms associated with vision loss, thus aiding in the evaluation and guiding diagnostic strategies.

Symptoms and Signs of Vision Loss Children with vision loss frequently do not complain about vision loss unless it is bilateral. Children often do not use the term blurred vision, but may say, “I can’t see,” “things are fuzzy,” or “things are double.” Signs of vision loss are much more helpful. When the child squints and closes the eyelids, the pinhole effect helps focus out-of-focus light. This behavior is common in children with refractive errors. Those with acute bilateral loss of vision will sit close to the television or become disinterested in activities occurring at a distance. They may hold objects very close to their faces to see them clearly. Children with new-onset strabismus associated with vision loss frequently close one eye to avoid diplopia. They may be sensitive to sunlight and shield their eyes because bright light may markedly decrease their visual acuity, especially when there is associated retinal dysfunction. Children may also tilt their heads when vision is reduced in one eye.

Differential Diagnosis of Vision Loss in Children Refractive errors are the most common cause of vision loss in children. This form of vision loss is usually detected by a pediatrician, who does a vision screening examination in the office, or by the school district that mandates vision checks in kindergarten or first grade. Vision loss may be unilateral or bilateral. When vision loss is caused by refractive error, correcting the refractive error yields 20/20 vision in each eye.

Amblyopia Amblyopia is a functional and structural condition wherein an abnormal visual stimulus leads to abnormal development of cortical visual processing cells with smaller cell size and abnormal intercellular connections. Amblyopia results from early visual deprivation, strabismus, or unequal refractive errors. These structural changes are reversible if detected early in life and treated with occlusion therapy. By removing the visual impairment, straightening the eye, or focusing the vision through spectacles, and then patching the unaffected eye to stimulate the immature visual system, amblyopia can be reversed. Whether or not vision can be restored depends on the age of detection. As a rule, most children with amblyopia should be detected and treated by the age of 6 months for the best visual prognosis.

Ocular Anomalies Causing Vision Loss In an infant with vision loss, it is helpful to approach the eye systematically from an external to an internal point to evaluate for causes of vision impairment.

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Eyelid Abnormalities: Ptosis.  Ptosis can be a cause of vision loss and a localizing sign of underlying impairment. It may be so profound that it occludes the visual axis, leading to deprivation amblyopia. The eyelid may rest over the cornea and be associated with significant astigmatism that can lead to anisometropic amblyopia. Other forms of congenital ptosis include congenital third nerve palsy and the congenital fibrosis syndrome, which are associated with abnormalities of all extraocular muscles with very abnormal eye movements. Neurologic causes of ptosis in children include infant botulism, congenital Horner syndrome (associated with congenital neuroblastoma), or Marcus Gunn jaw wink syndrome, a synkinesis with eyelid bobbing occurring during masseter muscle function and chewing as a result of synkinesis of cranial nerves V and III. Corneal Anomalies.  Although most corneal anomalies are structural anomalies seen in infants, such as Peters syndrome or scleralization of the cornea, acquired corneal dystrophies and degenerations can lead to vision loss. Some metabolic diseases manifest with corneal changes leading to vision loss. These include the mucopolysaccharidoses such as Hurler syndrome, which is associated with corneal clouding, and Fabry disease, which can lead to deposition of material in the cornea, decreasing visual acuity. Anomalies of the Retina.  Degenerative diseases of the retina can cause gradual loss of visual acuity and may be extremely difficult to diagnose in young children (Table 6-1).

Unlike congenital retinal dysfunction that leads to largeamplitude nystagmus, marked vision impairment, and clearcut electroretinographic findings, retinal degeneration in older children may be insidious in onset, unaccompanied by significant visual symptoms and with equivocal findings on electroretinography. One of the most common causes of visual dysfunction resulting from retinal dysfunction is Stargardt disease, also known as fundus flavimaculatus. This disease is a degenerative condition of the retinal pigment epithelium leading to photoreceptor dysfunction. Children have slowly decreasing visual acuity. There are characteristic changes on funduscopic examination, and diagnostic tests such as fluorescein angiography, visual-field testing, and electroretinography can help confirm the diagnosis (Figure 6-10). Retinitis Pigmentosa.  In retinitis pigmentosa, abnormalities of the retinal pigment epithelium can lead to photoreceptor dysfunction and death. Retinitis pigmentosa typically affects rods before affecting cones. This process leads to initial symptoms of night blindness and constriction of the peripheral visual field, eventually affecting cones and central visual acuity. A typical bone spicule pattern of the retinal pigment epithelium is diagnostic. Electrodiagnostic tests, such as electroretinography, may be helpful. Retinitis pigmentosa has been characterized as involving rods or cones, or both. All modes of inheritance patterns have been described, and there may be variations of phenotypic expression within families.

TABLE 6-1  Neurologic Disease Associated with Vision Loss and Retinal Abnormalities Condition

Cherry-Red Spot

Neuronal ceroid lipofuscinosis

Macular Dystrophy

Pigmentary Changes

+

+

Abetalipoproteinemia

+

Refsum disease

+

Cockayne syndrome

+

Bardet–Biedl syndrome

+

Kearns–Sayre syndrome

+

Hallervorden–Spatz syndrome

+

Aicardi syndrome

+

Alström syndrome

+

Gangliosidoses   Tay–Sachs disease   Sandhoff disease

+ +

Mucopolysaccharidoses   Hunter syndrome   Hurler syndrome   Sanfilippo syndrome   Scheie syndrome   Zellweger syndrome

+ + + + +

Friedreich ataxia Niemann–Pick disease

+

Sialidosis

+

Farber syndrome

+

Metachromatic leukodystrophy

+

Spinocerebellar ataxia Gaucher disease Adrenoleukodystrophy +, Positive association.

+

+

+

+

+ +



Neurometabolic Retinal Dysfunction.  Several neurometabolic disorders have been associated with retinal dysfunction and secondary vision loss. In neuronal ceroid lipofuscinosis, abnormal accumulation of neurotoxic products within the retina leads to cell dysfunction and death (see Chapter 41). There are multiple forms of neuronal ceroid lipofuscinosis occurring in different age groups. Characteristic of all forms of neuronal ceroid lipofuscinosis is the development of decreased visual acuity resulting from poor retinal function. Degeneration of the ganglion cell layer results in a typical funduscopic appearance, and ophthalmoscopic examination coupled with electrophysiologic testing can help diagnose these children who have seizures and progressive loss of milestones (Figure 6-10). Retinal dysfunction occurs in inherited mitochondrial cytopathies such as Kearns–Sayre syndrome, in which a pigmentary retinopathy is associated with decreased visual acuity, external ophthalmoplegia, and cardiac conduction defects.

Optic Nerve Disorders Papilledema.  The presence of increased intracranial pressure leads to edema of the optic nerve (i.e., papilledema). The borders of the optic nerve are indistinct and the vessels are swollen; the nerve itself is elevated, with surrounding hemorrhage or exudates (Figure 6-11). Papilledema in children can be caused by obstruction of the ventricular system, craniosynostosis, or communicating hydrocephalus. Whereas early papilledema in adults rarely causes visual symptoms, papilledema can be chronic in children, with slow onset and relatively late discovery of disease, and decreased visual acuity can be a presenting complaint. Usually, this does not occur unless the increase in intracranial pressure is rapid and significant in onset or has been of long duration, leading to chronic axonal compression and edema formation in the retina and causing decreased visual acuity or cell death and incipient optic atrophy. For papilledema in children, mandatory neuroimaging should be followed by lumbar puncture. Pseudotumor cerebri or benign intracranial hypertension is not an infrequent cause of papilledema in overweight children. The diagnosis is made after neuroimaging excludes an obstructive lesion and lumbar puncture reveals increased intracranial pressure and no abnormal cytology. Occasionally, pseudotumor cerebri may be associated with sinovenous thrombosis that can be detected with magnetic resonance venography (MRV). Because many drugs can cause benign intracranial hypertension, the treatment is withdrawal of inciting agents such as tetracycline and its derivatives, and vitamin A analogs. Visual dysfunction associated with possible secondary ischemic optic neuropathic changes should prompt consideration for optic nerve sheath fenestration or lumbar or ventriculoperitoneal shunting to relieve pressure to prevent permanent loss of visual acuity. Pseudopapilledema.  In pseudopapilledema, the optic nerve appears to be elevated, but there is a lack of edema surrounding the nerve, which is seen with true papilledema (Figure 6-12). Pseudopapilledema can be seen with optic nerve head drusen. Optic nerve drusen are extracellular deposits of material within the nerve fiber layer that cause a lumpy elevation of the optic nerve. Later in childhood, the material develops a glistening calcific appearance and can be easily detected by autofluorescence angiography or by ultrasonography. In earlier stages of the disease, the bright signal intensity and reflective characteristics are not as evident, making the diagnosis one of exclusion considered only after lumbar puncture and neuroimaging have eliminated more dangerous conditions. The absence of hemorrhages and of blurred

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disc margins suggests that pseudopapilledema is more likely to be present. Serial examinations and documentation by photography can help differentiate true papilledema from pseudopapilledema. Optic Neuritis.  Whereas adults with optic neuritis usually have unilateral disease, bilateral presentation is more common in children. Children rarely complain of decreased vision in one eye. Optic neuritis in children frequently follows viral illnesses; it is most commonly associated with inflammation and swelling of the optic nerve head, and may be accompanied by vasculitis (Figure 6-13). In children, there is usually edema of the optic nerve associated with loss of vision and an afferent pupillary defect, whereas in adults, most cases of optic neuropathy are retrobulbar with no visible changes on ophthalmoscopy. Any demyelinating episode may be the first sign of multiple sclerosis, and the risk of a pediatric patient eventually developing multiple sclerosis varies from 7% to 56% (Waldman et al., 2011). Children who have white matter changes on neuroimaging have a higher risk of developing multiple sclerosis and require close observation so that use of interferons may be considered. A particular form of optic neuritis that occurs more frequently in children than in adults is acute disseminated encephalomyelitis (ADEM), as described in Chapter 72. Neuromyelitis optica, or Devic disease, is a rare but debilitating form of optic neuritis that occurs in association with transverse myelitis; diagnosis is made by serologic detection of aquaporin-4 autoimmunity (NMOIgG), a test that should be performed on all children with optic neuritis. Optic Atrophy.  In children, optic atrophy is often not diagnosed until both eyes are affected (Table 6-2). The most worrisome cause of optic atrophy is compressive disease of the optic nerve. Atrophy may occur from increased intracranial pressure caused by obstructive intracranial lesions, or from compression of the optic nerve from orbital processes or intrinsic tumors of the optic nerve (e.g., optic nerve gliomas). Children with optic atrophy should undergo neuroimaging to establish a specific diagnosis. Children with neurofibro­ matosis type 1 and optic gliomas require close ophthalmic monitoring, as these tumors may demonstrate spontaneous regression, and treatment should be considered only if there is documented progressive loss of visual acuity or peripheral visual field. When neuroimaging fails to demonstrate compressive lesions, hereditary optic atrophy should be considered. Kjer optic atrophy is transmitted in an autosomal-dominant pattern; it presents with slow onset of visual acuity loss, first in a 20/80 to 20/100 range and then stabilizing in the 20/400 range. Wolfram syndrome includes optic atrophy as one of its clinical features (i.e., diabetes insipidus, diabetes mellitus, optic atrophy deafness [DIDMOAD]), and this autosomalrecessive condition maps to WFS1 on chromosome 4p. Neurometabolic diseases may cause optic atrophy and are usually diagnosed by the constellation of neurologic and physical findings associated with the disease. Ischemic optic neuropathy has been described in children with underlying renal insufficiency in which the patient develops sudden changes in blood pressure because of illness or blood loss. Other disorders that can lead to optic atrophy are the mitochondrial encephalopathies (see Chapter 37). Patients with maternally transmitted Leber hereditary optic neuropathy have loss of visual acuity in the second decade of life. This is associated with characteristic unilateral changes in the optic nerve head and telangiectatic changes in the optic nerve head vessels. There have been numerous genetic polymorphisms described in patients with Leber optic atrophy, and molecular DNA testing is available. Included in this group of

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TABLE 6-2  Neurologic Disease Associated with Vision Loss and Optic Atrophy Category

Disease or Syndrome

Category

Disease or Syndrome

Developmental anomalies

Optic nerve hypoplasia   Septo-optic dysplasia or de Morsier syndrome Prenatal or perinatal ischemia   Infarction   Periventricular leukomalacia   White matter disease of prematurity Cerebral structural anomalies   Hydrocephalus   Schizencephaly   Walker–Warburg syndrome   Encephalocele   Holoprosencephaly

Inflammatory conditions

Sarcoidosis Systemic lupus erythematosus Sjögren syndrome Collagen–vascular disease Autoimmune disorders Postvaccination inflammatory reaction

Ischemic conditions

Renal disease Sickle cell disease Moyamoya disease

Trauma

Direct Indirect

Leukodystrophies   Adrenoleukodystrophy   Krabbe leukodystrophy   Pelizaeus–Merzbacher disease   Alexander disease   Canavan disease   Leigh disease Lysosomal disorders   Gangliosidoses GM1 and GM2   Mucopolysaccharidoses   Niemann–Pick disease Ataxias   Friedreich ataxia   Charcot–Marie–Tooth disease Miscellaneous conditions   Neuronal ceroid lipofuscinosis   Wolfram syndrome   Zellweger syndrome

Demyelinating conditions

Optic neuritis Acute disseminated encephalomyelopathy Multiple sclerosis Leigh disease Aquaporin channelopathies

Compressive conditions

Pituitary tumor Hypothalamic tumor Craniopharyngioma Optic nerve glioma Optic nerve meningioma Rhabdomyosarcoma Papilledema Idiopathic intracranial hypertension Craniosynostosis or craniofacial dysostosis Germinoma Primitive neuroectodermal tumor

Hereditary conditions

Kjer optic atrophy Leber congenital amaurosis Mitochondrial cytopathies Congenital disorders of glycosolation Leber hereditary optic neuropathy

Toxicities

Lead Copper Streptomycin Hydroxyquinolones Methanol Ethambutol

Degenerative disease

Infectious diseases

Lyme disease—Borrelia burgdorferi Cat-scratch disease—Bartonella henselae Syphilis Tuberculosis West Nile virus Epstein-Barr virus Cryptococcus Human immunodeficiency virus (HIV)

disorders is Kearns–Sayre syndrome, mitochondrial encephalomyopathy with lactic acidosis and strokelike syndrome (MELAS), and myoclonic epilepsy with ragged red fiber disease (MERRF) (see Chapter 37).

Cerebral Vision Impairment Whereas cerebral vision impairment in infants results from ischemic encephalopathy or white matter disease, impairment in older children usually is traumatic in nature. An ischemic episode such as a near-drowning, meningitis, or stroke can also cause cortical vision impairment. Toxic cortical blindness can be caused by vincristine, cyclosporine, and tacrolimus. Visual acuity can be profoundly affected and show slow, progressive improvement over 1 to 2 years. The diagnosis is made by a combination of history, neuroimaging, and normal ocular examination findings.

NYSTAGMUS IN INFANCY Like the visual system, the ocular motor system is immature at birth. Abnormal eye movement such as ocular flutter, bobbing, saccadic intrusions, or saccadic paresis may be

transient in the first few weeks of life, but they usually resolve completely. Nystagmus, or oscillation of the eyes in a stereotypic fashion, is rarely seen at birth but usually develops by 2 months of age. There are three primary causes of nystagmus in infancy—problem with the eyes, problem with the brain, or infantile nystagmus—each having different visual consequences and health considerations (Papageorgiou et al., 2014). The presence of nystagmus can make assessment of visual function difficult, as normal fixation responses will be abnormal. All infants and children with nystagmus without a previous neurologic diagnosis should be seen by an ophthalmologist to determine whether there is an ocular cause for the abnormal eye movements (Table 6-3).

TRANSIENT EPISODIC VISION LOSS   IN CHILDREN To hear a child complain about occasional abnormal vision is not a rare phenomenon. School-aged children frequently complain about blurred vision after prolonged distance or near-visual tasks such as reading, taking tests, or taking notes from the white board. These symptoms are usually brief and



Vision Loss TABLE 6-3  Causes of Bilateral Infantile Vision Impairment Manifesting with Nystagmus by Age 2 Months Category

Cause of Impairment

Disorders of corneal clarity

Developmental anomalies Peters syndrome Rieger syndrome Sclerocornea Congenital glaucoma Forceps birth trauma

Crystalline lens opacity

Congenital cataract

Uveal anomalies

Aniridia Oculocutaneous or ocular albinism

Vitreous anomalies

Vitreous hemorrhage Persistent hyperplastic primary vitreous

Retinal anomalies

Leber congenital amaurosis Achromatopsia or monochromatopsia Retinopathy of prematurity Retinal dysplasia Chorioretinal scarring Congenital toxoplasmosis Chorioretinal coloboma

Optic nerve anomalies

Optic nerve hypoplasia Optic nerve atrophy Optic nerve coloboma Morning glory disc

41

resolve after a short period of rest. Complaints of more profound transient and episodic visual loss or blindness should make the clinician consider three causes: intracranial hypertension, migraine, and functional vision loss. Increased intracranial pressure can cause transient obscuration of vision, especially when children change position from supine to standing. They may also complain of positive scotoma and “black-out spells.” Migraines in children do not usually manifest as classic migraines but frequently have an atypical presentation with vision loss, frequent episodes of abdominal pain, and absence of headache. A child may complain about decreased visual acuity but have normal vision without ocular pathology. This form of functional visual loss has a variety of causes and may be difficult to diagnose and detect. Children most often complain about bilateral vision loss and initially report visual acuity in the 20/400 range. Their symptoms may be exaggerated, but the children rarely bump into objects when entering a room despite reports of markedly diminished visual acuity. This is a diagnosis of exclusion, and children should be carefully examined, perhaps on repeated occasions, before the diagnosis is made (Table 6-4).

TABLE 6-4  Causes of Vision Loss, Associated Findings, and Diagnostic Recommendations Cause of Vision Loss

Associated Findings/Syndrome

Diagnostic Evaluation

Leber congenital amaurosis

Large-amplitude, slow-frequency, roving nystagmus at 2 months of age; eye pressing (oculodigital sign)

Electroretinogram for photoreceptor function; renal consultation to rule out Senior syndrome

Ocular albinism/ oculocutaneous albinism

Moderate-amplitude nystagmus by 2 months, fair skin, X-linked inheritance; rule out Chediak– Higashi and Hermansky–Pudlak syndromes

Slit-lamp examination for iris transillumination defects; examine mother for signs of retinal hypopigmentation

Aniridia

Nystagmus at 2 months; consider WAGR syndrome

Slit-lamp examination shows lack of iris development; obtain genetic consult and urologic consultation to rule out and follow for Wilms tumor

Achromatopsia

High-frequency, low-amplitude nystagmus caused by lack of cone photoreceptor development; photophobia

Electroretinogram for photoreceptor function

Optic nerve coloboma

Nystagmus if severe and bilateral, strabismus if unilateral; CHARGE sequence, papillorenal syndrome

MRI of brain to rule out encephalocele and other structural anomalies; genetic and renal consultation to rule out other syndromes

Optic nerve hypoplasia

Nystagmus by 2 months if bilateral, strabismus if unilateral; septo-optic dysplasia/Aicardi syndrome; hypoglycemic at birth, signs of panhypopituitarism

MRI of brain—look for agenesis of corpus callosum, absence of septum pellucidum, absence or ectopy of pituitary bright spot, gray matter heterotopia in Aicardi syndrome

Retinopathy of prematurity

History of prematurity, oculodigital sign

Ophthalmic examination

Norrie disease

Nystagmus at 2 months, X-linked, bilateral retinal detachment with cataract

Ophthalmic examination; genetic consultation

Congenital cataract

Nystagmus at 2 months if complete cataract, strabismus if unilateral; stigmata of trisomies; metabolic signs if enzymatic or mitochondrial

Ophthalmic examination; if bilateral, consider galatosemia screen, urine amino acids (Lowe syndrome), urine for reducing substances, genetic consultation; examine parents to rule out autosomaldominant cataract; TORCH evaluation Continued on following page

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PART I  Clinical Evaluation

TABLE 6-4  Causes of Vision Loss, Associated Findings, and Diagnostic Recommendations (Continued) Cause of Vision Loss

Associated Findings/Syndrome

Diagnostic Evaluation

Optic neuritis

Vision loss, possible pain with eye movements, afferent pupil defect, focal neurologic findings; ADEM, neuromyelitis optica (Devic disease), multiple sclerosis, syphilis, Lyme disease, cat-scratch disease, toxin (nutritional, ethambutol, methanol), Leber hereditary optic neuropathy

Ophthalmic examination, MRI, lumbar puncture with opening pressure, serology and monoclonal bands, infectious disease consultation, genetic evaluation if positive family history; test for Leber hereditary optic neuropathy

Optic atrophy

Vision loss, strabismus, associated focal neurologic findings, endocrine signs/symptoms, deafness, loss of milestones in NCL/ neurometabolic disorders/Leigh disease; family history

Attention to pre- and perinatal history, neuroimaging, genetic consultation, endocrinologic consultation, assess for mitochondrial dysfunction

Cerebral visual impairment

Vision loss, sterotypic features: off/on, saccadic paresis; history of pre-/perinatal ischemia, intraventricular hemorrhage/prematurity, meningitis, cerebral developmental anomaly, cerebral palsy, seizure disorder

Neuroimaging; genetics if no known etiology

Refractive errors/amblyopia

Often sudden discovery or during screening examination; family history common; nonfocal neurologic examination; refractive errors correct with pinhole

Ophthalmic examination

Papilledema

Vision loss only if chronic or rapid onset, scotoma on change in position, constricted fields, esotropia with abducens paresis, headache, nausea; risk factors for idiopathic intracranial hypertension—obese, female, estrogen use, tetracycline, vitamin A, steroids, growth hormone, cerebral venous thrombosis

Ophthalmic examination—loss of spontaneous venous pulsations and edema of optic nerve, MRI and MRV, lumbar puncture with opening pressure

ADEM, acute disseminated encephalomyelitis; CHARGE, coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies; MRI, magnetic resonance imaging; MRV, magnetic resonance venography; NCL, neuronal ceroid lipofuscinosis; TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus; WAGR, Wilms tumor, genitourinary abnormalities, and mental retardation.

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Avery, R.A., Rajjoub, R.D., Trimboli-Heidler, C., et al., 2015. Applications of optical coherence tomography in pediatric clinical neuroscience. Neuropediatrics 46 (2), 88–97. Dutton, G.N., Jacobson, L.K., 2001. Cerebral visual impairment in children. Semin. Neonatol. 6 (6), 477–485. Fulton, A.B., Hansen, R.M., Manning, K.A., 1981. Measuring visual acuity in infants. Surv. Ophthalmol. 25 (5), 325–332. Hubel, D.N., Wiesel, T.N., 1962. Receptive fields, binocular interactions and functional architecture in the cats visual cortex. J. Physiol. 160, 106. Huo, R., Burden, S.K., Hoyt, C.S., et al., 1999. Chronic cortical visual impairment in children: aetiology, prognosis, and associated neurological deficits. Br. J. Ophthalmol. 83 (6), 670–675. Liu, G.T., 2001. Visual loss in childhood. Surv. Ophthalmol. 46 (1), 35–42. Papageorgiou, E., McLean, R.J., Gottlob, I., 2014. Nystagmus in childhood. Pediatr. Neonatol. 55 (5), 341–351. Waldman, A.T., Stull, L.B., Galetta, S.L., et al., 2011. Pediatric optic neuritis and risk of multiple sclerosis: meta-analysis of observational studies. J. AAPOS 15 (5), 441–446.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 6-1 Vision assessment in infancy. Fig. 6-2 Vision assessment in children. Fig. 6-3 Assessment of ocular motility. Fig. 6-4 Spectral domain optical coherence tomography. Fig. 6-5 Corneal edema caused by a forceps injury at the time of delivery. Fig. 6-6 Ocular coloboma. Fig. 6-7 Optic nerve hypoplasia and chorioretinal lacunas seen in patients with Aicardi syndrome. Fig. 6-8 Optic nerve hypoplasia. Fig. 6-9 Electroretinogram for a normal child (left) and a child with Leber congenital amaurosis (right). Fig. 6-10 Degenerative retinal disease. Fig. 6-11 Severe papilledema in a patient with idiopathic intracranial hypertension. Fig. 6-12 Optic disc drusen. Fig. 6-13 Frosted angiitis in an immunosuppressed patient with cytomegalovirus retinitis and neuritis.

7 

Hearing Impairment Lionel Van Maldergem, Guy Van Camp, and Paul Deltenre

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION The terms “hearing loss” (HL) and “hearing impairment” designate an abnormal auditory function whatever its type, localization, or the mechanism underlying it. In most circumstances the term “hearing loss” is used after a standard clinical audiogram has indicated elevated thresholds for detection of sound waves. But the hearing process cannot be reduced to this quantitative assessment. To fulfill its two main ecological functions, namely, keeping us aware of what is happening in our surroundings and sound-based communication, a normal auditory function must be able to influence behavior in a way appropriate to the meaning of the physical event having produced the detected sound. In real life, we do not perceive sound waves; we perceive mental images of their sources. Not only do we identify the sources around us, but also we are able to localize them in space. In case they are moving, we perceive whether they are approaching us or moving away. In most real-life situations there are several simultaneously active sound sources. The ears receive a mixture of sound waves, which our auditory system interprets to reconstruct the mental images of their respective sources. Our peripheral sensory organ named the cochlea provides the brain with a neural representation of sounds through the cochlear nerve. The cochlea does not perform source reconstruction: it has an analytic role based on filtering of complex multisource environmental sound waves, parsing them into an array of narrow frequency bands. The neural code conveyed by each afferent fiber of the cochlear nerve represents fluctuations in time of environmental sound intensities within a specific tonotopic frequency channel. As shown in Figure 7-1, the output of each cochlear filter comprises two components: the temporal fine structure that represents the instantaneous acoustic pressure variations and the envelope describing the overall amplitude variations over time. The central auditory nervous system (CANS) is faced with the enormous neurocomputing challenge of reconstructing sound sources from these individual spectro-temporal profiles. Processes by which the brain reconstructs our auditory environment from cochlear output have been named auditory scene analysis (ASA). These processes allow us to selectively attend to one among several speakers, a situation described as the cocktail party problem (McDermott, 2009). Deterioration of ASA mechanisms can occur in the absence of measurable threshold elevation and lead to auditory complaints taking the general form of poor understanding in noise despite normal thresholds, a combination recognized as obscure auditory dysfunction, King–Kopetzky syndrome, or central auditory processing disorder (CAPD). Efficiency of ASA processes can also be reduced as a consequence of peripheral sensory defects that not only cause a threshold elevation but also distort the primary neural code conveying the details of suprathreshold sound components.

ANATOMY AND PHYSIOLOGY OF THE EAR AND AUDITORY SYSTEM Interested readers will find information on the anatomy and physiology of the auditory system in the online version of this chapter as well as in recent books (e.g., Pickles, 2012) or on the Cochlea and Neuroreille websites (http://www.cochlea.eu/ en; http://www.neuroreille.com/promenade/english/start_gb .htm).

HEARING LOSS HL Classification Multiple descriptive dimensions of HL are used to provide a comprehensive evaluation in a given patient:

Classification by Definition of Impairment Site Current clinical and electrophysiological tools allow delineating four main categories: 1.  Conductive HL.  This type of impairment is caused by defective transmission of sound to the cochlea. It can occur because of an external ear or middle ear defect. By definition, the inner ear remains normal. Owing to bone conduction, conductive HL never exceeds 60 dB. 2.  Sensorineural HL.  This term points to a defect anywhere along the auditory pathway between the cochlea and the cerebral cortex. The vast majority are of endocochlear origin, a term referring to nonconductive HL secondary to cochlear defects, including the cochlear nerve in its intracochlear segment. Clinical and electrophysiological tools often do not allow precise identification of the defective structure involved in endocochlear deafness in contrast with major genetic advances made in recent years. Improved imaging and electrophysiological tools allow proper detection of many of the central defects. 3.  Auditory Neuropathy Spectrum Disorder.  Preserved outer hair cell (OHC) responses (cochlear microphonic and/ or otoacoustic emissions [OAEs]) and absent or severely disrupted auditory brainstem responses (ABR) including wave I are mandatory to make a diagnosis of auditory neuropathy spectrum disorder (ANSD). Many mechanisms interfering with the normal synchrony of the primary neural code sent to the brain by the cochlear nerves can lead to an ANSD profile (Starr et al., 2008). These include inner hair cell defects, ribbon synapse defects, or a defect of the cochlear nerve itself. Clinical manifestations are dominated by speech misunderstanding, usually worse than that which could be anticipated from the audiogram. Whenever the cochlear nerve alone is involved, a diagnosis of true neuropathy can be made.

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PART I  Clinical Evaluation

CF (kHz) 2

/ba/ 1

0.5

0

10

20

30 40 Time (ms)

50

60

0

10

20

30 Time (ms)

40

50

60

Figure 7-1.  Original acoustic waveform of the French synthetic syllable /ba/ (courtesy W. Serniclaes, ULB, Brussels) (A) compared with simulation of the output of three normal cochlear filters, respectively, centered on 0.5, 1, and 2 kHz (B), fed with the /ba/ waveform. Each cochlear filter extracts a spectral portion of the syllable and yields a composite signal describing variations of the temporal fine structure (red) and envelope (blue) components over time. CF, central frequency; ENV, envelope; TFS, temporal fine structure. TABLE 7-1  Hearing Loss Classification by Degree: ASHA and BIAP Schemes Hearing Loss Classification by Degree ASHA

BIAP

Degree of HL

Average Loss (dB HL)

Speech Perception

Normal to normal-subnormal

−10 to 15

90

>90

No speech perception

Normally voiced speech perceived; whispered/distant speech missed

ASHA, American Speech-Language-Hearing Association; BIAP, European Bureau International d’Audio-Phonologie; HL, hearing loss.

4.  Central HL.  Compression of brainstem auditory pathways by neighboring tumors is rare in children. Intrinsic tumors such as brainstem gliomas may interfere with auditory function. Hypomyelinating and demyelinating diseases may occasionally cause central HL (Pelizaeus–Merzbacher disease, adrenoleukodystrophy, multiple sclerosis, acute disseminated encephalomyelitis). Cortical deafness describes very rare instances of abnormal auditory reactivity caused by extensive bilateral auditory cortex destruction or deafferentation. Electrophysiological recordings exclude a cochlear origin, whereas behavioral testing is indicative of auditory agnosia. Most cases are attributable to cerebrovascular diseases and usually occur in adults. Landau–Kleffner syndrome produces similar central disturbances, affecting children who often appear to have HL of various severities related to auditory agnosia. Classical kernicterus and mild forms often called bilirubin-induced neurologic dysfunction spare the cochlea but affect the auditory nerve and central auditory pathways depending on the degree of hyperbilirubinemia. Resulting hearing deficits may range from normal thresholds with defective central processing to profound deafness.

Classification by Severity and Profile of Thresholds Elevation Most severity scales categorize HL severity on the basis of average audiometric pure-tones thresholds obtained at three to four frequencies: 0.5, 1, 2, and 4 kHz. Thresholds are

expressed in dB on the hearing level scale used in clinical audiometry, and so 0 dB represents the average threshold of normal subjects whatever the frequency. Most systems share four main descriptive categories: mild, moderate, severe, and profound, but may vary in their details. Table 7-1 illustrates a simplified version of the classifications recommended by the American Speech-Language-Hearing Association (ASHA; http://www.asha.org/public/hearing/Degree-of-Hearing -Loss/) and the European Bureau International d’AudioPhonologie (BIAP; http://www.biap.org/index.php).

EVALUATION OF AUDITORY FUNCTION Hearing tests are either behavioral (i.e., they seek a behavioral reaction to stimulus) or objective (i.e., independent from the subject’s willingness and cognitive state), being based on stimulus-induced physiological responses.

The Cross-Check Principle The cross-check principle, a cornerstone of pediatric audiology, states that a battery of independent tests is needed to provide an accurate description of hearing problems.

Behavioral Methods Behavioral methods depend on the developmental age and neurologic status, and reliable thresholds are often impossible to obtain in pediatric patients with moderate to profound



Hearing Impairment

intellectual disability. Even in normally developing children, one must wait until 36 months of age before reliable thresholds can be obtained across the entire population.

Objective Methods Tympanometry Acoustic immittance measurements by tympanometry yield a series of objective parameters: tympanic admittance or compliance, related to tympanic membrane mobility, Eustachian tube function, and external auditory ear canal volume, which is increased in case of perforated eardrum or permeable transtympanic ventilating tubes.

Objective Audiometry Otoacoustic emissions. OAEs are byproducts of sound processing by OHCs that lose control of a small fraction of incident energy and send it back to middle ear. OAEs are rapidly abolished with threshold elevation (≥35 dB) in sensorineural HL (SNHL) involving OHCs, which is the case of most endocochlear HLs, but not of retrocochlear HLs and ANSD. Auditory evoked potentials. They are classified according to three main characteristics: their latency range, time course, and dependency on cognitive processing. Early auditory evoked potentials (AEPs) represent the cornerstone of pediatric objective audiometry. Click-evoked ABRs are the centerpiece of electrophysiological evaluation of children at risk for hearing and complex neurologic disorders. Figure 7-6 illustrates how ABR morphology, amplitude, and latency evolve according to click level in a normal subject.

100

IMAGING Magnetic resonance imaging (MRI) is the main technique used for patients with SNHL for defining intralabyrinthine and intracranial anomalies. Computed tomography (CT) is more useful for middle ear and temporal bone assessment.

HEARING PROBLEMS IN THE PEDIATRIC POPULATION Conductive HL and External Ear Malformations Conductive HL is the most common cause of HL in children. Eighty percent of all children have had at least one episode of otitis media with effusion by age 10 years. Reversible conductive HL often coexists with cochlear HL, the combination being designated as mixed HL. An additional conductive loss may severely reduce auditory performances in the case of cochlear HL. Congenital malformations of the external or middle ear are often unilateral. Congenital anomalies of the external ear have an incidence of about 1 : 6000. Inner ear malformations are present in 11% to 30% of individuals with outer and middle ear malformations. External and inner ear mal­ formations frequently have a genetic basis and are rarely acquired. Syndromes associated with pinnae malformation include the branchio-oto-renal syndrome (OMIM 113650); auriculo-facio-vertebral syndrome or Goldenhar syndrome (OMIM 164210); coloboma, heart defect, atresia choanae, retarded growth, genital and ear anomalies (CHARGE) syndrome (OMIM 214800); Treacher–Collins syndrome (OMIM

0.31 V

95

A

90

IV I

85

II

III

75

VI

9

65

1 msec

60 55 JV Lat (ms)

dB nHL

VII

V

0.1 V

10

80 70

45

50 45 40 35

8

7

30 25 6

20 15 10

5

5

B

1.5 msec

C

0

10

20

30

40

50 60 dB nHL

70

80

90

100

110

Figure 7-6.  A, A normal click-evoked ABR waveform as it can be obtained from a normally hearing young subject. Stimulus level is 75 dB nHL. For brief stimuli such as clicks and tone-bursts, the nHL scale refers to the average threshold of a small group of normal subjects for a given stimulus. B, Effect of click intensity on ABR parameters: rise in latencies, drop in amplitudes, and progressive disappearance of early waves with reduction of intensity toward threshold. C, ABR wave V correlation between latency and intensity: individual data from 32 normal young subjects fitted by a quadratic function and 99% upper and lower confidence limits. Wave V is sometimes referred to as JV after D.L. Jewett, one of the ABR discoverers. ABR, auditory brainstem responses.

7

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PART I  Clinical Evaluation

154500); and Townes–Brocks syndrome (OMIM 107480). The size and morphological alterations in these conditions are more frequently bilateral and rather symmetric. Chromosomal anomalies are also associated with external ear malformations as seen with autosomal aneuploidies, namely, Down syndrome, Patau syndrome (trisomy 13), and Edwards syndrome (trisomy 18), but also for more complex chromosomal rearrangements.

Sensorineural HL Permanent SNHL is the most prevalent sensory impairment in childhood, affecting 1/700 infants. SNHL may result from genetic or environmental factors and can be syndromic or nonsyndromic. An enlarged vestibular aqueduct (EVA) is the most common inner ear malformation found in children with cochlear HL. The associated HL is variable in severity, may be asymmetric or unilateral, may be pre- or postlingual, and can fluctuate over time or suddenly progress. It is frequently observed in SLC26A4-related autosomal recessive nonsyndromic hearing loss (ARNSHL) and Pendred syndrome, and rarely in CHARGE syndrome, Waardenburg syndrome (WS), or Branchio-Oto-Renal syndrome. Toxoplasmosis, other (viruses), rubella, cytomegalovirus, herpes simplex (infection) (TORCH) infections may cause HL, often not isolated but associated with CNS involvement, including intracranial calcifications and destructive lesions seen on MRI and CT. CMV infection remains a frequent cause of acquired SNHL in neonates worldwide. Its prevalence is 0.58% in developed countries. CMV explains up to 21% of acquired HL at birth and up to 25% at the age of 4 years. Congenital toxoplasmosis and bacterial meningitis remain a concern, as up to 5% to 35% of survivors experience bilateral SNHL when infection occurs before the age of 2 years.

Ototoxicity Aminoglycosides antibiotics, mainly gentamycin, streptomycin, and vancomycin, are major ototoxic drugs, their deleterious role being modulated by the presence of m.1555A>G mutation. Macrolides may also be associated with some druginduced deafness, as are antineoplastic cis- and carboplatin agents, rarely used in infancy and childhood. Nonsteroidal antiinflammatory drugs and antimalarial medications may also cause a reversible ototoxicity. High doses of ionizing radiation used in cranial radiotherapy have been reported to cause HL, as can excessive noise exposure.

ADNSHL). Infrequently, HL follows the rules of X-linked or mitochondrial inheritance. NSHL is a highly heterogeneous trait, with more than 80 genes identified. It is likely that many more gene abnormalities remain to be identified. A continuously updated overview of genes associated with hereditary HL is available online at the Hereditary Hearing Loss Homepage (HHLH; http://www.hereditaryhearingloss.org).

Nonsyndromic Hearing Loss Genes that have been associated with NSHL fall into different categories. Most show an expression pattern largely restricted to the inner ear, as they encode proteins involved in cochlea development or function. Others have a broad expression pattern, encoding proteins present in other organs. The frequency of HL mutation carriage in unaffected individuals varies across populations and ethnicities. Data are only available for a small number of genes.

Autosomal Recessive Inheritance ARNSHL is caused by mutations in a limited set of genes, including GJB2, SLC26A4, MYO15A, OTOF, CDH23, and TMC1. GJB2 mutations represent the most frequently reported cause of ARNSHL. Over 100 different mutations have been reported in this gene (http://davinci.crg.es/deafness/index .php). It is frequent in European countries close to the Mediterranean (up to 50% of ARNSHL cases). One is particularly prevalent in European populations because of a founder effect: 35delG. Another common mutation is SLC26A4, which also is involved in a syndromic form of ARNSHL, Pendred syndrome, in which HL is accompanied by a thyroid goiter. However, as goiter usually appears later in life, or in some cases never appears, it is also considered an NSHL gene. An ARNSHL gene in which mutations are associated with a recognizable audiological phenotype is that encoding otoferlin (OTOF). Mutations in this audiological gene often result in prelingual, profound ARNSHL associated with an ANSD electrophysiological profile.

Autosomal Dominant Inheritance In contrast to ARNSHL where GJB2-related and SLC26A4related HL are overrepresented, none of the ADNSHL genes is particularly frequent. Dominant mutations in WFS1 encoding wolframin and those in COCH encoding cochlin are associated with a recognizable phenotype.

Auditory Neuropathy Spectrum Disorder

X-Linked and Mitochondrial Inheritance

ANSD is not a rare entity: it is associated with 8% of newly diagnosed pediatric cases of HL and 10% of children with permanent HL. Both genetic and nongenetic causes have been established.

Although X-linked and mitochondrial inherited HL are not frequent, representing together less than 3% of cases, a couple of mutations are often included in diagnostic panels because of their nature (point mutations) or their associated anomalies (see syndromic HL section). Mutations in POU3F4 cause an X-linked form of HL characterized by a mixed or purely sensorineural HL and temporal bone malformation on MRI. Its diagnosis has therapeutic consequences because the presence of a POU3F4 mutation can represent a contraindication for stapes surgery, hence the importance of temporal bone imaging in any basic workup of congenital HL. One mitochondrial gene is especially noteworthy. This is MT-RNRI, encoding the mitochondrial small subunit ribosomal RNA. The 1555A>G substitution causes HL induced by administration of clinically appropriate doses of aminoglycosides. In some individuals, HL can be present without exposure to aminoglycosides, suggesting involvement of modifier genes.

GENETIC HEARING LOSS Genetic HL can be divided into syndromic (SHL) and nonsyndromic forms (NSHL). Both have a monogenic cause in many cases, and all major types of inheritance patterns are observed. The most frequent type is autosomal recessive HL (ARNSHL) that accounts for almost 80% of cases. ARNSHL is typically congenital and severe to profound in nature, although at a later age at onset, milder forms or a progressive character is described in a minority of cases. Approximately 20% of cases are dominantly inherited, mostly of later onset and usually progressive (autosomal dominant nonsyndromic hearing loss;



Hearing Impairment

Genetic Diagnostics for Nonsyndromic Hearing Loss For more than two decades, attempts at establishing the molecular basis of HL have been made by Sanger sequencing. Although genes routinely analyzed for NSHL may differ between countries and labs, some are more common (e.g., GJB2, GJB6, and SLC26A4), or those giving rise to a recognizable audiological or clinical phenotype when mutated (Table 7-2). Traditional DNA diagnostic strategies usually deal with a small number of genes and a one-by-one sequential basis, meaning that the vast majority of HL genes remain unexplored outside a research setting. However, as next-generation sequencing (NGS) is becoming more available, it is now possible to sequence a large number of genes. Universities and private labs are able to offer testing for up to 125 HL genes, including both syndromic and nonsyndromic forms. In addition, multiple family members can be analyzed by NGS, allowing segregation studies, that is, characterization of those individuals from the family that inherited different genetic markers. This approach allows diagnosis of a specific HL type in a family, but also in up to 15% of families establishing a digenic inheritance by diagnosing a combination of two different types of deafness within the same family. However, although Sanger sequencing has a claimed sensitivity of 99%, the sensitivity of NGS-related techniques remains dependent on the number of reads, and a small percentage of mutations will be missed.

Syndromic Hearing Loss Syndromes in which deafness is not isolated but associated with other anomalies or involving other systems represent a

47

significant part (about one third) of the so-called genetic deafness. Two points deserve consideration (Toriello and Smith, 2013). The first is that of an enhanced interest in nonsyndromic deafness through availability of gene panels has rendered more frequent extensive audiological and imaging work-ups in previously unexplored children, thus dramatically increasing our knowledge of previously obscure rare conditions and drawing attention to new entities. This extended workup also led to reassignment of a number of nonsyndromic cases to the syndromic group by recognition of new entities and recognition of unsuspected known syndromes and subtle unreported clinical signs by reverse phenotyping. The other point pertains to the dramatic increase in the number of HL syndromes that has to be considered, and it is beyond the scope of this chapter to provide a detailed description of the clinical features of these syndromes (Hennekam et al., 2010). Because of the large number of conditions causing HL, there is a need for differentiating the vast majority of conditions in which deafness is an occasional finding, entities remaining private by the small number of families described so far from bona fide regular and frequent HL syndromes. These, less than two dozen major deafness syndromes, most, if not all, following the rules of mendelian inheritance, will be the subject of this section (Table 7-3). Waardenburg syndrome. WS is a clinically and genetically heterogeneous condition that manifests with HSNHL and abnormal pigmentation of the hair, skin, and iris. Four subtypes have been described. A neurologic variant (peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, Hirschsprung disease, PCWH) has also been delineated. Its classical phenotype includes WS type 1 with telecanthus and PAX3 mutations, WS type 2 without telecanthus and MITF or SOX10 mutations, and

TABLE 7-2  Frequently Analyzed NSHL Genes in Routine Genetic Diagnostics Gene

Inheritance Pattern

Phenotype

GJB2

AR

Most frequent gene associated with ARNSHL in many populations. Its mutations in GJB2 give rise to severe to profound HL in most cases, although rarely mild to moderate HL is observed. It may be combined with GJB6 deletion.

SLC26A4

AR

Both a frequent gene and a recognizable phenotype. Enlargement of vestibular aqueduct or Mondini dysplasia is seen on inner ear imaging. Mutations in this gene are also determining Pendred syndrome.

OTOF

AR

Congenital severe hearing loss caused by auditory synaptopathy, characterized by initially normal otoacoustic emission responses and preserved cochlear microphonic, whereas auditory brainstem responses are absent.

TECTA

AR/AD

By contrast to most cases of ARNSHL, which are severe to profound in nature, a milder phenotype is observed in TECTA-related ARNSHL (OMIM 603629). HL is typically moderate to severe, mainly affecting the midfrequencies. There is heterogeneity of mode of inheritance for TECTA-related HL, because some mutations give rise to an autosomal dominant transmission (ADNSHL; OMIM 601543).

WFS1

AD

Mild or moderate nonprogressive HL, only affecting the low frequencies. An autosomal recessive syndrome with multisystemic involvement is observed in case of homozygosity or compound heterozygosity (Wolfram Syndrome; OMIM 222300).

COCH

AD

Usually onset in the third decade with progressive hearing loss, accompanied by vestibular dysfunction, leading to absence of cochlear and vestibular function after during the fourth decade. The condition is particularly frequent in Belgium and the Netherlands because of a founder effect of P51S mutation (OMIM 603196).

POU3F4

XL

Sensorineural or mixed hearing loss associated with defects in bony labyrinth, including enlargement of the auditory canal, Mondini dysplasia, and/or stapes fixation (OMIM 300039).

MT-RNR1

Mitochondrial

m.1555A>G mutation in this gene is a relatively frequent cause of an aminoglycoside-induced HL, although in some cases it causes HL without aminoglycoside exposure.

This table contains a list of frequently analyzed NSHL genes in routine genetic diagnostics because of their high prevalence like GJB2 and SLC26A4 or as a result of the distinctive recognizable pattern of the HL they are associated with, differing from the severe to profound sensorineural HL caused by most genes. ADNSHL, autosomal dominant nonsyndromic hearing loss; ARNSHL, autosomal recessive nonsyndromic hearing loss; CM, cochlear microphonic; HL, hearing loss; NSHL, nonsyndromic hearing loss.

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PART I  Clinical Evaluation

TABLE 7-3  Examples of Syndromes Involving Hearing Loss Syndrome

Syndromic Features

Alport syndrome (OMIM 301050, 203780, 104200)

Kidney

Branchio-oto-renal syndrome (OMIM 113650)

Kidney, external ear

Treacher–Collins syndrome (OMIM 154500)

Craniofacial

Pendred syndrome (OMIM 274600)

Endocrine

Waardenburg syndrome (OMIM 193500, 193510, 148820, 277580)

Integuments, eye

Jervell–Lange–Nielsen syndrome (OMIM 220400)

Heart

Usher syndrome (OMIM 276900, 276901, 276902)

Eye

This table contains a list of syndromes associated with hearing loss and their syndromic feature. For additional information, please refer to the following section and/or to specific (http://www.ncbi .nlm.nih.gov/omim) and (http://www.ncbi.nlm.nih.gov/books/ NBK1434/).

type 4, sometimes called WS, recessive phenotype, which is a severe, early-onset subtype often associated to Hirschsprung syndrome. There is genetic heterogeneity of this subtype, with mutations in genes encoding endothelin 3, its receptor, and mutations in SOX10, encoding a transcription factor being also at cause in recessive forms. In SOX10-related type 4 WS, temporal bone imaging studies frequently show an enlarged vestibular aqueduct that could point to the diagnosis. Interestingly, some SOX10-mutated patients have instead of WS, a Kallmann disease phenotype, and some others have a sporadic deafness-only phenotype, without any pigmentary, olfactive, or dysmorphic features, that can be diagnosed by appropriate interpretation of temporal bone MRI. Since 1998, approximately 100 heterozygous point mutations or deletions of SOX10 have been reported, first in WS4 (WS with Hirschsprung disease), then in its neurologic variant, and recently in WS2. Although very rare, mutations in genes encoding endothelin 3 or receptor (EDN3-related, EDNRB-related) are also described. The common features of WS syndrome are SNHL and depigmentation of scalp, skin, and irides. A white forelock is the most remarkable sign, but premature, widespread graying of hair or depigmented skin macules are seen. Because of variable expressivity common to AD disorders, asking for the presence of this type of anomalies in relatives during the taking of a patient’s history is of value in cases of apparently sporadic deafness: it is not uncommon to have a hearing relative with one or several of these signs. Type 3 WS is an exceedingly rare occurrence of homozygosity for PAX3 mutations determining a more severe phenotype that includes short stature and bone deformity. Usher syndrome. US is another instance in which the differential timing at onset of different components of the syndrome may critically delay diagnosis. US comprises three main phenotypes. US type I combines congenital profound HL with vestibular areflexia, followed by delayed progressive retinitis pigmentosa (RP). Vestibular function is preserved in types II and III. Because vision is doomed to extinction in US, it is particularly important to perform cochlear implantation at an early age in order to optimize speech development before the visual channel is lost. Visual impairment can be diagnosed by fundoscopy and by electroretinography (ERG), the latter allowing a more reliable and earlier detection of RP. In US type I, the earliest clinical signs are delayed walking and hypotonia because of the vestibular deficit, and so these

findings in a congenitally profoundly deaf child should prompt ERG investigations. US is the principal cause of deaf-blindness. Treacher–Collins syndrome. Also known as Franceschetti– Klein syndrome, Treacher–Collins syndrome is the most frequent mandibulofacial dysostosis. It has a very characteristic facial dysmorphia that combines hypoplasia of zygomatic bones and mandible, external ear abnormalities, notching of lower eyelid, malar hypoplasia, downward slant of palpebral fissures, and microretrognathia. It is often associated with medial cleft palate. HL is present in nearly 50% affected individuals. It is of the conductive type, with fusion or undermodeling of the ossicles being at cause. Although dysmorphic features of variable severity are present at birth, conductive deafness may become obvious only later in life. Besides a prevalent autosomal dominant form caused by heterozygous mutations in TCOF, autosomal recessive forms have been demonstrated to be caused by mutations in genes encoding subunits of the polymerase complex POLR1D and POLR1C. Refsum disease and infantile Refsum disease. Although very rare, Refsum disease deserves mention because early diagnosis, often based on detection of visual impairment associated with anosmia and neurologic features, can lead to specific treatment and prevent otherwise irreversible complications. This is a singular inborn error of metabolism linked to a single peroxisomal enzyme deficiency, either the one encoding phytanoyl-CoA hydroxylase or PEX7. It induces signs and symptoms that include peripheral neuropathy, ichthyosis, visual impairment due to retinitis pigmentosa and, lately, hearing loss. Dietary lowering plasma concentration of phytanic acid or iterative plasmapheresis allows a partial control of progression of ichthyosis, peripheral neuropathy, and/or RP. There are other inborn errors of metabolism in which progressive HL has been linked to accumulation of toxic metabolites. Very-long-chain fatty acids, biliary acids, and phytanic acid are such metabolites thought to play such a role in much more severe conditions belonging to the group of generalized peroxisomal disorders or peroxisome biogenesis defects. For historical reasons, one of these severe diseases has been unfortunately given the name infantile Refsum disease, resembling too closely to the completely different adult Refsum disease and a source of confusion, as the neurodevelopmental outcome of the former is much more severe than that of the latter. More than 40 different enzyme deficiencies versus a single enzyme deficiency explain this discrepancy. Stabilization or even regression of HL has been achieved after orthotopic liver or hepatocyte transplantation in infantile Refsum disease. SLC26A4-related deafness, Pendred syndrome. This mixed type of autosomal recessive deafness is usually nonsyndromal, accounting for about 12% of AR cases and is the second cause after connexin 26–related deafness. However, a small percentage of mutated patients have thyroid gland dysfunction and goiter, usually manifest during the second decade of life, defining one of the first deafness syndromes described by Pendred in 1896. CHARGE syndrome. Elucidation of the molecular basis of what has been called CHARGE association (and not syndrome) for decades, an acronym for coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear malformation by a Dutch group in 2004, resulted in considerable expansion of its clinical phenotype, CHD7 heterozygous mutation, now being observed not only in a number of incomplete phenotypes, but also in case of sporadic deafness observed in association with isolated or multiple cranial nerve palsies. Also, it does not occur as a de novo mutation, but as a mutation inherited from an asymptomatic parent in up to 10% of



the cases. In terms of genetic counseling, to differentiate between these distinct situations is of importance (A mutation is important as it may induce deafness in association with a wide spectrum of other symptoms. In intermediate situations, deafness is found in association with insulin-dependent diabetes mellitus, or more complex phenotypes with either ataxia or stroke-like episodes, in the context of lactic acidosis. Another interesting deafness/mitochondrial mutation is the m.1555A>G mutation, for its double-sided expression: on the one hand, it may give rise to a classical postlingual deafness in the absence of any triggering factor; on the other hand, it is associated with deafness related to aminoglycoside exposure. There are many other mitochondrial DNA mutations that are associated with deafness (OMIM). Co-occurrence of an associated movement disorder, cardiomyopathy, and elevated creatinine kinase level, presence of a tubulopathy, or lactic acidosis should prompt consideration of this possibility. Alport syndrome. In this condition, postlingual HL is associated with kidney disease detected by hematuria prior to end-stage renal insufficiency. It is important to recognize because it is inherited in most cases as an X-linked recessive condition, with up to 15% of carrier females eventually becoming symptomatic. Its cardinal features are hematuria with subsequent renal insufficiency leading to dialysis and renal transplantation in a majority of patients. SNHL deafness generally occurs after the onset of renal disease. Carrier females are at risk of giving birth to affected male offspring, and in addition to determination of whether or not they have deafness, a urinalysis to screen for hematuria is indicated. Additional genetic studies of the family may be helpful as the mutation may not occur de novo. The alpha 5 chains of type 4 collagen are deficient, because of mutations in the corresponding gene COL4A5. Rarely, the disease is transmitted in an autosomal recessive manner, with an increased severity and mutations affecting COL4A3 and COL4A4. Marshall–Stickler spectrum. This syndromic autosomal dominant condition, also because of a collagen deficiency, is remarkable by its distinctive dysmorphic features that include flattening of the face, nasal hypoplasia and upturned nares, eye involvement (high myopia, retinal detachment), high arched palate and/or cleft palate, micrognathia, and short stature. Mutations are usually identified in the gene encoding the alpha 1 chain of type 2 collagen (COL2A1), but have also been described in association to involvement of type 9 collagens. Jervell–Lange–Nielsen syndrome. Autosomal dominant and recessive forms of a similar condition coexist and are characterized by the long QT syndrome, which is inconstantly associated with HSNHL in the context of the presence of voltage-gated potassium channelopathies (KCNQ1 and KCNE1). Because profound to moderate deafness is the clinical presentation and prolonged QT interval can only be diagnosed after recording an electrocardiogram (ECG), it is of paramount importance to include this test in the evaluation of a congenitally deaf patient or even in children or older

Hearing Impairment

49

patients with postlingual deafness. In patients with Jervell– Lange–Nielsen Syndrome, appropriate treatment (betablockers) and surveillance could be initiated, keeping in mind that sudden death because of ventricular fibrillation is the most severe complication. In some families, there is a history of intrauterine fetal death.

CONSEQUENCES OF HEARING IMPAIRMENT Consequences of HL are to be understood in the context of speech development during critical maturational periods (Kral, 2013). Lack of auditory reference to real words, objects, and events leads to adverse cognitive effects. Uncorrected congenital or early acquired profound HL has far reaching consequences impinging on literacy development and cognitive abilities. There is accumulating evidence that this is also true for mild losses and even unilateral ones. Intervention programs recommend screening before 1 month, definite diagnosis no later than 3 months, and intervention by 6 months (Joint Committee on Infant Hearing). Any provider of pediatric healthcare involved with a child whose diagnosis or intervention program is not secured could play a major role in this respect. It cannot be overemphasized that in caring for a child with suspected HL or who has known risk factors (e.g., congenital CMV infection, positive family history), passed neonatal screening does not exclude significant HL as it may be delayed in onset or progressive in nature (Kral and O’Donoghue, 2010).

CLINICAL EVALUATION AND SPECIALIZED TESTING OF SUSPECTED HL Patient and Family Histories A detailed family history and pedigree are an integral part of the evaluation of every newly identified hearing-impaired child. Of importance is the pedigree reconstruction. Each parent should be questioned on his/her sibship with first name, maiden name, year of birth, number of offspring, and miscarriage(s). Special attention should be paid to grandparents, the place where they were born, and any history of hearing impairment, keeping in mind that presbyacusia is physiological after age 50. Of significance is any kind of relationship between the parents, pointing to autosomal recessive inheritance.

Clinical Evaluation and Specialized Testing Once the pedigree and a detailed clinical history have been completed, a suspected mode of inheritance can usually be ascertained. If HL is thought to be of sporadic occurrence, one must still consider that autosomal recessive inheritance is possible as is autosomal dominant inheritance as a de novo mutation, or when a parent is mildly affected (variable expressivity). In addition, nonpenetrance, as well as mitochondrial inheritance or X-linked inheritance remains to be considered. Likewise, the absence of family history does not preclude a genetic basis and the possibility of an environmental etiology must also be looked for. The clinical examination is of great importance and may yield diagnostic clues. In addition to growth parameters, attention should be paid to whether there are facial dysmorphic features, abnormal pinnae, branchial cleft pits, cysts or fistulae, preauricular pits or nodules, telecanthus, heterochromia iridis and pigmentary anomalies, high myopia, pigmentary retinopathy, increased or decreased occipitofrontal head circumference, nasolabial folds, submucous cleft palate, goiter, limb anomalies, organomegaly, disproportionate short or

7

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PART I  Clinical Evaluation

tall stature, muscle wasting, ataxia, and so on. Neurologic examination should determine the presence or absence of pyramidal signs, cranial nerve involvement, a movement disorder, and abnormal deep tendon reflexes. In autosomal dominant forms of syndromic HL that tend to have a variable expression, a key diagnostic feature may be found in a relative rather than in the proband. A complete blood count is important, including platelets size, as megathrombocytopenia is a good marker of MYH9-related deafness (OMIM 153650). The presence of hematuria on a urinalysis may suggest Alport syndrome (OMIM 301050, 203780, 104200) and Fanconi syndrome. Screening for inborn errors of metabolism, especially mitochondrial when diabetes mellitus, ptosis, cardiomyopathy, failure to thrive, or seizures are present. Screening for disorders of amino acid and organic acid metabolism, obtaining plasma lactate and pyruvate levels, and chemistry profiles, including liver enzymes, are all helpful. A muscle biopsy with biochemical and immunological study of the respiratory chain can be instrumental if additional clinical signs and symptoms are compatible with a mitochondrial cytopathy. Elevation of liver enzymes, associated with a visual deficiency or the presence of retinitis pigmentosa in an infant or toddler, should elicit a search for a peroxisomal biogenesis defect, including assessment of very-long-chain fatty acids, bile acids, and phytanic acid followed by a skin/ liver biopsy in case of positive findings. A lysosomal storage disorder must be considered if the liver or spleen is enlarged, and if there are coarse facial features or stiff joints, distended abdomen, or a history of chronic otitis media assessment for a storage disorder should be considered. A search for vacuolized lymphocytes is a basic test, as is the search for an accumulation of urinary glycosaminoglycans. However, the first one requires expertise and the latter has a low specificity. Hence, asking for direct assessment of suspected enzyme deficiency in fresh leukocytes may accelerate the diagnostic process. For example, detection of iduronate-sulfatase is indicative of Hunter disease and alpha-iduronidase is indicative of Hurler syndrome. In a different set of conditions, skin lesions may provide diagnostic clues. Examples include the presence of angiokeratoma in patients with Fabry disease or an oligosaccharidosis like beta-mannosidosis and H syndrome, a recently described histiocytosis with cutaneous rash and frequently associated HL. It introduces a new class of genetic deafness where inflammatory cutaneous lesions can give suggest a different category of diagnostic entities. A second example includes the pigmentary anomalies seen in patients with WS.

Audiological Evaluation Recommendations on techniques that should be applied and information that should be gathered have been issued for the audiological assessment of infants between birth and 6 months. Recommendations to fit the needs of older subjects with delayed development, multiple handicaps, or increased risk of auditory nervous system anomalies may be summarized and commented on as follows: 1. External and middle ears assessment by otoscopy and tympanometry, including acoustic reflexes and appropriate selection of probe frequency according to age 2. Evoked potentials recording to define type, degree, and configuration of HL and detect abnormal neural con­ duction along the cochlear nerve and/or brainstem pathways 3. Otoacoustic emissions 4. Behavioral audiometry 5. Speech detection and recognition

6. Follow up and monitoring of the infant’s communication skills. Several forms of HL are delayed or progressive. It has been estimated that 1/56 children with permanent HL at 1 year had delayed-onset HL.

MANAGEMENT OF HEARING LOSS A primary aim of rehabilitation efforts is promoting or restoring an infant’s or child’s communication skills and optimizing the level of language development on which cognitive and socioemotional behavior is contingent. A secondary aim is to provide environmental auditory object identification and localization. Efficient management often requires the combined expertise of otologists, audiologists, speech and language therapists, psychologists, special educators, and social workers. Currently available assistive devices (conventional hearing aids, cochlear implants, frequency modulation systems) allow many severe to profound HL children to be to a regular classroom setting.

Reconstructive Surgery for External and   Middle Ears Malformation Surgery is usually performed after the age of 8 years. Meanwhile, at least in children with HL, bone conduction hearing aids must be fitted early to avoid hearing deprivation during critical developmental periods.

Choice of Communication Mode for Severe to Profound HL Among the two main communication strategies, namely, speech-based (oralism) and sign-based (sign language), the oral mode is usually preferred to sign communication to promote integration in the hearing population. In some individuals, parents will make the choice of acculturation of their child to the deaf signing world rather than to the hearing, speaking one, because, being profoundly deaf themselves, they use sign language in daily life or because they wish to respect and protect the communicative and social modes developed by their child. Choosing between these options is not a simple matter and has to be thoroughly discussed with the parents and the multidisciplinary rehabilitation team, before selecting what appears most appropriate for an individual child and his/her family.

Assistive Devices Two main types of assistive devices are used to restore or improve auditory perception: conventional hearing aids (amplification devices) and cochlear implants. Frequency modulation systems are of great help: acquiring the teacher’s speech by a collar-worn directional microphone, the system sends the target signal to the child’s hearing aid by radio waves, and so ambient noise surrounding the subject is not amplified as it would have been with a child-worn microphone. Binaural amplification is recommended because it improves sound source localization and hearing in noise performances.

Cochlear Implants Cochlear implants are now well established as the gold standard for restoring useful hearing in bilateral severe-to-profound HL for which amplification fails to allow satisfactory progress. The best results are obtained in two situations: cases of postlingually acquired deafness and early implantation of congenital cases. The optimal age for implanting congenital cases is between 6 months and 2 years.



Brainstem Implants An auditory brainstem implant stimulating the surface of cochlear nucleus can be indicated when cochlear implantation is impossible. The main indication for auditory brainstem implantation is type 2 neurofibromatosis.

FUTURE DEVELOPMENTS Advances in HL research over the next decade will focus on electrophysiological applications to better understand the mechanisms of speech development, use of newer imaging technologies, improvement of conventional hearing aid functionality, and in the implementation of hearing restoration therapies. Measurement of the quality of neural coding within the CANS using digital signal processing techniques and perceptual training will possibly improve central representation of speech items. Functional imaging and diffusion tensor imaging are likely to be useful in the study of functionally or structurally abnormal CANS pathways. Digital signal processing techniques that can now be implemented in conventional hearing aids should contribute to alleviate the consequences of at least some forms of neural code distortion. Gene, stem cells, and molecular therapies are beginning to show efficiency in animal models, and it is hoped that they will be applied to use in humans in the forthcoming decades. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Hennekam, R., Allanson, J., Krantz, I., 2010. Gorlin’s Syndromes of the Head and Neck, fifth ed. Oxford Monographs on Medical Genetics. Oxford University Press, New York.

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Kral, A., O’Donoghue, G.M., 2010. Profound deafness in childhood. N. Engl. J. Med. 363, 1438–1450. Kral, A., 2013. Auditory critical periods: a review from system’s perspective. Neuroscience 247, 117–133. McDermott, J.H., 2009. The cocktail party problem. Curr. Biol. 19, R1024–R1027. Pickles, J.O., 2012. An Introduction to the Physiology of Hearing, fourth ed. Emerald, Bingley, UK. Starr, A., Zeng, F.G., Michalewski, H.G., et al., 2008. Perspectives on auditory neuropathy: disorders of inner hair cell, auditory nerve and their synapse. In: Basbaum, A.I., Kaneko, A.Shepherd, G.M. (Eds.), The Senses: A Comprehensive Reference Audition. Academic Press, San Diego, pp. 347–412. Toriello, H., Smith, S.D. (Eds.), 2013. Hereditary Hearing Loss and Its Syndromes. Oxford Monographs on Medical Genetics. Oxford University Press, New York.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 7-2 Acoustic pressure variation time course for a sinusoidally amplitude-modulated pure tone at 1 kHz. Fig. 7-3 The intricate relationship of the semicircular canals, vestibule, and cochlea. Fig. 7-4 Microphotograph of the inner hair cell ribbon synapse. Fig. 7-5 Air conduction thresholds. Fig. 7-7 Auditory brainstem response differential diagnosis between conductive and sensorineural hearing loss. Fig. 7-8 Data from a 2-year-old girl with pontine tegmental cap dysplasia. Fig. 7-9 Midsagittal T2-weighted MR imaging.

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8 

Vertigo Joseph M. Furman and Amy Goldstein

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Vertigo in children may escape recognition because of the child’s inability to describe the symptoms, the short duration of most vertiginous episodes, the presence of overwhelming autonomic symptoms, or the mistaken idea that an episode of vertigo may be a manifestation of a behavioral disorder. Vertigo is defined in clinical practice as a subjective sen­ sation of movement, such as spinning, turning, tilting, or whirling, of the patient or the surroundings. Dizziness is a nonspecific term used by patients to describe sensations of altered orientation to the environment that may or may not include vertigo, and often is used to describe lightheadedness or presyncopal symptoms. Although vertigo may be a symptom of a vestibular disor­ der in the pediatric population, patients react to and describe dizziness in different ways in relation to their age. For instance, young children cannot accurately relate symptoms of dizzi­ ness. Preschool children rarely complain of vertigo or dizzi­ ness but may feel clumsy or be perceived as such by family or teachers. Older children and adolescents are usually able to explain their symptoms well, with their explanations differing little from the explanations of adults. In any case, a vestibular abnormality should be suspected in a child who is observed to be clumsy or displays unpro­ voked fright, or who spontaneously clings to a parent. Sudden and recurrent bouts of unexplained nausea and vomiting also are suggestive of a vestibular abnormality. In children, as well as in adults, a careful history, physical examination, and laboratory testing can establish the cause of dizziness in most patients.

PHYSIOLOGIC BASIS OF BALANCE When a hair cell is stimulated by rotation, translation, or change in orientation with respect to gravity, the firing rate in the eighth nerve fiber innervating that particular hair cell either increases or decreases. Movements that cause the stereo­ cilia to bend toward the kinocilium result in a depolarization of the hair cell and cause the eighth nerve fiber to increase its firing rate, whereas movements that bend the stereocilia away from the kinocilium decrease the neural firing in the eighth nerve. The eighth nerve synapses in the vestibular nuclei, which consist of superior, medial, lateral, and inferior divi­ sions. In addition to the input from the labyrinth, the vestibu­ lar nuclei receive input from other sensory systems, such as vision, somatic sensation, and hearing. The sensory informa­ tion is integrated and the output from the vestibular nuclei influences eye movements, truncal stability, and spatial orientation. The oculovestibular reflex is a mechanism by which a head movement automatically results in an eye movement that is equal to and opposite of the head movement so that the visual axis of the eye stays on target: that is, a leftward head move­ ment is associated with a rightward eye movement and vice versa. Another feature of the oculovestibular reflex is that the two vestibular nuclear complexes on either side of the

52

brainstem cooperate with one another in such a way that, for the horizontal system, when one nucleus is excited, the other is inhibited. The central nervous system (CNS) responds to differences in neural activity between the two vestibular com­ plexes. When there is no head movement, the neural activity, i.e., the resting discharge, is symmetrical in the two vestibular nuclei. The brain detects no differences in neural activity and concludes that the head is not moving (Fig. 8-1A). When the head moves, e.g., to the left, endolymph flow produces an excitatory response in the labyrinth on the side toward which the head moves, e.g., on the left, and an inhibitory response on the opposite side, e.g., on the right. Thus neural activity in the vestibular nerve and nuclei, e.g., on the left and right, increases and decreases respectively (Fig. 8-1B). The brain interprets this difference in neural activity between the two vestibular complexes as a head movement and generates appropriate oculovestibular and postural responses. This reciprocal push-pull balance between the two labyrinths is disrupted as a result of labyrinthine injury. An acute loss of peripheral vestibular function unilaterally, e.g., on the right, causes a loss of resting neural discharge activity in that vestibular nerve and the ipsilateral nucleus (Fig. 8-1C). Because the brain responds to differences between the two labyrinths, this will be interpreted by the brain as a rapid head movement toward the healthy labyrinth, i.e. vertigo. “Corrective” eye movements are produced toward the oppo­ site side, resulting in nystagmus, with the slow component moving toward the abnormal side, e.g., the right, and the quick components of nystagmus moving toward the healthy labyrinth, e.g., the left.

EVALUATION OF PATIENTS WITH DIZZINESS At the initial visit, in addition to the chief complaint, a com­ plete medical history that includes associated symptoms, medical history, family history, and medication use is mandatory. After the interview, a complete physical examination should be performed, with particular emphasis on the cranial nerves, including an examination of eye movements. In some patients, further testing may be medically neces­ sary if the diagnosis is not clear, including the use of vestibular testing in a specialized laboratory.

History Chief Complaint It is important that the child explain the symptoms in his or her own vocabulary and describe associated sensations, such as headache, nausea, vomiting, or motion sickness. It might be helpful to relate the patient’s symptoms to experiences, such as being on a merry-go-round or a boat. It is important to establish the onset, duration, and frequency of dizziness episodes and to associate the episodes with certain activities. Triggering factors include change in position, coughing or sneezing, sleep deprivation, and psychological stressors.



Vertigo No head movement

+ –

Polarity of hair cells

Vestibular nerve

+ –

Right Vestibular Left horizontal nuclei Right horizontal semicircular canal semicircular canal

A

Left

Vestibular nerve

Head movement to left

+ –

B

+ Vestibular nerve

Vestibular nerve Right Vestibular Left horizontal nuclei Right horizontal semicircular canal semicircular canal

–

Left

53

mus is tested by having the patient look straight ahead with and without fixation (i.e., in primary gaze). Gaze-evoked nys­ tagmus is assessed by having the patient deviate the eyes later­ ally (no greater than 30 degrees) with fixation. End-gaze nystagmus with eyes fully deviated laterally is a normal finding. Positional testing is performed with the use of maneu­ vers that may produce nystagmus or vertigo. Static positional nystagmus is assessed by placing the patient in each of the these six positions: sitting, supine, supine with the head turned to the right, supine with the head turned to the left, and right and left lateral positions. Positional nystagmus pres­ ents as soon as the patient assumes the position and persists for as long as the patient remains in the provocative position. Assessment of vestibulospinal function with a foam pad should be performed with or without a visual conflict dome. In addition to a history and physical examination, an assessment may include vestibular testing. Vestibular labora­ tory testing is recommended in any child with a history of vertigo in whom a thorough history and physical examination have not established a diagnosis, in order to differentiate between a peripheral or central vestibular lesion, and to iden­ tify the side of the lesion in a peripheral abnormality. In addition, vestibular laboratory testing provides permanent documentation, and changes can be followed by repeat testing. Vestibular laboratory testing includes oculovestibular and ves­ tibulospinal tests. Both types of tests provide only an indirect measure of the function of the vestibular end organs, in that they rely on measures of motor response, e.g, eye movements or postural sway, resulting from vestibular sensory input.

Right acute peripheral vestibular injury

Videonystagmography + –

C

Vestibular nerve

Vestibular nerve Right Vestibular Left horizontal nuclei Right horizontal semicircular canal semicircular canal Left

Figure 8-1.  Schematic illustrations of the “push-pull” effect of the oculovestibular reflex. A, No head movement in healthy subject. B, Head movement to the left in healthy subject. C, Right acute peripheral vestibular injury.

The clinician should inquire about the presence of hearing loss, its onset, evolution or progression, fluctuation and wors­ ening, and improving or stable status. Does the patient have tinnitus or a feeling of fullness? Is the hearing loss bilateral or unilateral? To establish the presence of neurologic symptoms, the clinician should determine whether there have been instances of seizure activity, altered mental status, ataxia, weakness, numbness, disturbances of swallowing or taste, coughing, facial paralysis, or blurring and loss of vision.

Physical Examination In addition to a complete neurologic examination, the child should also be observed when walking or running for incoor­ dination of movements, i.e., ataxia. Also, an assessment of nystagmus is especially important. Spontaneous nystagmus is an involuntary, rhythmic movement of the eyes not induced by any external stimulation. Spontaneous nystagmus has two components: slow and fast. Nystagmus is named by the fast component, which is easily identified. Spontaneous nystag­

Videonystagmography is currently the most widely used method of recording eye movements; it uses infrared light. Ocular motor testing, positional testing, and caloric testing constitute a common test battery that requires about 1 hour. Sedatives and vestibular suppressant medications should be discontinued for 2 days before testing. Ocular motor testing evaluates neural motor output independent of the vestibular system. Abnormalities in the ocular motor system may cause misleading conclusions from vestibular testing that relies on eye movements. Testing saccades uses a computer-controlled sequence of target jumps. Saccade abnormalities are defined as overshooting the target (hypermetric saccades) and under­ shooting the target (hypometric saccades). Disorders in the saccadic system suggest a CNS abnormality. Spontaneous nys­ tagmus and gaze-evoked nystagmus are recorded with and without fixation (closing the eyes or darkness), and by asking the patient to look 30 degrees to the right and left. Spontane­ ous nystagmus present in darkness without fixation, which decreases or resolves with visual fixation, suggests a peripheral vestibular disorder. However, spontaneous nystagmus that is present with fixation and does not significantly decrease with loss of fixation is most likely a CNS abnormality. Ocular pursuit involves asking the patient to follow a moving target back and forth along a slow, pendular path. Normal subjects can follow a target smoothly without interruption. Abnor­ malities of pursuit tracking are caused by lesions in the CNS. Laboratory testing of optokinetic nystagmus uses black-andwhite stripes moving left and right. Abnormalities include asymmetries or absence of responses, which suggest a CNS abnormality. Positional testing includes both static and paroxysmal (dynamic) testing. As in the clinical assessment, during static positional testing, the patient is placed in the sitting, supine, head left, head right, left lateral, and right lateral positions in darkness. Static positional nystagmus, contrary to paroxysmal nystagmus, presents as soon as the patient assumes the

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PART I  Clinical Evaluation

provocative position and persists for as long as the patient stays in that position. Static positional nystagmus is a nonspe­ cific, nonlocalizing vestibular sign. Paroxysmal positional testing employs the Dix–Hallpike maneuver, a maneuver that involves bringing the patient from sitting with the head straight to sitting with the head turned 45 degrees to one side to lying down with the head still turned and the neck extended 20 degrees below the horizontal. The patient is then seated upright again, and the maneuver is repeated with the head turning to the opposite side. Upon attainment and mainte­ nance of each head-back stance, the eye movements are noted. Latency to onset of nystagmus, a rotational component to the nystagmus, and attenuation of the nystagmus with mainte­ nance of the position all suggest the diagnosis of benign par­ oxysmal positional vertigo, especially if this maneuver reproduces the patient’s symptoms. This condition is rare in children and, when present, is thought to be a childhood migraine variant.

Caloric Testing Caloric testing aims to assess each labyrinth separately by producing nystagmus via thermal stimulation of the vestibular system. The patient is placed in a position in which the hori­ zontal semicircular canals lie in the vertical plane (head ele­ vated 30 degrees). Caloric stimulation causes a convection current in the horizontal semicircular canal that causes a deflection of the cupula (into which the hairs of the hair cells are embedded) and a change in activity of the vestibular nerve. Cold irrigation produces a fast nystagmus component away from the irrigated ear; warm irrigation produces a fast nystag­ mus component toward the irrigated ear. The common mne­ monic COWS “cold opposite, warm same,” refers to the direction of the fast-beating nystagmus. Binaural bithermal caloric testing uses stimuli of 30° C and 44° C, and each canal is irrigated for 30 seconds with 250 mL of water. There is a rest period of 5 minutes between irrigations. The most common method of measuring the caloric response is to compute the peak slow-component velocity of the nystagmus induced by the thermal stimulus, which reflects the intensity of the vestibular response. To compare the responsiveness of one ear to the other ear, it is established practice to use Jong­ kees’ formula to compute a percentage of reduced vestibular response: [[(R 30° + R 44°) − (L 30° + L 44°)] [R 30° + R 44° + L 30° + L 44°]] × 100 percent For many laboratories, normal limits are considered to be a reduced vestibular response of more than 24%. A reduced vestibular response suggests a peripheral vestibular lesion.

Rotational Testing Rotation is the natural stimulus to the semicircular canals. Rotational testing causes minimal discomfort and is precise and well tolerated, even by infants and young children (who can be placed on a parent’s lap). Rotation stimulates both labyrinths at the same time and thus does not provide lateral­ izing information. Caloric response and rotational testing are complementary. The most common type of rotational testing uses sinusoidal harmonic acceleration. The eye velocity pro­ duced by the rotation is compared with stimulus velocity. Three parameters are derived from rotational testing: gain, phase, and symmetry. Gain is a measure of the size of the response. Reduced gain indicates decreased vestibular sensitiv­ ity. Unilateral vestibular loss may or may not reduce gain. Thus reduced gain usually indicates bilateral vestibular loss. Phase describes the timing relationship between the rotational chair

velocity and the eye velocity. Ideal eye movements have zero phase lead, whereas large phase leads are usually abnormal. Phase is a highly sensitive but nonspecific measure of vestibu­ lar system abnormalities. The directional preponderance (i.e., deviation from symmetry) of the eye movements is derived by comparing the velocity of the eye movement to right and left. Directional preponderance is a nonspecific sign. Note that gain, phase, and degree of symmetry do not indicate the site or the side of the lesion. However, rotational testing measures change in response to vestibular disease and can be used to monitor a child’s progress.

Computerized Dynamic Platform Posturography Computerized dynamic posturography, known commercially as EquiTest® (NeuroCom International, Inc.), consists of a floor and a visual scene that can move (Fig. 8-6A). By combin­ ing visual and floor conditions, six different sensory condi­ tions can be used to assess the patient’s ability to use combinations of sensory inputs (Fig. 8-6B). Conditions 5 and 6 assess how patients use vestibular information when it is the only available sense providing reliable information; reduced or distorted sensory information from the visual system and somatosensory system forces patients to rely on their vestibu­ lar sensations to maintain upright balance.

Posturography and Vestibular Disorders—  Results from the Medical Literature Several studies have suggested that, after successful vestibular compensation, posturography test results normalize and patients lose their “5, 6 pattern” (i.e., their abnormal response to conditions 5 and 6 on posturography testing) and may, in fact, have normal postural sway (Furman, 1995). Thus pos­ turography may provide valuable information regarding the status of compensation for a peripheral vestibular deficit.

Vestibular-Evoked Myogenic Potentials Vestibular-evoked myogenic potentials (VEMPs) refer to elec­ trical activity recorded from neck muscles in response to intense auditory clicks. VEMPs provide information about the status of the sacculus and inferior vestibular nerve. A limita­ tion of VEMPs is that it requires normal middle ear function when performed using air-conducted stimuli. VEMPs have been performed successfully in children. Children as young as age 3 can tolerate testing.

DISORDERS PRODUCING VERTIGO Vertigo in children can be divided into three broad categories: 1. Acute nonrecurring spontaneous vertigo 2. Recurrent vertigo 3. Nonvertiginous dizziness, disequilibrium, and ataxia (Table 8-1) A recent study of 2000 children found that vertigo in children was caused by: a migrainous equivalent, 25%; benign parox­ ysmal vertigo of childhood, 20%; head trauma, 10%; ocular disorders, 10%; inner ear malformations, 10%; vestibular neu­ ronitis, 5%; labyrinthitis, 5%; and posterior fossa tumors, less than 1% (Wiener-Vacher, 2008). A more recent study of 6965 10 year olds in the United Kingdom found a 5.7% prevalence of vertigo. Of these children, vertigo symptoms made them stop their activity, and 60% of them also had headache. A change in hearing while vertiginous was reported in 20% (Humphriss and Hall, 2011).



Vertigo

55

8

A

Figure 8-6.  The EquiTest® system. A, EquiTest® system (NeuroCom International, Inc.) shows the child standing on the platform surrounded by a visual scene. A safety harness is attached to the child in case loss of balance should occur. The platform surface and visual surround are capable of moving independently or simultaneously. Pressure-sensing strain gauges beneath the platform surface detect the patient’s sway by measuring vertical and horizontal forces applied to the surface. B, The six sensory testing conditions of the EquiTest® posturography platform. (With permission from NeuroCom International, Inc., Clackman, Ore.)

EquiTest® conditions 1 Normal vision

B

2 3 Absent Sway-referenced vision vision

Fixed support

4 Normal vision

5 6 Absent Sway-referenced vision vision

Sway-referenced support

TABLE 8-1  Comparison of Disorders Causing Childhood Dizziness Disorders

Duration of Symptoms/Episodes

Hearing

Vestibular Laboratory Abnormalities

Nonrecurrent Vertigo Vestibular neuritis Trauma-labyrinthine concussion Perilymphatic fistula

Days Days Variable

Normal Often impaired SNHL* Often impaired SNHL

Unilateral caloric reduction Possible unilateral caloric reduction Possible unilateral caloric reduction

Recurrent Vertigo Ménière’s disease Migraine Anxiety Seizure disorder Periodic ataxia

Minutes to hours Variable Minutes Seconds to minutes Hours to days

Low-frequency SNHL Normal Normal Normal Normal

Unilateral caloric reduction Directional preponderance Directional preponderance Normal Normal

Nonvertiginous Dizziness Bilateral vestibular loss

Constant

Usually normal but may be impaired

Otitis media Cerebellar lesions

Constant Constant

Conductive Normal

Bilateral caloric reduction/reduced gain on rotation Abnormal posturography Abnormal ocular motor testing

*SNHL; sensorineural hearing loss. (Modified with permission from Tusa RS et al. Dizziness in childhood. J Child Neurol. 1994;9:261.)

56

PART I  Clinical Evaluation

Acute Nonrecurring Spontaneous Vertigo Acute nonrecurring spontaneous vertigo is unusual in chil­ dren. In an acute vestibular syndrome, the vertigo that is expe­ rienced results in a reduction in the normal baseline activity in the ipsilateral vestibular nerve. Because the brain responds to differences in activity between the two vestibular nuclear complexes, the patient experiences vertigo. Additionally, the child may experience autonomic symptoms, including nausea and vomiting. Typically, children adapt to an acute loss of unilateral peripheral vestibular function within several days.

Head Trauma Head trauma can cause an acute episode of vertigo via a laby­ rinthine concussion. The mechanism of injury in labyrinthine concussion is poorly understood but may relate to pressure waves transmitted to the labyrinth. Other mechanisms of vertigo after head trauma include injury of the CNS, specifi­ cally, a brainstem or cerebellar contusion, or a temporal bone fracture. Another diagnostic consideration for a patient with head trauma followed by vertigo or nonspecific dizziness is that of perilymphatic fistula, i.e., an anomalous connection between the inner ear and middle ear spaces that has been well documented in children. Vertigo is a common complaint in patients with postcon­ cussion syndrome, with 81% reporting dizziness.

Vestibular Neuritis Vestibular neuritis is rarely seen in children younger than 10 years old. It should be considered when a viral syndrome is followed by symptoms suggestive of an acute unilateral peripheral vestibular loss. It presents with acute severe vertigo, nystagmus, nausea, and vomiting. The vertigo is worsened by head movements, and patients often prefer to lie down, usually with the affected ear up. There is no hearing loss or tinnitus. Management is supportive and symptomatic, with early ambulation. Vestibular suppressants such as meclizine may be given, but only for a short course, as they may delay long-term recovery.

Recurrent Vertigo Recurrent vertigo in children can be a result of disease of the peripheral or central vestibular system. However, most recur­ rent vertigo in children is due to a CNS disorder rather than a peripheral vestibular disorder.

Migraine-Related Dizziness Migraine is probably the most common cause of recurrent vertigo in children. Whereas migraine typically presents as headache in adults, other manifestations of migraine, includ­ ing recurrent vertigo and disequilibrium, are more common in children. Benign paroxysmal vertigo of childhood, which is likely to be of migrainous origin, as well as paroxysmal torti­ collis of infancy, can present with recurrent vertigo in children. Nonvertiginous symptoms of vestibular dysfunction can also be related to migraine. The manifestations of migraine in childhood are quite varied (Balkany and Finkel, 1986). Benign paroxysmal vertigo of childhood was first described by Basser (Basser, 1964). Vertigo occurs in isolation, without tinnitus and hearing loss. The age of onset is usually by 4 years, but can be as late as 12 years. Vertigo usually lasts less than 1 minute but may last only seconds. Vertigo may occur while sitting, standing, or lying. Pallor, nausea, sweating, and occasionally vomiting occur. Consciousness is not impaired, and the child can recall the episode. There may be no pain or headache associated with the attacks. Immediately after the

attack, the child resumes normal activities. The interval between the attacks varies from weekly to every 6 months. Vertigo attacks usually cease spontaneously after a few years. Physical examination, including a neurologic evaluation, is normal, as is imaging of the skull and temporal bones. Basser reported a moderate or complete canal paresis on caloric testing. However, the response to bithermal caloric testing has been found to be highly variable (Finkelhor and Harker, 1987; Mira et al., 1984). Other testing is normal. Children with benign paroxysmal vertigo of childhood often have a positive family history of migraine, and migraine headaches may develop in later years (Koehler, 1980; Lanzi et al., 1994) and may respond positively to antimigraine treatment. The initial treatment of migrainous vertigo in children is dietary restrictions of foods known to provoke migraine. If this is unsuccessful, the next step is symptomatic treatment with a vestibular suppressant, such as meclizine, during episodes. However, the episodes are usually very brief. If the spells are frequent and especially if they impair school performance, use of a prophylactic antimigraine agent, such as propranolol or topiramate, should strongly be considered (Cass et al., 1997). In younger children, cyproheptadine has also been used successfully.

Ménière’s Disease Ménière’s disease, a syndrome presumably caused by endo­ lymphatic hydrops, can occur spontaneously or as a delayed sequela of a previous insult from trauma or viral infection. The disorder rarely occurs in children. Ménière’s disease is characterized by a combination of dizziness, unilateral hearing loss, and unilateral tinnitus, which are usually preceded by a feeling of fullness in the affected ear. Following episodes, chil­ dren are more likely to recover auditory function than are adults. Ménière’s disease can be bilateral. Also, with time, a reduction in the responsiveness of the involved peripheral vestibular system occurs. Management of endolymphatic hydrops in children includes reassurance and explanation of the condition to the parents, in addition to salt restriction and a diuretic (Cyr et al., 1985).

Seizure Disorders Seizure disorders are often accompanied by some sense of dizziness and disequilibrium, although seizures are not fre­ quently associated with true vertigo. However, the term tornado epilepsy has been used to describe seizures that are associated with a sense of spinning that can mimic the symptoms of a peripheral vestibular ailment. If a typical vertiginous spell is followed by a generalized tonic-clonic seizure, the diagnosis becomes clearer.

Familial Episodic Ataxia Familial episodic ataxia is a rare syndrome with autosomaldominant inheritance and is characterized by episodes of diz­ ziness, disequilibrium, and gait instability that may last for several hours. At least eight types of the syndrome have been identified, and genetic testing is available. These syndromes differ in the duration of the paroxysms of ataxia and associ­ ated features. Treatment with acetazolamide can be very helpful for those responsive to it.

Nonvertiginous Disequilibrium Patients with both peripheral and central vestibular disorders can have nonvertiginous disequilibrium, imbalance, and ataxia. Indeed, many disorders affecting the CNS are symp­ tomatic in this way. Bilateral peripheral vestibular disorders



Vertigo

57

typically occur without vertigo and thus may mimic a central disorder. Numerous CNS abnormalities can be associated with nonvertiginous dizziness. Many of these abnormalities involve the cerebellum and include cerebellar hypoplasia or atrophy, posterior fossa tumors, and Chiari malformations. Also, medi­ cation side effects should not be overlooked when evaluating a child with dizziness and disequilibrium.

Treating anxiety disorders in children is challenging because of medication side effects. If the anxiety symptoms are severe, patients should be referred to a child psychiatrist. Some children with sensory integration disorder, with or without developmental delay, may be overly responsive to vestibular stimulation. An early intervention therapeutic program that helps desensitize the child may help immensely.

Bilateral Peripheral Vestibular Loss

Treatments

Bilateral peripheral vestibular loss can be either congenital and due to inner ear malformations or acquired from menin­ gitis, ototoxicity, and autoimmune disease of the inner ear. Regardless of etiology, bilateral vestibular loss, if severe, is called Dandy’s syndrome. Dandy’s syndrome is characterized by two specific symptoms: oscillopsia (i.e., jumbling of the visual surround during head motion) and severe gait instabil­ ity in darkness. Children with bilateral vestibular loss often learn to use alternative sensory inputs, such as vision and proprioception. Also, they modify strategies of eye move­ ments. Environments and tasks that require vestibular func­ tion, such as ambulating in dimly lit spaces or trying to maintain stable vision during walking, are extremely challeng­ ing for individuals with bilateral vestibular loss.

In addition to the medications that have been discussed, ves­ tibular rehabilitation therapy (VRT) may also be helpful in the treatment of vertigo. Exercises designed to help compensate for an inner ear deficit are taught by specialized physical thera­ pists. VRT can be helpful for benign paroxysmal positional vertigo (BPPV), Ménière’s disease, labyrinthitis, vestibular neu­ ritis, and postconcussion vertigo when the symptoms persist for more than a few weeks.

Central Nervous System Disorders Numerous CNS disorders cause dizziness, disequilibrium, imbalance, and ataxia. In childhood, cerebellar abnormalities, such as cerebellar vermian hypoplasia, posterior fossa tumors, and Chiari malformation, are the most common disorders encountered. Cerebellar atrophy and ataxia syndromes, such as those caused by familial spinocerebellar ataxia disorders, can also cause these symptoms and are typically progressive. The clinical presentation of such patients may be confusing because they are unlikely to have vertigo and may not display evidence of limb ataxia if their abnormalities affect solely midline cerebellar structures.

Drug-Induced Dizziness Many drugs can cause nonvertiginous dizziness. For example, the aminoglycosides, especially gentamicin, can cause ototox­ icity, which may result in bilateral peripheral vestibular loss. In the pediatric age group, phenytoin is used in the treatment of epilepsy and may produce dizziness and nystagmus as signs of intoxication. With this in mind, any child in whom dizzi­ ness develops while on a regular medication should be viewed as a possible case of iatrogenic dizziness.

Nonneurotologic Disorders Another cause of dizziness in children is psychosomatic diz­ ziness, which usually occurs in children of school age. It may be associated with depression, adjustment reaction of adoles­ cence, and behavior problems. Such children usually have normal vestibular and auditory testing, normal electroenceph­ alograms, and normal imaging studies. When evaluating a child with dizziness, it is essential to determine whether the patient has an associated anxiety disorder, either as the sole cause of their vertiginous complaints, as an accompaniment to an underlying balance system abnormality, or indirectly related to the dizziness, e.g., through a common brainstem ailment causing both disequilibrium and an anxiety disorder.

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Balkany, T.J., Finkel, R.S., 1986. The dizzy child. Ear Hear. 7 (3), 138–142. Basser, L., 1964. Benign paroxysmal vertigo of childhood. Brain 87, 141–152. Cass, S.P., et al., 1997. Migraine-related vestibulopathy. Ann. Otol. Rhinol. Laryngol. 106 (3), 182–189. Cyr, D.G., et al., 1985. Vestibular evaluation of infants and preschool children. Otolaryngol. Head Neck Surg. 93 (4), 463–468. Finkelhor, B.K., Harker, L.A., 1987. Benign paroxysmal vertigo of childhood. Laryngoscope 97 (10), 1161–1163. Furman, J.M., 1995. Role of posturography in the management of vestibular patients. Otolaryngol. Head Neck Surg. 112 (1), 8–15. Humphriss, R.L., Hall, A.J., 2011. Dizziness in 10 year old children: an epidemiological study. Int. J. Pediatr. Otorhinolaryngol. 75 (3), 395–400. Koehler, B., 1980. Benign paroxysmal vertigo of childhood: a migraine equivalent. Eur. J. Pediatr. 134 (2), 149–151. Lanzi, G., et al., 1994. Benign paroxysmal vertigo of childhood: a long-term follow-up. Cephalalgia 14 (6), 458–460. Mira, E., et al., 1984. Benign paroxysmal vertigo in childhood. Diag­ nostic significance of vestibular examination and headache provo­ cation tests. Acta Otolaryngol Suppl. 406, 271–274. Wiener-Vacher, S.R., 2008. Vestibular disorders in children. Int. J. Audiol. 47 (9), 578–583.

E-BOOK TABLES AND FIGURES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 8-2 The Pediatric Clinical Test of Sensory Organization and Balance. Fig. 8-3 Examples of normal responses and abnormalities of the saccadic eye movement system, the pursuit system, and optokinetic nystagmus. Fig. 8-4 Recording of spontaneous nystagmus. Fig. 8-5 Mechanism of caloric stimulation of the horizontal semicircular canal (see text for details).

8

9 

Taste and Smell Julie A. Mennella, Nuala Bobowski, and Djin Gie Liem

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

CHEMICAL SENSES The chemical senses of taste, smell, and chemical irritation convey a range of information, warning us of environmental hazards and determining the flavor—good or bad—of ingested foods and liquids (Doty, 2015). The pleasure or displeasure experienced upon ingesting food results from a complex process mediated by the chemical senses in the periphery and then by multiple brain substrates, which are remarkably well conserved phylogenetically. The degree to which the chemicals that stimulate these flavor senses are liked or disliked is determined by interactions of innate factors and experience. Hardwired from birth, the basic biology of humans steers us to seek out sweet foods dense with energy, salty foods dense with minerals, and savory foods rich in proteins and to reject bittertasting toxins and unripe sour foods (Mennella, 2014). In essence, these senses function as gatekeepers throughout the life span: they control one of the most important decisions an animal is required to make—whether to reject a foreign substance or consume it.

Taste, Smell, and Flavor The Taste System Taste, or gustation, refers to the sensation that occurs when chemicals stimulate taste receptors located on a large portion of the tongue’s dorsum and other parts of the oropharynx, such as the larynx, pharynx, and epiglottis. The taste system is attuned to a small number of perceptual classes of experience, the so-called basic tastes (i.e., sweet, salty, savory, bitter, and sour), each of which specifies crucial information about nutrients or dangerous substances. These basic tastes either stimulate intake (sweet, salty, and savory) or inhibit it (bitter and perhaps sour). From an evolutionary perspective, these taste qualities likely evolved to detect and reject that which is harmful (e.g., bitter) and to seek out and ingest that which is beneficial (e.g., sweet, salty). Unlike our modern, commercially produced diet, which has led to the widespread use of added sugars and salts in many parts of the world, the diet of our primitive past was drastically different: salt and sugar were rare and difficult to obtain. Thus the preference for salty and sweet tastes, which is heightened during childhood (Mennella, 2014), is thought to have evolved to attract us to minerals and energy-producing sugars (and their accompanying vitamins) during periods of maximal growth, whereas rejection of bitter-tasting and irritating substances evolved to protect us from poisons, and rejection of concentrated sours evolved to protect us from unripe fruits. The hedonics of taste are intimately connected to the ingestion or rejection of foods and beverages and thus can pose a nutritional risk when foods and beverages containing highly preferred tastes (sweet, salty) are consumed in excess. Indeed, many chronic diseases (e.g., hypertension, obesity) that plague modern society derive in large part from poor food choices, dictated by our taste preferences. The senses can also pose a

58

risk when healthful foods such as bitter-tasting vegetables are avoided and when children fail to comply with a medication regimen due to the bad taste of the drugs. Many active pharmaceutical ingredients taste bitter or irritate the mouth and throat. Although encapsulating the medicine in pill or tablet form to avoid unpleasant tastes is effective for adults, this is problematic for children, many of whom cannot or will not swallow pills and thus often consume their medication in a liquid formulation. Children cannot benefit from medicines they will not take, and their heightened sensitivity to some bitter tastes makes this especially challenging (Mennella et al., 2013). The taste receptors in the oral cavity are localized in taste buds, which are innervated by branches of three cranial nerves: the facial (VII), glossopharyngeal (IX), and vagal (X) nerves (Fig. 9-1). Major progress has been made in identifying the initial events in taste recognition. It appears that two different strategies have evolved to detect taste molecules (Bachmanov et al., 2014). For salty and sour tastes, it is widely believed that ion channels serve as receptors. Here H+ (sour) and Na+ (salty) ions are thought to flow through the channels into the cell. However, for both of these taste qualities, the molecular identity of the receptors and their exact mechanisms are still under investigation. For sweet, umami (savory), and bitter tastes, G-proteincoupled receptors (GPCRs) appear to play the most prominent roles. These GPCRs bind taste molecules in a sort of lock-and-key mechanism. For sweet and umami, a family of three GPCRs, named T1R1, T1R2, and T1R3, act in pairs (T1R1 + T1R3 for umami, and T1R2 + T1R3 for sweet) to detect molecules imparting these taste qualities. The bitter receptors, the T2Rs, comprise a substantially larger family of GPCRs, with about 25 members (Bachmanov et al., 2014). Not only are the chemicals that elicit these three taste qualities detected by specialized receptors on the tongue and other parts of the oral cavity, but many of these receptor proteins are expressed in a wide variety of other tissues, including the gastrointestinal tract, testes, respiratory epithelium, brain, and heart. Although their function in these tissues is still under investigation, this is an emerging area of research. For example, it was recently discovered that bitter receptors expressed in the ciliated cells of the sinonasal epithelium can trigger immune responses when stimulated with chemical signals from bacteria. Thus the expression of these bitter taste receptors in respiratory epithelium may also play a vigilant role in upper airway immunity.

The Olfactory System Smell, or olfaction, occurs when chemicals stimulate olfactory receptors located on a relatively small patch of tissue high in the nasal cavity. Odor stimuli can reach the olfactory receptors in two ways: by entering the nostrils during inhalation (orthonasal route) or by traveling from the back of the oral cavity toward the roof of the nasal pharynx (retronasal route). Individual experiences largely determine how much a person



Taste and Smell

59

Clinical Disorders of Taste and Smell

Arcuate nucleus of thalamus

Sphenopalatine ganglion V Great superficial petrosal nerve Vidian nerve

SSPN

Lingual nerve

Otic ganglion

Chorda tympani

Circumvallate papillae

Solitary tract and nucleus

?

VII IX X

Lower medulla oblongata

Figure 9-1.  Taste innervation is supplied by cranial nerves VII, IX, and X. Filiform, fungiform, and circumvallate papillae are present, with most taste sensation originating from the fungiform and circumvallate papillae. The anterior two thirds of the tongue is innervated by the chorda tympani, a branch of cranial nerve VII; the posterior one third of the tongue and palate are innervated by cranial nerves IX and X. Central connections of the pathways of the cranial nerves in the nucleus solitarius ascend through the thalamus to the parietal operculum. SSPN, small superficial petrosal nerve.

likes or dislikes an odor, although there is some evidence that some odors may be innately biased in a positive or negative direction.

Flavor Flavor, as an attribute of foods and beverages, is defined as the integration of multiple sensory inputs of the taste, retronasal olfaction, and irritation (e.g., sensations of burn, viscosity, and temperature, resulting from stimulation of nerve endings in the soft membranes of the buccal and nasal cavities of a substance in the oral and nasal cavities. However, the perceptions arising from the taste and smell senses are often confused and misappropriated—odors perceived through the mouth (retronasally) are referred to the oral cavity, whereas odors perceived through the nose (orthonasally) are referred to the external world. For example, the sensations of vanilla, fish, chocolate, and coffee are often erroneously attributed only to the taste system, but much of the sensory input results from retronasal olfaction. Holding the nose while eating interrupts retronasal olfaction and thereby eliminates many of the subtleties of food or medicines, leaving only the taste components.

The common confusion between taste and retronasal olfaction is highlighted when patients, young and old, report they cannot taste when they suffer only from olfactory loss. Approximately two thirds of patients who present to specialized chemosensory clinics complain of taste loss, but most patients are diagnosed with a measurable smell dysfunction, rather than a gustatory one, as the basis of their “taste” complaint. A retrospective review of patients evaluated for chemosensory dysfunction complaints revealed that severe, generalized taste deficits (i.e., complete or nearly complete taste loss) do occur but are extremely rare, whereas profound olfactory deficits are more common. Although complete taste loss is rare, clinical disorders that influence taste and smell perception are more common (Mott and Leopold, 1991; Cowart et al., 1997). As shown in Box 9-1 and Box 9-2, disorders of taste and smell can arise from a variety of sources (Mott and Leopold, 1991; Schecklmann et al., 2013; Doty, 2015); however, many of the conditions listed are based on adult patients’ reports and not on standardized test assessments of chemosensory functioning or controlled clinical trials. This lack of systematic analysis, as well as patient confusion between taste and retronasal olfaction, underscores the need for careful sensory evaluation of these causes. Moreover, clinical disorders that influence taste and olfactory perception involve multiple organ systems and require a multidisciplinary approach for appropriate diagnosis and management. Despite advances in our understanding of the mechanisms and functions of the chemical senses, there are no internationally accepted standards of impairment for the chemical senses, and the treatment options for taste and smell disorders remain limited. Olfactory dysfunctions resulting from impairment of odor access to the olfactory receptors may be treated. For example, patients may experience improvements in olfactory ability after adenoidectomy or surgical management of nasal polyps, which can reestablish nasal airflow. However, individuals whose deficit involves the olfactory neuroepithelium or central olfactory or cortical pathways typically have no treatment options other than time and possible spontaneous recovery. Similarly, the prognosis for severe taste loss is mixed, and gradual recovery was the most common pattern observed in such patients. In addition to a careful medical history and otolaryngologic examination, assessment of a smell or taste complaint should involve standardized testing using a variety of psychophysical techniques (e.g., detection thresholds, magnitude estimates, quality identification) in a clinical setting. This is particularly important for evaluating olfactory and taste functioning in young children (younger than 5 years of age), who are more prone to attention lapses, tend to answer questions in the affirmative, have limited ability to read and identify labeled choices, and are likely to be unfamiliar with many stimuli used in adult tests. To address the need for brief, comprehensive assessment tools that can be used by clinicians and researchers in a variety of settings, the National Institutes of Health (NIH) Blueprint for Neuroscience Research established and then funded the Toolbox Initiative to assemble tools to assess the domains of cognition, emotion, motor function, and sensation. Included in the sensation tool set is a validated, specialized battery of tests to assess taste and smell for diverse populations from 3 to 85 years of age (Coldwell et al., 2013). Information on the NIH Toolbox tests to assess taste and olfaction can be obtained from the NIH website (www.nihtoolbox.org) and from a special issue of the journal, Neurology (vol. 80, no. 11, suppl. 3).

9

60

PART I  Clinical Evaluation

BOX 9-1  Conditions Associated with Disturbances of Taste • Genetic conditions • Familial dysautonomia • Turner syndrome • Endocrine, metabolic, and autoimmune conditions • Adrenal insufficiency • Cronkhite-Canada syndrome • Diabetes mellitus • Hypothyroidism, pseudohypoparathyroidism • Hyperthyroidism • Lupus erythematosus • Primary amyloidosis (affecting tongue) • Reiter syndrome • Scleroderma • Sjögren syndrome • Gastrointestinal and liver diseases • Acute hepatitis • Chronic liver disease • Obstructive jaundice • Hypertension • Iatrogenic conditions • Acoustic tumor removal • Hypophysectomy • Laryngectomy • Tonsillectomy • Cerebellopontine angle meningioma removal • Chorda tympani injury or stretching • Radiation or chemotherapy • Temporal lobectomy • Infectious conditions • Upper respiratory tract infection • Candidiasis

• Ulcerative lesions (e.g., gonorrhea, herpes simplex, mycoses, syphilis, varicella zoster) • Local processes • Glossitis • Hansen disease • Oral mycosis • Otitis media • Parotid infection or tumor • Submandibular gland carcinoma • Neurologic conditions • Bell palsy • Brain tumor • Guillain-Barré syndrome • Head trauma • High-altitude syndrome • Migraine • Multiple sclerosis • Seizure disorders • Uremia or dialysis • Miscellaneous conditions • Bulimia • Acquired immunodeficiency syndrome (AIDS)-related periodontitis • Cancer • Dental caries • Gastric reflux disease • Gingivitis (acute and chronic) • Occupational exposure

(Data taken with permission from Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991;75:1321; and from Bromley SM, Doty RL. Clinical disorders affecting taste: Evaluation and management. In: Doty RL, ed. Handbook of olfaction and gustation, 2nd ed. New York: Marcel Dekker, 2003:935.)

For further information about taste and smell disorders, see the National Institute on Deafness and Other Communication Disorders (NIDCD) Information Clearinghouse, a national resource center for information about hearing, balance, smell, taste, voice, speech, and language for health professionals, patients, industry, and the public (www.nidcd.nih.gov/health/ misc/pages/clearinghouse.aspx), as well as the NIDCD website (www.nidcd.nih.gov) and the National Institute of Dental and Craniofacial Research website (www.nidcr.nih.gov). Specific clinical questions can be addressed to the NIDCD, the Monell Chemical Senses Center, or the University of Pennsylvania Health Taste and Smell Clinic.

THE ONTOGENY OF TASTE PERCEPTION   AND PREFERENCES The convergence of findings from the scientific literature suggests that human infants, as well as children, have functioning gustatory and olfactory systems that modulate their feeding and expressive behaviors. This responsiveness is not the same as that of adults; these chemosensory systems mature postnatally (Table 9-1) and are influenced by experiences in ways we are just beginning to understand (Mennella, 2014). Little is known about the infant’s perception of chemical irritation (e.g., sensations of burn, viscosity, and temperature). Thus this section focuses on the senses of taste and smell, but we acknowledge that other chemical senses may play important roles in the behavior of infants.

The fetus and newborn infants have functioning chemosensory systems, and infants’ feeding and expressive behaviors are modulated by taste and smell stimuli. Although these sensory systems are operable early in ontogeny, the fetus and newborns are not merely miniature adults because their sensory systems mature postnatally and are influenced by experience in ways not yet fully understood. Like other sensory systems, taste is experienced through a “sensory window” that changes with age and experience and is partially defined by genetics. Children have well-developed sensory systems for detecting tastes, as well as smells and chemical irritants, and their basic biological preferences for sweet and salty and rejection of bitter tastes are heightened during childhood until late adolescence, when they decline to levels observed in adults. These sensory and biological considerations shed light on why children are so vulnerable to the current food environment rich in added sugars and salt (Mennella, 2014) and why children often reject the bad taste of medicines (Mennella et al., 2013).

Clinical Significance of Taste in   Infants and Children Taste dysfunctions are described by several terms (Cowart et al., 1997). Ageusia refers to a complete loss of gustatory function, whereas hypogeusia refers to diminished sensitivity to detect a specific taste quality or class of compounds (e.g., phenylthiocarbamide). Dysgeusia and phantogeusia refer,



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BOX 9-2  Conditions Associated with Disturbances of Olfaction • Genetic conditions • Cleft palate (males) • Down syndrome • Familial dysautonomia • Kallmann syndrome • Turner syndrome • Central nervous system malformations • Septo-optic dysplasia • Holoprosencephaly • Endocrine or metabolic conditions • Adrenal insufficiency • Diabetes mellitus • Hypothyroidism • Pseudohypoparathyroidism • Iatrogenic conditions • Laryngectomy • Ethmoidectomy • Hypertelorism procedures • Orbitofrontal lobectomy • Radiotherapy • Rhinoplasty • Submucous resection, nasal septum • Temporal lobectomy • Infectious conditions • Herpes simplex meningoencephalitis • Human immunodeficiency virus (HIV) infection • Upper respiratory tract infection • Liver disease • Acute viral hepatitis • Cirrhosis

9 • Local processes • Hansen disease • Nasal obstruction (adenoid hypertrophy, large inferior turbinates) • Polyposis • Sjögren syndrome • Tumors • Neurologic conditions • Alzheimer disease • Head trauma • Huntington disease • Korsakoff syndrome • Multiple sclerosis • Meningiomas • Migraines • Parkinson disease • Seizure disorders • Temporal lobe tumors • Myasthenia gravis • Psychiatric conditions • Hypochondriasis • Major depression • Posttraumatic stress disorder • Schizophrenia • Uremia or dialysis • Miscellaneous conditions • Cystic fibrosis • Giant cell arteritis • Occupational exposure • Sarcoidosis

(Adapted with permission from Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991;75:1321–53; psychiatric conditions updated from Schecklmann, et al. J Neural Transm 2013;120:121–30.)

TABLE 9-1  Developmental Changes in Response to Tastes Primary Taste

Taste Example

Fetuses and Premature Infants

Newborns

Older Infants (1–24 months)

Children

Sweet

Sugars

Preference*†

Preference*†

Preference*†

Preference*†

Sour

Citric acid

Not known

Rejection*

Rejection*

Preference*†

Bitter

Quinine Urea

Not known Not known

Rejection* Indifference* Rejection‡

Not known Rejection

Rejection*

Salty

NaCl

Not known

Indifference* Rejection§

Indifference Preference*¶

Preference*†

Umami

MSG

Not known

Preference‖

Preference‖

Not known

*Responses to various taste solutions relative to water or diluent. †Heightened preference compared with adults. ‡Facial expressions suggest rejection, whereas intake studies suggest indifference. §Sucking measures suggest rejection, whereas intake and facial expression studies suggest indifference. ¶Preference emerges at approximately 4 months of age; before that, indifference or rejection occurs, depending on the methods used. ‖Preference seen only when monosodium glutamate (MSG) is mixed with soup; MSG solution alone is rejected relative to plain water.

respectively, to distortion in the perceived qualities of a taste stimulus and the experience of a taste sensation in the apparent absence of a gustatory stimulus. The study of clinical abnormalities in taste perception in pediatric populations has received little scientific attention, in part because, as discussed earlier, the clinical assessment of taste is not well developed. Some reports in these age groups, although limited, are highlighted here. Box 9-1 lists conditions that sometimes are associated with taste disorders in adults.

A few disorders with neurologic symptoms have been associated with taste disturbances in infants and children. Familial dysautonomia is a hereditary autonomic and sensory neuropathy that affects almost exclusively Jewish children of Ashkenazi extraction. Patients with this disorder could detect but failed to label correctly salty, bitter, sweet, and water stimuli, but sour taste and the sense of smell were preserved. Surgical procedures of the head or neck may sometimes result in taste distortion. For example, tonsillectomy

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has been associated with taste dysfunction, perhaps because of damage to the lingual branch of the glossopharyngeal nerve. Approximately one third of patients experience taste disturbance 2 weeks after undergoing a tonsillectomy; levels decrease to 8% at 6 months and 2% at 18 months after surgery. Surgical procedures that involve the middle ear may damage the chorda tympani nerve (branch of cranial nerve VII), which mediates taste perception on the anterior tongue. Damage to or anesthesia of the chorda tympani nerve can increase taste sensations (particularly bitter) from the glossopharyngeal branch of cranial nerve IX and cranial nerve X and blunt retronasal olfactory sensations from cranial nerve I. Likewise, middle ear infections or oral infections that reach the middle ear through the eustachian tubes may affect the chorda tympani nerve as it passes between the malleus and incus and thus affect taste perception. Insults to the chorda tympani nerve may explain some taste disruptions. In particular, occurrence of otitis media during childhood was associated with losses of bitter taste on the tip of the tongue and, when severe, reduced perception of sweetness throughout

the mouth, which was associated with a higher risk for obesity. Endocrine, metabolic, and nutritional disorders causing loss of taste are rare in adults and presumably in pediatric populations. Children with chronic renal failure exhibited reduced preference for sweet-tasting foods, which was unrelated to plasma zinc levels, whereas infants and children diagnosed with second- and third-degree protein-energy malnutrition preferred soup to which savory tastes (e.g., casein hydrolysate) had been added over soup alone. Such findings provide information that may be useful for clinicians in planning palatable diets for these patients. The most common etiologic factor contributing to taste disturbances in adults appears to be medication use (Schiffman, 1983), but there are few reports regarding similar effects in pediatric populations. Not all individuals taking a particular drug are affected, and the mechanisms by which these medications alter chemosensory function are not well understood. Nevertheless, a variety of medications have been reported sometimes to cause taste (and smell) dysfunction in adults (see Table 9-2).

TABLE 9-2  Drugs Associated with Taste and Smell Dysfunction* Medication Class

Specific Drug

Chemosensory Dysfunction

Anesthetic

Benzocaine Lidocaine Cocaine Tetracaine

Ageusia Anosmia Anosmia Ageusia

Antibacterial

Procaine penicillin Metronidazole Tetracycline Doxycycline

Metallic dysgeusia Metallic dysgeusia Metallic dysgeusia Anosmia, parosmia

Antiepileptic

Carbamazepine Tegretol

Hypogeusia Hypogeusia

Antidiabetic

Biguanide

Metallic dysgeusia

Antifungal

Amphotericin B

Hypogeusia

Antiinflammatory

Phenylbutazone Azelastine

Ageusia Bitter, metallic dysgeusia

Immunosuppressive/antineoplastic

5-Fluorouracil Methotrexate Cisplatin

Sour, bitter dysgeusia Sour, metallic dysgeusia; ageusia Ageusia

Antirheumatic

Allopurinol Penicillamine

Metallic dysgeusia Metallic dysgeusia

Antithyroid

Methylthiouracil

Ageusia and anosmia

Cardiovascular

Captopril Diltiazem Nifedipine

Increased taste thresholds Hypogeusia, hyposmia Dysgeusia and parosmia

Dental products

Chlorhexidine Hexidine Sodium lauryl sulfate

Ageusia, loss of salty taste, persistent aftertaste Altered taste Loss of sweet and salty taste; dysgeusia

Muscle relaxant

Baclofen

Ageusia, hypogeusia

Opiate

Codeine Morphine

Olfactory depression Olfactory depression

Sympathomimetic

Amphetamines

Bitter dysgeusia; parosmia

Tranquilizers

Chlormezanone

Ageusia; metallic and bitter dysgeusia

Vasopressors

Midodrine

Metallic dysgeusia; antiseptic (“Dettol/Pine-Sol”) parosmia

*This is a partial listing of the medications associated with taste and smell disturbances in adults. Not all individuals taking a particular drug are affected, and the mechanisms by which these medications alter chemosensory function are not well understood.



THE ONTOGENY OF OLFACTORY AND   FLAVOR PERCEPTION Infants are able to detect and discriminate a wide variety of odors shortly after birth. They hedonically respond to differences in odor quality, appear to be as sensitive to odors as adults (if not more so), and are capable of retaining complex olfactory and flavor memories. The early state of maturity and plasticity of the olfactory system favor is related to its involvement in adaptive re­­ sponses to development. First, experience-induced plasticity in response to odors is a means to tune the olfactory system to stimuli deemed relevant in an individual’s environment. Second, salient memories formed during the first 10 years of life will likely be olfactory. Autobiographical memories triggered by olfactory information mainly occurred during the first decade of life, whereas those associated with verbal and visual cues more often occurred later in adolescence and early adulthood. The normal fetus has open airway passages that are bathed in amniotic fluid and inhales more than twice the volume it swallows during the latter stages of gestation; thus the fetus may be exposed to a unique olfactory environment before birth. This experience represents the first exposure to flavors (tastes and retronasally perceived odors) that will subsequently be provided in mother’s milk and then in table foods. Such retronasal perception of odors in amniotic fluid and then in mother’s milk provides the infant with the potential for a rich source of various chemosensory experiences and facilitates transition from a diet consisting exclusively of human milk to a mixed diet by providing the infant with bridges of familiarity, such that the infant experiences common flavors in the two feeding situations (Mennella, 2014). Because the infant’s first flavor experiences occur before birth in amniotic fluid, breast milk forms a bridge between the experiences of flavors in utero and those in solid foods. The types and intensity of flavors experienced in breast milk may be unique for each infant and serve to identify the culture to which the child is born and raised. When an infant is exposed to a flavor in the amniotic fluid or breast milk and is tested sometime later, the exposed infants accept the flavor more than infants without such experience. This pattern makes evolutionary sense because the foods that a woman eats when she is pregnant and nursing are likely the ones to which her infant will have the earliest exposure. Breastfeeding conferred an advantage when infants first tasted a food, but only if their mothers regularly eat similartasting foods. If their mothers eat fruits and vegetables, breastfed infants will learn about these dietary choices by experiencing the flavors in mother’s milk, thus highlighting the importance of a varied diet for both pregnant and lactating women. These varied sensory experiences with food flavors may help explain why children who are breastfed are less picky and more willing to try new foods; this, in turn, contributes to greater fruit and vegetable consumption in childhood. Learning about foods and flavors continues during and after weaning. Regardless of whether infants are breastfed or formula-fed, they can learn through repeated dietary experience and dietary variety. Both formula-fed and breastfed infants ingest significantly more of a particular pureed fruit or vegetable after repeated exposure (8 to 10 days) to that particular food. Merely looking at the food does not appear to be sufficient because children have to taste the food to learn to like it. Furthermore, the dietary experience does not have to include the specific food, because exposure to a variety of foods between and within a meal, not just repeated exposure to a single food, facilitates acceptance of novel fruits and vegetables within that particular food category.

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The food habits established during infancy track into childhood and adolescence for both nutrient-dense and nutrientpoor foods. Such dietary patterns, which begin to be identified during childhood, are significant determinants of the quality of the adult diet. This raises important issues about high-risk neonates, whose early sensory experiences are often drastically different from those of a typical infant, lacking continuity with prenatal sensory experiences. For example, preterm infants are often unable to coordinate sucking, swallowing, and breathing, so nasogastric or orogastric tube feeding is used to provide adequate nutrition. When fed by a tube, infants likely have a relatively constrained olfactory and flavor experience in the context of feeding because their nutrition bypasses the oral and nasal cavities. High-risk infants are also faced with a wide array of medical conditions that contribute to temporary or permanent alteration of taste and smell as adults. Many medications, including antibiotics and antiinflammatory agents (Schiffman, 1983), have been shown to alter taste and smell (see Table 9-2), and these medications are commonly given to high-risk neonates. Gastroesophageal reflux disease is another common problem in preterm infants and results in a sour or bitter taste in the mouth from reflux of stomach acid up the esophagus and into the throat. The long-term effects of these alterations on the development of flavor preferences in the child are not known.

Clinical Significance of Olfaction in   Infants and Children The terminology used to describe olfactory dysfunction parallels that used for taste disorders (Doty, 2015). Anosmia refers to the complete absence of olfactory functioning, whereas hyposmia refers to diminished olfactory functioning. In some patients, there may be a deficit in the perception of only a specific odorous compound (e.g., androsterone) or a class of compounds; this condition is commonly referred to as specific anosmia. Hyperosmia refers to an increased sensitivity to smell, dysosmia or parosmia refers to distortions in the perceived qualities of an odor stimulus, and phantosmia refers to the perception of an odor when the odor stimulus is not present. Box 9-2 lists several conditions that are associated with olfactory disorders in adults. Paranasal sinus disease, prior upper respiratory tract infection, and head trauma account for more than two-thirds of adult cases of olfactory dysfunction. One of the more common forms of head trauma among athletes, concussion, is also associated with olfactory dysfunction, particularly difficulty in identifying odors. Of particular relevance to the neurologist is the fact that a cardinal feature of several neurodegenerative diseases (e.g., Alzheimer, Parkinson) is an olfactory deficit. The loss of smell (and hearing) is less common after head trauma in children than in adults. Common causes associated with impaired olfactory sensitivity in children include nasal obstruction; allergic, chronic, or hypertrophic rhinitis; and nasal polyps (frequently seen in children suffering from cystic fibrosis). Olfactory functioning improves after adenoidectomy in children with nasal obstruction caused by adenoid hypertrophy. Evaluating a child with partial or complete loss of smell may require referral to an otorhinolaryngologist to determine whether there are any local pathologic findings (e.g., foreign body, nasal polyp). Shearing of the olfactory nerves, hemorrhage into the olfactory bulb, fractures of the cribriform plate, and frontal lobe contusions have all been reported in children, but their effects on chemosensory functions remain unknown. As for the sense of taste, little is known about genetic and congenital disorders of smell perception in infants and

9

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children. Although the majority of cases of anosmia are acquired, a small minority of individuals is born anosmic; however, the exact cause for this congenital condition remains unknown (Feldmesser et al., 2007). The principal genetic syndrome associated with permanent anosmia, Kallmann syndrome, is associated with mutations in a variety of genes, many of which are related to defects in neuronal migration. Like the sense of taste, a variety of medications can affect olfactory perception in adults (Schiffman, 1983) (Table 9-2). Moreover, certain metals (e.g., cadmium, zinc, mercury), tobacco products, and a variety of industrial substances cause olfactory loss or distortion. Several psychiatric conditions are associated with olfactory dysfunction among adults (Box 9-2). Although many posit that relationships exist between olfactory dysfunction and neuropsychiatric disorders among children (Schecklmann et al., 2013), the lack of standardized methodologies and control measures, and potential confounds such as attention and medication use make definitive diagnoses or conclusions difficult. Nevertheless, many disorders are often associated with changes in feeding behaviors (e.g., “picky” eating), which may involve each of the chemical senses. In assessing picky eating, a thorough medical history and physical examination are recommended to assess the child’s growth and nutritional status and to determine the presence of underlying conditions that may result in feeding problems, such as premature birth, gastroesophageal reflux, swollen tonsils, viral infection, or food allergies. A focused feeding history should be completed, including the duration of the feeding problem, whether the child has shown signs of difficulty swallowing, whether the child was ever placed on nothing-by-mouth (nil per os [NPO]) for prolonged periods of time, and whether associated medical interventions centered on the mouth area. Parents should be asked to report on the child’s behaviors associated with the feeding problem, including whether anything specific aggravates or alleviates the problem, whether the child indicates hunger or demonstrates an appetite, typical meal duration, and even parental temperament and expectations during feeding times. Because underlying causes of picky eating are oftentimes not due to a medical condition but may be due to lack of prior experience— for example, limited exposure to particular foods or a variety of foods and flavors—understanding all aspects of a child’s feeding history is imperative to developing treatment strategies to help the child improve eating behavior.

SUMMARY The chemical senses of taste, smell, and chemical irritation convey information that warns us of environmental hazards and determines the flavor of ingested foodstuffs. The complex process that generates pleasure or displeasure upon ingesting food is mediated both by the chemical senses in the periphery and by multiple brain substrates, which are remarkably well conserved phylogenetically. Hardwired from birth, the basic biology of humans steers us to seek out sweet (energy-dense), salty (mineral-dense), and savory (protein-rich) foods and to reject bitter-tasting toxins and unripe sour foods. The fetus and newborn infants have functioning chemosensory systems, and infants’ feeding and expressive behaviors are modulated by taste and smell stimuli. Although these sensory systems are operable early in ontogeny, the fetus and newborns are not merely miniature adults, because their sensory systems mature postnatally and are influenced by experience in ways not yet fully understood. Like other sensory systems, taste is experienced through a “sensory window” that changes with age and experience and is partially defined by genetics. Children’s basic biological preferences for sweet and

salty and rejection of bitter tastes are heightened during childhood. These sensory and biological considerations shed light on why it is difficult to make lifestyle changes in young children and why it is difficult for children to eat nutritious foods when these foods do not taste good to them or take medicines that taste extremely bitter. We cannot easily change the basic ingrained biology of liking sweets and avoiding bitterness. What we can do is modulate children’s flavor preferences by providing early exposure, starting in utero, to a wide variety of healthy flavors and moderating exposure to salt. The reward systems that encourage us to seek out pleasurable sensations and the emotional potency of food- and flavor-related memories initiated early in life together play a role in the strong emotional component of food habits throughout the life span. An appreciation of the complexity of early feeding and a greater understanding of the cultural and biological mechanisms underlying the development of food preferences will aid in our development of evidence-based strategies and programs to improve the diets of our children. Better understanding of the scientific basis for distaste and how to ameliorate it is a public health priority for advancing availability of formulations of drug products that will be accepted by children and getting children off to a good start in food choices and preferences. The study of smell and taste perception in clinical populations of infants and children and the influence of chemosensory dysfunction on nutritional status have received little scientific attention, and they remain important areas for future investigations. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bachmanov, A.A., Bosak, N.P., Lin, C., et al., 2014. Genetics of taste receptors. Curr. Pharm. Des. 20 (16), 2669–2683. Coldwell, S.E., Mennella, J.A., Duffy, V.B., et al., 2013. Gustation assessment using the NIH Toolbox. Neurology 80 (11 Suppl. 3), S20–S24. Cowart, B.J., Young, I.M., Feldman, R.S., et al., 1997. Clinical disorders of smell and taste. Occup. Med. 12 (3), 465–483. Doty, R.L. (Ed.), 2015. Handbook of Olfaction and Gustation, third ed. Wiley Blackwell, New York. Feldmesser, E., Bercovich, D., Avidan, N., et al., 2007. Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia. Chem. Senses 32 (1), 21–30. Mennella, J.A., 2014. Ontogeny of taste preferences: Basic biology and implications for health. Am. J. Clin. Nutr. 99 (3), 704S– 711S. Mennella, J.A., Spector, A.C., Reed, D.R., et al., 2013. The bad taste of medicines: Overview of basic research on bitter taste. Clin. Ther. 35 (8), 1225–1246. Mott, A.E., Leopold, D.A., 1991. Disorders in taste and smell. Med. Clin. North Am. 75 (6), 1321–1353. Schecklmann, M., Schwenck, C., Taurines, R., et al., 2013. A systematic review on olfaction in child and adolescent psychiatric disorders. J. Neural Transm. 120 (1), 121–130. Schiffman, S.S., 1983. Taste and smell in disease (second of two parts). N. Engl. J. Med. 308 (22), 1337–1343.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 9-2 Lateral depiction of the innervation of cranial nerves. Fig. 9-3 Major structures involved in olfaction.

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Neuropsychological Assessment Margaret Semrud-Clikeman and Kenneth F. Swaiman

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Pediatric neuropsychology differs from adult neuropsychology because development is incomplete and brain differences emerge through childhood and adolescence that interact with the environment changing brain structure and neural pathways (Giedd, 2004). A discussion of neuropsychological assessment can be found in several excellent texts (Lezak et al., 2004). The teaming of neurology and neuropsychology can provide state-of-the-art service to children, particularly those with complex and refractory disorders. Because development is an important aspect at both ends of the life span, it is important to recognize the neuropsychological differences that may occur and the manner in which they may relate to interventions. Moreover, an important aspect for children is the ability to do well in school. Executive functioning is an important aspect of academic and social success. Executive functioning in the areas of planning, organization, emotional control, and inhibition are all important skills for success. Frequently physicians are consulted about difficulties in these areas. An important reference to assist physicians, teachers, and parents in working with children with difficulties in this area has been published by Lynn Meltzer (Meltzer, 2007). Finally, studies that link brain imaging differences in children with autism (Adolphs, 2002) and attention-deficit/hyperactivity disorder (ADHD) (SemrudClikeman et al., 2006) are providing new windows into our understanding of these disorders.

NEUROPSYCHOLOGICAL ASSESSMENT What is a Neuropsychological Assessment? Neuropsychological assessments are frequently completed to provide additional information about a variety of developmental disorders. The most common referral questions con­ cern medical disorders including genetic disorders, concussion/ traumatic brain injury, recovery from cancer/brain tumors, and other neurologic concerns such as epilepsy and movement disorders. In addition, children who have acquired disorders such as those resulting from exposure to lead or other teratogenic substances are also frequently referred for an evaluation. Disorders such as dyslexia, ADHD, autism spectrum disorder, and fetal alcohol spectrum disorder are common reasons for referral for assessment, particularly when typical interventions have not been successful. Psychiatric disorders such as obsessive-compulsive disorder, anxiety and depression, and behavioral dysregulation are referred for evaluation to more fully understand the child’s difficulty and to provide recommendations for intervention in the home and at school. Child clinical neuropsychology is best viewed within an integrative perspective for the study and treatment of child and adolescent disorders. By addressing brain functions and the environmental influences inherent in complex human behaviors, such as thinking, feeling, reasoning, planning, and executive functioning, clinicians can assist neurologists and

pediatricians in providing the most appropriate service to children with severe learning, psychiatric, developmental, and acquired disorders (Chapters 50 and 58 and chapters in part XIX). Although clinical psychologists and neuropsychologists use similar measures, the interpretation differs. A neuropsychologist views test findings through the lens of neurodevelopment. With our burgeoning knowledge of neural development from studies of serial magnetic resonance imaging, we are able to more fully understand how the environment, genetics, age, gender, and experience can alter brain activity and brain development (Shaywitz et al., 2004). Attention to the scope and sequence of development of cortical structures and related behaviors that emerge during childhood allows further understanding of the effect of interventions, instructional opportunities, and enrichment on the neurodevelopmental process. Due to the complexity of the brain, and in particular the developing brain, it is most appropriate to utilize a transactional approach to the study and treatment of childhood and adolescent disorders. A description of a transactional approach is that it takes into consideration how abnormalities or developmental complications interact with the environment, how development itself affects the nature and severity of impairment, how to most efficiently assess these difficulties, and how to determine the most appropriate interventions. In this model, neuropsychological assessment—correctly completed—is therapeutic. In this view, the child’s performance on appropriate measures plus the feedback to the medical professional, parent, and school provide a basis for understanding the child’s strengths and weaknesses and for participating in the development of appropriate interventions. A transactional approach stresses consultation and collaboration with the caregivers of the child (as well as assisting the child in adjusting to his/her areas of challenge) but also with medical practitioners. In summary, child clinical neuropsychology is best viewed within an integrated framework, incorporating behavioral, psychosocial, cognitive, and environmental factors into a comprehensive model for the assessment and treatment of brain-related disorders in children and adolescents. Current theory posits that regions of the brain have a bidirectional influence on various neural functional systems, which in turn affect the intellectual and perceptual capacity of the child. The child’s behavioral, psychological, and cognitive manifestation of a childhood disorder is likely influenced by the interaction of these functional systems. In addition, the child’s neurologic functioning also interacts with his/her social, family, and school environments that facilitate compensatory or coping skills in the individual child, which are either helpful or problematic. Theorists have hypothesized that developmental regulation underlies behavioral and biological functioning. In other words, biological vulnerabilities influence and are influenced by coping skills and stresses experienced in the child’s life. Such adaptation may or may not be efficient or “healthy” but can be viewed as the child’s attempt to achieve self-stabilization. In such a paradigm, the individual reacts to both internal and

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external environments as he or she attempts to make his or her way in the world. Children who experience severe neglect and/or abuse in utero have been found to exhibit significant dysregulation and disruption of the hypothalamic-pituitaryadrenal axis affecting emotional and neuropsychological development (Tarullo and Gunnar, 2006). The transactional model incorporates these findings by assuming a dynamic interaction among the biogenetic, neuropsychological, environmental, cognitive, and psychosocial systems. Further, biogenetic forces shape the child’s experiences and are most predominant during embryogenesis and early infancy. As the child develops, the social and cultural environment in which he or she lives begins to influence the child’s neurologic development. Moreover, the child’s temperament also interacts with all of these environments and causes changes in these environments. The quality of fit between the caregiver’s and the child’s temperaments can result in adaptation to difficult behavior or exacerbation of this behavior. For example, a child who is fussy and difficult will not fare as well with an anxious or domineering parent as with a more even-tempered parent. Similarly, an “easy” child will generally work well with any parent. A “difficult” child-“easy” parent match may be advantageous in that the parent can help reduce the adverse effects of the child’s inborn biological tendencies. So, although parental caretaking may not change the biological tendencies of the child, it may buffer biological vulnerabilities (Rothbart and Sheese, 2007). For those children who experience early deprivation and/or abuse, parental caretaking begun at later ages may not be able to fully buffer neurologic differences that are laid down early on. Rather, the child may always have these difficulties and will need additional support to develop appropriate coping mechanisms. The physician is well placed to understand neurologic development within the lens of transactional theory.

MULTICULTURAL FACTORS It is important to note that most neuropsychological measures have not been standardized on ethnicities beyond middleclass whites. Cultural expectations and mores have just begun to be studied in neuropsychology. In the past, neuropsychology has suggested that the brain may not be culturally bound. Currently, culture and neurodevelopment has been implicated in handedness, specialization of the cerebral hemispheres for tasks, and self-reports of behavioral functioning (Carlson et al., 2000). Differences in language may also affect neuropsychological assessment even when an interpreter is utilized. Some words or concepts do not readily translate from English. Moreover, the standardized norms may not apply to the patient’s ethnicity. An example of these difficulties is exemplified in a study by Keith and Fine (2005) which focused on possible ethnic differences in learning. Quality and quantity of instruction, previous achievement, and motivation were statistically evaluated across Anglo-American, African American, Hispanic, Native American, and Asian American groups. Although higher quality of instruction was found to lead to better achievement across the groups, quality of instruction appeared to be less important for Native American groups than quantity of instruction. Quantity of instruction was also found to be important for the Asian American population. In contrast, academic motivation and prior achievement were the best predictors for learning for the Anglo-American students. There were also differences for African American and Hispanic students where motivation, previous achievement and coursework were the strongest influences on their resultant learning. These findings indicate that children of different ethnicities

may benefit from differing strategies and that cultural differences may play a major role in task performance.

NEUROPSYCHOLOGICAL TESTING Neuropsychological testing can be very useful to the neurologist in assisting in developing appropriate interventions. Neuropsychological testing is generally an adjunct to the neurologic assessment and can be helpful in establishing areas of strengths and weaknesses that can then be translated into assistance in the school setting. Most neuropsychologists use a flexible battery that covers the main domains of functioning to assess children. Generally, the focus in neuropsychological assessment with children and adolescents revolves around the following tenets: a. It is important to discriminate between behaviors pres­ ent within a normal neurodevelopmental framework from those which are delayed or which are a result of alterations of the central nervous system given the child’s social-environmental context. b. Learning deficits/disorders and behavioral difficulties are examined within the context of brain function. c. Recovery of function after brain injury, neurosurgery, and radiologic/chemotherapy treatment is monitored to assess the effect of these treatments on normal development and emotional/behavioral adjustment. d. Focus is present on the different neuropsychological domains of functioning, particularly in the areas of cognition, executive functioning, memory, motor, behavior, and emotion during recovery or during a neurodevelopmental course. e. Neuropsychology investigates the psychiatric disorders of children with severe neurologic disorders. f. Neuropsychology assists in the design of remediation programs, particularly when used within an integrated clinical framework. Scores on neuropsychological measures are generally one of four types. Scaled scores are generally found on the subtests of major measures including the Wechsler Intelligence Scales, executive functioning scales, as well as some of the achievement batteries. Average scaled scores are between 7 and 13 with a mean at 10. Scores between 5 and 7 are below average and those 4 and lower are considered significantly below average. Scaled scores between 13 and 15 are above average and those above 15 are significantly above average. Figure 10-1 illustrates these different types of scores. Standard scores are those with a mean of 100 and average performance between 85 and 115. Most overall IQ measures, adaptive functioning, and executive functioning measures are based on these standard scores. As seen in Figure 10-1, scores 116 to 130 are considered high average and those above 130 superior. Scores from 70 to 84 are considered low average and those below 70 are considered significantly below average. T scores are used with some ability measures (Kaufman Assessment Battery for Children and Differential Ability Scales) and with developmental measures (Mullen Scales of Early Learning) as well as with many behavioral rating scales. Average T scores range from 40 to 60 with scores above 60 classified as high or above average and those below 40 as below average or low average. In some cases, scores will be presented with percentiles. Percentiles cannot be used as precisely as scaled, standard, or T scores and cannot be subtracted or added. Rather, they give an idea of how the child compares to other children his/her age. At times, age equivalents and grade equivalents may be reported, but these are only rough estimates and should be used with extreme caution. A child in third grade who scores at a first grade level is not performing as a first grader would



67

Neuropsychological Assessment

Number of cases

10

Standard deviations

Low average Low 2.14%

Deficient 0.13% 4

High average

13.59%

3

Superior 2.14%

Average

2

34.13% 1

34.13%

Mean Test score

13.59% 1

2

3

Very superior 0.13% 4

Percentile ranks 1

5

10

20 30

50

70 80

90

95

99

T scores 10

20

30

40

50

60

70

80

Standard scores (SD  15)

55

70

85

100

115

130

145

Standard scores (SD  3)

1

4

7

10

13

16

19

90

Figure 10-1.  Normal curve showing standard scores, T Scores, Percentiles, and Z-Scores. (Modified from www.assessmentpsychology.com. ©2005–2014. William E. Benet, PhD, PsyD. All rights reserved.)

on the material; rather, it means that the child shares with the average first grader the number of items correct on the test and should only be interpreted in reference to the child’s current grade comparison group. Similarly, age equivalents are obtained by computing the average raw score obtained by children at different ages. Table 10-1 describes the major measures used by most child neuropsychologists. It is not meant to be an exhaustive list of all available measures as that is beyond the scope of this chapter. Table 10-1 is intended to provide basic information about the measures frequently reported in neuropsychological assessments. Unless noted otherwise, higher scores are desirable.

WHEN TO REFER FOR NEUROPSYCHOLOGICAL EVALUATION Neuropsychological evaluations are generally recommended under the following conditions: 1. Conditions affecting the central nervous system, such as head trauma, chemotherapy/radiation treatment, genetic disorder, neurodegenerative disorders, transplant (solid organ or bone marrow), and seizures. Serial evaluations are particularly important for these children in order to monitor recovery as well as to assess treatment efficacy. 2. Learning difficulties that have not responded to traditional educational intervention, particularly when there are soft neurologic signs present. Soft signs include toe-walking, concurrent movement in a body part not required for a motor task (synkinesia), problems with perception of finger location as well as tactile sensations (agnosia), problems with completing rapid alternating movement in a limb or body part (dysdiadochokinesis), and tactile localization as well as minor reflex asymmetries in the presence of normal cognitive development. 3. Severe mood and behavioral dysregulation that have been resistant to traditional psychopharmacological, psychological, or behavioral interventions.

4. Acute onset of memory, cognitive, academic, motor, speech/language, behavioral, and behavioral dysregulation disorders. 5. Regression of skills previously mastered.

THE NEUROPSYCHOLOGICAL REPORT A good neuropsychological evaluation and report will include measures of cognition, executive functioning, learning/ memory (visual and oral), fine motor, visual-motor, behavior, and emotion. Generally, neuropsychological reports begin with an explanation of the referral question and then move into background information concerning the child’s gestation, delivery, early development, and medical history. One of the most important aspects of the neuropsychological report is the section describing the behavioral observations. This section describes the child’s reaction during the session as well as any unusual observed behaviors. Particular emphasis is given to the child’s attention to task, frustration tolerance, and the ease with which rapport is established. These aspects of the child’s behavior affect the results that are found and are very important for understanding the validity and reliability of the assessment. Good neuropsychological reports not only synthesize in an understandable manner the findings from tests, but they also incorporate the background information, medical history, and behavioral observations into a coherent story to assist with treatment. In addition, the report should provide tailored recommendations for home, school, and if appropriate, medical treatment. Table 10-2 provides the aspects of a good neuropsychological report. A Roman numeral will highlight these aspects in the following excerpts. The sample report contained in this section is representative of a report that was found to be useful by the neurologist who referred the child: I. Reason for Evaluation: Sasha Small is a 9-year, 10-month old, right-handed male who was referred to the Pediatric

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PART I  Clinical Evaluation

TABLE 10-1  Most Commonly Used Neuropsychological Measures Neuropsychological Measure DEVELOPMENTAL SCALES Bayley Scales of Infant Development III (BSID III)

Age Range

Description

Comments

1–42 mos

Provides overall cognitive scores as well as scores in the areas of language, motor, and behavior. Provides scores and age equivalents for expressive language, receptive language, fine motor, gross motor, and visual reception (measure of problem solving). Provides age equivalents in the areas of motor, language, and social.

Excellent overall measure. Reliability and validity are very good. Must be administered by a trained professional. Very child friendly—attractive tasks which are quite hands on. Can be administered by trained nurses as well as psychologists. Good screening measure and should be used to refer for further testing if needed. Nurses and nurse practitioners can administer.

Provides overall score as well as scores on verbal comprehension, perceptual reasoning, working memory, and processing speed. Similar to WPPSI.

Excellent measure of cognitive ability for children without language difficulties.

Mullen Scales of Early Learning

Birth to 68 mos

Denver Developmental Screening Test II

Birth to 6 yrs

COGNITIVE Wechsler Primary and Preschool Scale of Intelligence (WPPSI) IV

2–6 : 7–3

Wechsler Intelligence Scale for Children V

6.0 : 16–11

Kaufman Assessment Battery for Children II

3–18

Stanford-Binet Intelligence Scale 5

2–85+

Differential Abilities Scale II

2–6 : 17–11

Woodcock-Johnson Test of Cognitive Abilities Cognitive Battery IV

2–85+

Universal Nonverbal Intelligence Test

5–0 : 17–11

Leiter International Intelligence Scale-3 Comprehensive Test of Nonverbal Intelligence 4

3–75+

Nonverbal test.

6–0 : 89–11

Nonverbal measure.

3–16

Comprehensive test of measures of memory (verbal and visual), attention, inhibition, verbal fluency, sensorimotor skills.

Delis-Kaplan Executive Function System

8–89

Behavior Rating Inventory of Executive Functioning

2–18

Comprehensive measure of executive functioning including measures of working memory, metacognition, perspective taking, attention, planning, and organization. Parent, teacher, and self-rating of basic executive functioning skills.

Wisconsin Card Sorting Test

6–6 : 89

EXECUTIVE FUNCTIONING A Developmental NEuroPSYchological Assessment (NEPSY II)

Provides a measure of cognitive functioning with less dependence on language. Results in scores for planning, knowledge, simultaneous, and sequential reasoning; also has a nonverbal score. Provides scores for verbal ability, perceptual reasoning, working memory, and overall ability. Provides measures of verbal skills, memory, and nonverbal processing. Also has an achievement scale. Measures of fluid reasoning, auditory processing, memory, attention, visual-motor skills. More like an academic test. Provides an overall measure of ability— does not use language.

Measure of cognitive flexibility, attention, distractibility, and problem solving.

One of the best measures of overall ability, providing information about working memory and processing speed as well as general language and perception. Very strong psychometric properties. Requires advanced training for administration and interpretation. Good measure for children of different cultures or whose first language is not English. Is relatively easy to administer and score. Usually administered by psychologists/neuropsychologists. Excellent measure for younger children with difficulty with attention and motor control. With older ages, the load on language is substantial. Excellent measure for children with reduced attentional skills, autism, and behavioral regulation difficulties. Very long battery than can take over 90 min to administer. Not frequently used by neuropsychologists—more often used in education. Excellent measure for hard-of-hearing children as well as English-as-a-secondlanguage learners. Good for deaf, hard-of-hearing and English-as-a-second-language learners. Fairly good screen for ability but as defined there is no language component. Excellent measure for executive functioning as well as for memory and motor skills. Most clinicians do not use the full battery as it can take more than 2 hours to administer. Requires a psychologist/ neuropsychologist to administer. Excellent measure of executive functioning. Requires a skilled neuropsychologist for interpretation. Most clinicians use some subtests rather than full battery as it can take more than 2 hours to administer. Provides measure of emotional control, behavioral regulation, and metacognition. Computer scored. Can be administered by medical personnel as well as psychology. Complex administration and scoring require additional training—generally administered by neuropsychologists.



Neuropsychological Assessment

69

TABLE 10-1  Most Commonly Used Neuropsychological Measures (Continued) Neuropsychological Measure

10

Age Range

Description

Comments

MEMORY California Verbal Learning Test—Children’s version

5–16.11

Good and relatively easy measure of short- and long-term memory as well as learning rate.

Wechsler Memory Scale-IV

16–0 : 90–11

Requires the child to learn a list of words and provides 4 additional practice trials. Also provides a delay as well as cues to remembering the list. Appropriate for patients 16 yrs and older. Provides a comprehensive evaluation of memory as well as individual scores of visual and auditory memory.

Rey-Osterrieth Complex Figure Test

5–0 to adult

Test of Memory and Learning-2

5–0 : 59–11

Requires the patient to copy a very complex figure and then 20 minutes later to draw from memory. Measures of visual and auditory memory as well as the patient’s ability to learn a novel task.

Good measure of memory, both long and short-term. Full test requires more than 1 hour to administer. Most clinicians use a part of the measure. Generally administered by psychologists. Easy to administer—requires some training for interpretation. Measures planning and organization as well as visual-motor skills. Good measure of overall memory.

MOTOR Purdue Pegboard Test

3–adult

Measure of fine motor dexterity.

Grooved Pegboard Test

5–adult

Measure of fine motor dexterity.

Tapping

5–adult

Measure of fine motor speed.

Grip Strength

6–adult

Measure of hand strength.

6–0 : 23–11

Measure of reading accuracy, rate, and comprehension. Provides a detailed measure of reading ability, mathematics, written language, and auditory comprehension. Provides a detailed measure of reading, mathematics, and written language as well as oral comprehension.

Good and fairly quick measure of overall reading ability. Requires some training for administration. Must be computer scored.

2–adult

This is a comprehensive measure of behavior and emotional development. Provides T scores for externalizing, internalizing, and adaptive behaviors.

18 mos–90+

This is a comprehensive measure of behavior and emotional skills. T scores are available for internalizing and externalizing behaviors.

Has a parent, teacher, and self-report form. Easy to administer and relatively easy to interpret. Has computer scoring. Is unique as it also has adaptive behavior scales. Different forms for preschool, ages 8–11, ages 12–21, and adults. Widely used. Has a teacher, parent, and self-report form. Easy to administer and relatively easy to interpret with computer scoring. Assessment has multicultural applications in Africa, Asia and South America.

0–90

This measure provides parent, caregiver, and/or teacher input as to the child’s performance in communication, daily living skills, socialization and for children ages 5 and under, fine and gross motor skills. There is also a measure of problematic behaviors. Has 5 forms based on age. Is completed by parents and teachers. Provides 3 adaptive domains (communication, socialization, daily living skills).

ACHIEVEMENT Gray Oral Reading Tests IV Woodcock-Johnson Test of Achievement Battery V Wechsler Individual Achievement Test III BEHAVIOR RATING SCALES Behavior Assessment System for Children-2

Achenbach System of Empirically Based Assessment (Child Behavior Checklist)

ADAPTIVE BEHAVIOR SCALES Vineland Adaptive Behavior Scale

Adaptive Behavior Assessment System, 3rd edition

2–85+ 4–0 : 50–11

0–89

Can compare dominant, nondominant, and both [hands] together scores. Easy to administer and score. Can compare dominant and nondominant hands. More complex than Purdue as it has pegs that fit only one way into the hole. Provides scores for dominant and nondominant hands. Patient must tap quickly on a key. Easy to administer and score. Provides measure of hand strength for dominant and nondominant hands. Easy to administer and score.

Requires some training for administration, scoring, and interpretation.

Relatively easy to administer and score. The scale can be compared with ability scores as well as to language skills. There are two forms—the rating scale completed independently by the parent or the interview scale. The interview scale requires additional training. Very easy for parents to complete. Has parent, teacher/day care provider forms as well as an adult form.

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PART I  Clinical Evaluation

TABLE 10-2  Details of an Optimal Neuropsychological Report Report Aspect

What is Included

I. Reason for Referral

Clear, concise, explanation for referral; name of referring professional; relevant medical information.

II. History

Provides relevant information about parental education, family composition and history, current stressors, medical and social history.

III. Behavioral Observation

This very important section provides information about how the child approached the tasks, attention, language, mood, and how easily rapport was established. It also includes a statement as to how valid and reliable the results are which were obtained.

IV.  Tests Administered

This is a brief list of what measures were utilized.

V. Test Interpretation and Impressions

This is the body of the report and includes information as to how the child scored on measures of cognition, language, attention, memory, and motor skills. It concludes with a summary statement that not only provides information as to what these findings mean and what diagnoses are appropriate, it also links these findings to neurologic and psychological functioning.

VI. Recommendations

This section provides recommendations and is generally grouped into three sections: school, medical, and home.

Neuropsychology Clinic by the Neurofibromatosis Clinic. Sasha has a history of neurofibromatosis type 1 (NF1), a genetic syndrome that is associated with physical manifestations such as skin abnormalities, as well as increased risk for learning disabilities and behavioral problems. At present, Sasha attends fourth grade in a regular education classroom. He receives speech therapy to address concerns related to articulation. His parents reported several behavioral concerns, including immature behaviors, difficulty making friends, and frequent angry outbursts. The purpose of the current evaluation was to assess Sasha’s neurocognitive functioning and to assist with educational and treatment planning. The next part of the report should provide a short synopsis of the family and social history. This section should include information about the parents and their education, the family makeup, and any stressors currently being experienced. In addition, the developmental and medical history should provide information about the pregnancy and delivery as well as developmental milestones and any concerns that were present during infancy and toddlerhood. It should also provide information as to whether the child has had any head injuries, experienced any domestic violence or other trauma, and information about the child’s vision, hearing, sleep, and appetite. After this section, information about the child’s school history is very helpful, particularly outlining whether the child has any special accommodations, has been evaluated by his or her school or another clinician, and what reports the teachers have made as to the child’s academic progress and social and behavioral functioning. It should also provide information about what psychological services (therapy) have been put into place for this child. Finally, within this section,

it is optimal to have a summary section that concisely discusses the child’s current level of functioning. The following excerpt illustrates this summary: II. Current Functioning: Sasha’s parents reported primary concern regarding Sasha’s difficulties with behavioral regulation and social development. His mother indicated that Sasha’s behavior can be difficult to manage when he is angry or he does not get his way. He will have long “fits” if his parents tell him to do things he does not want to do (e.g., brush teeth, change clothes, take a shower, turn off electronics, or practice math/reading). Sasha frequently becomes angry or jealous of his sister, who does not tend to misbehave or get into trouble. He will frequently yell at her and sometimes he will become aggressive and hit her. His parents noted that despite these behaviors, Sasha can also be sweet, kind-hearted and gentle at times. As stated, the behavioral observations section is very important for understanding how the child was during the assessment, his/her level of engagement, how difficult/easy it was to establish rapport, and to describe areas of functioning such as language, attention, and mood. By reading the next excerpt one should be able to picture Sasha during the assessment and whether to have faith in the results. III. Behavioral Observations: Sasha’s mother accompanied him to the evaluation. Sasha presented as a casually dressed boy who appeared his chronological age. He was appropriately dressed, but frequently walked around with untied shoelaces. He willingly accompanied the examiner and his mother to the testing room. After being seated and beginning the testing, Sasha did not take off his heavy winter coat until the examiner had prompted him to do so. Sasha was able to transition into testing without difficulty. Rapport was easily established and maintained. Sasha’s speech was fluent, but he had difficulties with articulation and made several sound substitutions particularly the “r” sound (e.g., “three” = “thwee,” “break” = “bwake”). His speech was usually intelligible, although the examiner occasionally needed to prompt him to repeat himself to understand what he said. Sasha asked questions or commented on the tests frequently, and occasionally made requests (e.g., asking for a break or a snack). Sasha frequently made comments when he felt that a test item was difficult. Sasha’s eye contact was appropriate. No problems were apparent with fine or gross motor skills, and no unusual motor movements were observed. He wrote and drew with his right hand. It was notable that during a pegboard task, Sasha dropped pegs several times when trying to place them in the board. Sasha was generally pleasant and cooperative throughout the evaluation. He had some difficulty regulating his body and would frequently stand up in his chair during the tasks. On some tasks he had difficulty waiting for directions to be completed before attempting to start the task, and the examiner often needed to prompt him to listen to all of the instructions. He was generally attentive to the tasks, although toward the end of the session he appeared more distracted and often looked elsewhere when the examiner talked with him. He was occasionally distracted by looking at some playground equipment outside the testing room window. His affect varied according to the topic but was appropriate to the situation. He appeared fatigued toward the end of testing and occasionally asked how much time was left. He took multiple long bathroom breaks during testing. Sasha showed a few behaviors that seemed more typical of a younger child. For example, when asked a question about whether he had ever purposefully hurt himself, he began hitting his head and joked that it was



Neuropsychological Assessment

“fun.” When the examiner followed up with additional questions, he denied a desire to hurt himself. Overall, Sasha seemed to put forth good effort on the testing and worked to the best of his abilities. Therefore the results of testing are thought to be a valid and accurate indicator of Sasha’s functioning in the areas assessed. The next section discusses the findings and should provide a concise and systematic review of the measures. Discussion of cognitive ability, memory, executive functioning, and behavioral/emotional functioning should be discussed. It is also important to tie these results to whatever medical, genetic, or brain difference is present. The following is very short excerpts of a much longer report to give a flavor of what should be included in a good neuropsychological report. Tests that were used are in italics and underlined allowing more efficient use of Table 10-1. IV. Result and Impressions: Sasha Small is a 9-year, 10-month old boy with a history of neurofibromatosis type 1 (NF1). NF1 is an inherited neurologic disorder that can affect multiple systems of the body. It is associated with symptoms such as skin changes, neurofibromas (tumors that form on the nerves under the skin), skeletal abnormalities, and other complications. Additionally, problems with behavioral health can be one of the most significant features of the syndrome for many individuals. Research indicates that children with NF1 are at higher risk for cognitive and learning disabilities than unaffected children, as well as for social and behavioral difficulties. Due to this increased risk, it can be useful to obtain periodic developmental assessments to inform educational and treatment planning. This paragraph sets the stage for understanding the relationship between NF1 and the neuropsychological findings. The report then moves into the various domains that were assessed beginning with cognition: Results of the current evaluation indicate that Sasha’s overall intellectual abilities are broadly within the average range (Wechsler Intelligence Scale for Children-V). Sasha performed slightly weaker on verbal tests (i.e., those assessing his knowledge of verbal concepts and his ability to reason with words), scoring mildly below average. Finally, like many individuals with NF1, Sasha performed below average range on tests of working memory, suggesting a relative weakness in the ability to hold information in mind for short periods of time while solving a problem. Taken together, Sasha’s profile suggests that he has intact intellectual functioning, but he does better on tasks that require him to process visual information than tasks that depend on verbal or working memory abilities. Consistent with his overall average cognitive abilities, Sasha performed within the average range on a measure assessing his verbal learning and memory (California Verbal Learning Test-Children’s Version). The next section begins to characterize attention and executive functioning, two areas that significantly impacted children with NF. These findings did not result in a diagnosis of ADHD but did result in a finding of frontal lobe executive dysfunction. Frontal lobe executive dysfunction is a disorder characterized by difficulties with organization, working memory, and planning. These difficulties often translate into problems in academic skills particularly in the areas of mathematics: Attention skills are an area of concern for many children with NF1, and many children with this diagnosis also qualify for a

71

diagnosis of attention-deficit/hyperactivity disorder (ADHD). Results of the current assessment indicate that Sasha does demonstrate some weaknesses in attention, but at the current time these symptoms are not sufficiently impairing to warrant a diagnosis of ADHD (Test of Variables of Attention). Sasha does show evidence of difficulties with managing his impulses. On a questionnaire measure of executive functioning skills Behavior Rating Inventory of Executive Function (BRIEF), Sasha’s mother indicated significant concerns related to initiating tasks, managing his emotions, and monitoring his behaviors. On a similar questionnaire (BRIEF), his teacher indicated significant concerns related to inhibiting behaviors and self-monitoring. Sasha performed within normal limits on clinic-based measures of executive functioning (e.g., his ability to quickly generate words according to letter and category cues and his ability to rapidly scan and sequences sets of numbers and letters) (Delis Kaplan Tests of Executive Function). Results of the current evaluation suggest that Sasha does well with tasks when provided guidance and prompting by the examiner, but struggles with impulse control and selfmonitoring when working independently. These results are consistent with a frontal lobe and executive function deficit, which is commonly seen in children who exhibit ADHD symptoms and encompasses Sasha’s difficulties with organizing an approach to schoolwork tasks. A good neuropsychological report also addresses the child’s psychological/emotional/behavioral functioning. The following section is an example of how a diagnosis of NF1 can affect the child’s adjustment. Emotionally, parent and teacher ratings did not indicate problems severe enough to indicate a mood or anxiety disorder, although his NF1 diagnosis and family history indicates that Sasha is at risk for these problems in the future. Therefore his social-emotional well-being should be monitored over time. On a questionnaire measure, his mother reported significant aggressive behaviors (e.g., often argues with parents, loses temper too easily, annoys others on purpose) and has depressive symptoms (e.g., is easily upset, complains about not having friends, is negative about things), suggesting that Sasha may be developing frustration surrounding his difficulties managing his behaviors and directs this frustration toward others (Behavior Assessment System for Children-2). Indeed, Sasha’s responses to a self-report measure indicated mild concerns related to negative thinking patterns and depression (e.g., feeling that he has too many problems, doesn’t seem to do anything right, and is not understood by others). Finally, a summary of the test results is very useful, and it is frequently the paragraph that most physicians turn to as the bottom line for the child: In summary, we are pleased to note that Sasha is functioning at age-expected levels in a variety of areas including intellectual functioning, his ability to learn and retain new information, and his mental flexibility. Overall, Sasha does not show significant intellectual or learning problems seen in some children with NF1, consistent with his overall mild features. These strengths suggest that Sasha has the capability to continue to do well academically. Sasha’s weaknesses with impulse control, social awareness, and mood regulation are commonly seen in children with NF1 and can be addressed in the classroom, at home or in recreational settings. The final section of the report should include recommendations that are reasonable and which can be implemented (Part VI in Table 10-2). Generally, recommendations in three

10

72

PART I  Clinical Evaluation

areas are provided: academic, behavioral, and psychological. The academic recommendations are written to assist schools in providing appropriate services for children and may recommend assessment for an Individual Educational Plan required under law for children suspected of a disability. In Sasha’s case, he may qualify under the category of “Other Health Impaired” or, in some states, “Other Health Disability” due to his diagnosis of NF1. If he does not qualify for special education, he may qualify for assistance under the Americans with Disabilities Act that allows for support within the regular classroom for children with medical disorders. The behavioral section often addresses the need for psychotherapy as well as for additional supports for emotional development. In this section, recommendations for parental support are also provided as well as directions for further evaluation if the child experiences more difficulty. For example we made the following recommendations: V. We recommend that Sasha’s family, school professionals, and therapist continue to monitor Sasha for symptoms of a mood disorder. In the future, if his caregivers observe an increase in behavioral outbursts, diminished interest or pleasure in activities, withdrawal from activities he previously enjoyed, increased irritability, or if Sasha is experiencing increased worries that become distressing or difficult to control, they may wish to have him re-evaluated by a psychologist or a neuropsychologist to determine whether further mental health supports are needed. We recommend that Sasha’s caregivers focus on praising/ rewarding Sasha for his effort and for improvements in his ability to regulate his behavior (e.g., “Wow! I liked how you kept thinking about that problem until you figured out a solution; nice work, buddy!,” or “Awesome job listening!”) rather than praising him for specific achievements or successes. For children like Sasha, too much focus on outcomes (e.g., grades, test scores, athletic achievements such as points scored in a game) may serve to create high levels of competitiveness and self-doubt. Praise that is focused on accomplishments and achievements can actually serve to increase negative selfperceptions if the child finds himself struggling to meet a goal. Instead, reinforcement of things like Sasha’s effort, persistence and good attitude can help to take his focus off of “winning” and “achieving” and will likely result in Sasha being able experience more fun and enjoyment in his daily activities. As a follow-up to this case, the school used this report to develop a treatment plan to provide Sasha with appropriate interventions to assist with his development. Sasha had been participating in play therapy, which was not providing any

success in changing his behaviors or mood. After our discussion, therapy was shifted from play therapy to a more directed therapy that provided Sasha with tools to manage his behaviors.

CONCLUSION Pediatric neuropsychological assessments can serve as an important adjunct to clinical practice. A good neuropsychological report will not only provide a summary of the findings but will also provide appropriate interventions and support. The feedback to the parents of the results is an important therapeutic tool that can assist them in adjusting to some of the child’s difficulties while also emphasizing the strengths that the child possesses. Neurology and neuropsychology are a natural alliance that can assist with appropriate support for children and their families. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Adolphs, R., 2002. Neural systems for recognizing emotion. Curr. Opin. Neurobiol. 12 (2), 169–177. Carlson, C.I., Uppal, S., Prosser, M., 2000. Ethnic differences in processes contributing to the self-esteem of early adolescent girls. J. Early Adolesc. 20 (1), 44–67. Giedd, J.N., 2004. Structural magnetic resonance imaging of the adolescent brain. Ann. N. Y. Acad. Sci. 1021, 77–85. Keith, T.Z., Fine, J.G., 2005. Multicultural influences on school learning: similarities and differences across groups. In: Frisby, C.L., Reynolds, C.R. (Eds.), Comprehensive Handbook of Multicultural School Psychology. John Wiley & Sons, Hoboken, NJ, pp. 457–482. Lezak, M.D., Howieson, D.B., Loring, D.W., 2004. Neuropsychological Assessment, fourth ed. Oxford University Press, New York. Meltzer, L., 2007. Executive Function in the Classroom. Guilford, New York. Rothbart, M.K., Sheese, B.E., 2007. Temperament and emotion regulation. In: Gross, J.J. (Ed.), Handbook of Emotion Regulation. Guilford Press, New York, pp. 331–350. Semrud-Clikeman, M., Pliszka, S.R., Lancaster, J., et al., 2006. Volumetric MRI differences in treatment—naïve vs chronically treated children with ADHD. Neurology 67, 1023–1027. Shaywitz, B.A., Shaywitz, S.E., Blachman, B.A., et al., 2004. Development of left occipitotemporal systems for skilled reading in children after a phonologically-based intervention. Biol. Psychiatry 55, 926–933. Tarullo, A.R., Gunnar, M.R., 2006. Child maltreatment and the developing HPA axis. Horm. Behav. 50, 632–639.

PART II

11 

Neurodiagnostic Testing

Spinal Fluid Examination David J. Michelson

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION For more than a century, physicians have employed lumbar puncture (LP) and examination of the cerebrospinal fluid (CSF) in the diagnosis and management of neurologic diseases. Major and lasting contributions to the study of CSF are represented by the textbooks written by Merritt and FremontSmith (1938) and Fishman (1992). CSF evaluation is contributing to our still-evolving understanding of the pathophysiology of central nervous system (CNS) disorders, while continuing to play an as yet indispensable role in the clinical management of many of those disorders.

CEREBROSPINAL FLUID FORMATION, FLOW, AND ABSORPTION CSF is principally formed by secretion from the choroid plexus, villous invaginations of the walls of the lateral, third, and fourth ventricles that are richly vascularized and lined by a ciliated epithelium. The choroid plexus of the lateral ventricles is continuous through the foramina of Monro with the choroid plexus of the roof of the third ventricle. The arterial supply to this portion of the choroid plexus originates from the anterior choroidal arteries, which branch off from the internal carotid arteries, and from the posterior choroidal arteries, which are branches of the posterior cerebral arteries. The posterior inferior cerebellar arteries usually supply the choroid plexus of the fourth ventricle. Blood flow to choroidal vessels is almost 10 times greater than that to the cerebral cortex. The capillaries of the choroid plexus, unlike those found in most other areas of the brain, have large fenestrations that offer little resistance to the passage of fluid, ions, and small macromolecules. Passage of blood past these capillaries creates an ultrafiltrate of plasma within the interstitial space at the basolateral surface of the epithelial cells. CSF secretion depends on active transport proteins that are differentially localized on the apical and basolateral membranes of the choroid plexus epithelial cells. Water follows the flow of sodium (Na+) and chloride (Cl-) ions from the interstitial fluid (ISF) into the CSF. Carbonic anhydrase within the epithelial cells catalyzes the formation of carbonic acid (H2CO3) from water (H2O) and carbon dioxide (CO2). Carbon dioxide diffuses freely into the epithelial cells from the bloodstream, but the dissociation products of carbonic acid, bicarbonate (HCO3-), and hydrogen (H+), are exported across the basolateral membrane by Na+/H+ and Cl-/HCO3- exchangers. Sodium is then transported across the apical membrane, into the CSF, via Na+/K+ ATPases (Figure 11-2).Water flows passively along the osmotic gradient created by this net ion flux from the ISF to the ventricles through aquaporin-1 channels.

Other specific active transport proteins present along the basolateral membrane allow transport into the CSF of essential hydrophilic micronutrients, including glucose, amino acids, purines, nucleosides, and vitamins. Transport proteins along the apical membrane work to clear the CSF of potentially toxic metabolites, such as organic acids and bases. Tight junctions link the choroid plexus epithelial cells, limiting the free diffusion of ionic molecules and creating the blood–CSF barrier. Although protein diffusion is largely restricted, most of the small amount of protein found in the CSF is nevertheless of plasma origin. Maintenance of a relatively stable CSF composition, despite wide variation in the composition of the plasma, reflects the integrity of the blood– CSF barrier and the work of active transporters against concentration gradients. The choroid plexus produces from 70% to 90% of the CSF, with the remainder deriving from movement of brain parenchymal ISF across the ependyma into the ventricles and across the pial membrane into the subarachnoid space. The rate of CSF formation in healthy adults averages 0.35 mL per minute, or roughly 500 mL each day. Children produce proportionally less CSF, depending on their height and weight, with as little as 25 mL produced per day in newborns. Postmortem studies have provided estimates that total CSF volume ranges from 50 mL in term neonates to 150 mL in adults, with only a small percentage contained within normal-sized ventricles. The total volume of the CSF undergoes complete replacement three to four times each day. CSF production can be greatly reduced in experimental animals given the sodium–potassium ATPase inhibitor ouabain. Carbonic anhydrase inhibitors, such as acetazolamide, can reduce CSF production by 50% to 100% in rats. Acetazolamide reduces CSF production in humans just 6% to 50%, which explains the limited clinical effectiveness of this medication in the treatment of increased intracranial pressure. Furosemide and other loop diuretics also weakly inhibit carbonic anhydrase activity but also reduce CSF production through inhibition of sodium, potassium, and chloride cotransporters. CSF produced in the lateral ventricles passes through the foramina of Monro into the third ventricle and then flows through the aqueduct of Sylvius into the fourth ventricle. CSF exits the ventricular system through the lateral foramina of Luschka to enter the prepontine cistern and cerebellopontine angles. Alternatively, CSF can leave the fourth ventricle through the midline foramen of Magendie, entering the cisterna magna, from which it can flow upward over the cerebellar hemispheres or downward into the spinal subarachnoid space and around the brainstem into the basal cisterns, including the interpeduncular cistern. CSF flows predominantly

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CSF Na+,

HCO3

–,CI– &

H2O

K+ 3Na+

CI– 2K+

HCO3– Na+

Na+ 2CI–

H+

K+ C.A CO2 + H2O → H+ + HCO3–

HCO3–

H2O Figure 11-2.  Major processes involved in cerebrospinal fluid secretion. 1, Carbonic anhydrase catalyzes the production of bicarbonate (HCO3-) ions and protons (H+) from water (H2O) and carbon dioxide (CO2). 2, Bicarbonate is exchanged for chloride (Cl-) across the basolateral membrane. 3, Bicarbonate and chloride flow into the CSF through anion channels, down an electrochemical gradient, and through sodium (Na+)–potassium (K+)–chloride cotransport. 4, Sodium is exchanged for protons across the basolateral membrane and for potassium across the apical membrane. 5, Water follows the osmotic gradient created by the combined secretion of sodium, chloride, and bicarbonate into the CSF. (With permission from Damkier HH, Brown PD, Praetorius J. Physiology [Bethesda]. 2010;25[4]:239–49.)

downward posterior to the spinal cord and upward anterior to the cord. The fluid eventually reaches the basal cisterns, from which flow is mainly upward over the brain convexity. In the steady state, the rate of CSF absorption is equal to that of its production. Most CSF is absorbed into the venous sinuses across the arachnoid villi and granulations, arachnoid membrane invaginations through the dural lining of the sinuses that are concentrated near the sagittal sinus. Absorption across the arachnoid villi occurs by vesicular transport. This action demonstrates a dependence on the hydrostatic pressure gradient across the villous surface, such that the villi act as one-way pressure valves that open above a threshold pressure, usually 20 to 50 mm H2O. Modern research utilizing radioactive tracers has shown that significant CSF absorption also occurs across the capillaries, veins, and lymphatics of the spinal cord and spinal roots, and, via the perineural subarachnoid space around olfactory nerve rootlets, through the cribriform plate and nasal lymphatics (Kapoor et al., 2008).

CEREBROSPINAL FLUID FUNCTION The CSF provides buoyancy and physical protection to the brain, absorbing the stretching and compressive forces generated by normal head movement and lessening the impact of the deceleration and rotational forces created by head trauma. A second protective function derives from the ability of the CSF to redistribute in response to acute changes in other intracranial contents, helping to maintain normal intracranial pressure. The CSF is also thought to serve as a route for the transport of centrally acting hormones, such as for the diffusion of hypothalamic releasing factors across the third ventricle. The CSF aids in the excretion of metabolites through bulk absorption of the ISF of the brain and spinal cord. This “sink

action,” along with the various mechanisms by which the CSF composition is maintained, suggests that the CSF plays a significant role in normal physiology and in the compensatory response to pathologic situations.

DIAGNOSTIC SAMPLING OF CEREBROSPINAL FLUID Indications Changes in the composition of the CSF have been associated with a wide variety of neurologic conditions. Sampling of the CSF is considered helpful in the diagnosis and management of several such conditions in children, and may be most useful in cases of suspected meningitis, encephalitis, subarachnoid hemorrhage, intracranial hypertension (as in pseudotumor cerebri), leptomeningeal carcinomatosis, pediatric neurotransmitter diseases, and neurodegenerative diseases. In each case, the potential benefits of the information that can be obtained should be weighed against the risks of the procedures used for CSF sampling. Families should be involved as much as possible in the decision-making process to allow them to provide truly informed consent.

Contraindications and Cautions LP through a soft tissue infection such as cellulitis is discouraged because of concern that this can introduce bacteria into deeper tissues and cause an epidural abscess, osteomyelitis, or meningitis. The risk of a bleeding complication, other than a bloody tap, from a diagnostic or therapeutic lumbar puncture in patients with even severe thrombocytopenia is very low. Many pediatric hospitals follow a protocol for holding anticoagulants prior to lumbar puncture (low-molecular-weight heparin [LMWH] for 24 hours and unfractionated heparin [UH] for 4 hours) and restarting several hours afterward (4-6 hours for UH and 6-9 hours for LMWH), with a low risk of complications reported (Avila et al., 2014). There is considerable and understandable fear that LP in patients with a CSF obstruction can unbalance the pressure across the area of obstruction and contribute to cerebral herniation or spinal cord compression. Neuroimaging, usually with cranial computed tomography (CT), is often performed before LP, especially in patients with suspected meningitis. However, herniation has been reported after normal neuroimaging, and LP has been performed safely in patients with abnormal CT scans, leading many to continue to debate the appropriate use of neuroimaging before LP. Because it is considered essential that antibiotic administration not be delayed when meningitis is suspected, especially with meningococcal disease, current recommendations are to start antibiotics as soon as possible, regardless of when LP can be performed (Gaieski et al., 2012).

Procedure The success of an LP is determined by the correct positioning of the needle and the patient, and depends almost as much on the relaxation of the patient and on the skill and experience of the assistants as it does on that of the needle-wielding physician. Local analgesia, with or without the use of additional anxiolytics, may be sufficient for cooperative older children, but moderate to deep sedation is often necessary for younger children. Although aggressive assistants can easily overpower neonates and young infants, obviating the need for sedation, they must take care not to cause airway compromise. Patients with abnormal lumbar spine anatomy, such as that resulting from a congenital defect such as spina bifida or an acquired



deformity such as scoliosis, may require direct imaging of the spine with fluoroscopy or ultrasound. The lower end of the spinal cord, the conus medullaris, is found by MRI to be at the L1-L2 vertebral interspace in most subjects and safely above the L3 vertebral body in all subjects without spinal deformity. To avoid damaging the conus, only the interspaces below L3 are used for LP. With a patient lying in the lateral recumbent position, the L3-L4 interspace can be found at the level of the superior iliac crests. This area should be carefully palpated and marked to ensure that it can be identified after the patient is cleaned and draped. Having the patient curl with the neck and hips flexed can maximize the size of the interspace. Whether the patient is placed in a lateral recumbent or seated position, care should be taken to maintain the alignment of the shoulders and hips, avoiding rotation of the spine. Having the patient’s back near the edge of the bed and at a proper height can aid in the comfort and success of the physician. The patient’s skin should be prepared using a microbicidal agent, such as a 10% solution of povidone-iodine. The skin should be given time to dry and then wiped clean and draped with sterile towels. A local anesthetic, such as a 1% solution of lidocaine, can be injected into the area to minimize the pain of repeated needlesticks. Anesthesia provides little benefit when the LP can be accomplished with a single needlestick, because the pain of the anesthetic injection often equals or exceeds that of the spinal needle insertion. A reasonable alternative is the use of a topical analgesic cream, such as the 5% emulsion of lidocaine and prilocaine commonly referred to as eutectic mixture of local anesthetics (EMLA). EMLA requires 20 to 30 minutes of application but has been associated with a decreased pain response, even in neonates. The most commonly used spinal needles are 2.5- or 5-cmlong, 20- or 22-gauge Quincke needles, which are beveled and fitted with a stylet. The sharply beveled tip of the Quincke needle should be turned to face the patient’s side so that its cutting edge can push between, rather than cut, the longitudinal fibers of the dura. Atraumatic needles, such as the Whitacre and Sprotte needles, have duller tips that make dural injury less likely. These needles are also more flexible, encounter more tissue resistance, and require the use of an introducer, making them more difficult to position. Advancing the needle without its stylet in place may increase the chances of successful and nontraumatic CSF collection, but has been discouraged because of concern that this will introduce cells that might later form a spinal epidermoid tumor. The needle is gradually advanced, the ligamentum flavum and dura are pierced, and a slight popping sensation is felt as the subarachnoid space is entered. The stylet is removed to allow CSF to drain to the needle hub. If no fluid appears, the needle should be rotated a quarter-turn in case a nerve rootlet or strand of arachnoid is obstructing the opening. If this does not initiate CSF flow, the needle can be introduced a few millimeters more, sometimes resulting in a second popping sensation. If there is still no CSF, the stylet should be replaced and the needle slowly withdrawn for redirection of the needle toward the same interspace or for selection of another interspace. After CSF is flowing from the needle, a stopcock and manometer should be attached to the needle hub. The opening pressure should be measured with the child relaxed and in the lateral decubitus position. There should be no direct pressure on the abdomen during the measurement. Slow CSF flow may be caused by partial needle obstruction or by low CSF pressure. One way to ensure that a low manometry reading is a true reflection of the CSF pressure is to apply firm pressure to the patient’s abdomen. In the absence of an outflow obstruction or disconnection between the needle and manometer,

Spinal Fluid Examination

75

there should be a rapid rise in the manometer reading, followed by a rapid fall as abdominal pressure is released. An accurate manometry reading should also be accompanied by small fluctuations in the height of the fluid column with the pulse and respirations. Opening pressures in adults and older children have historically been considered normal between 120 and 200 mm H2O, with pressures as high as 250 mm H2O considered normal for obese adults. A prospective multicenter study of opening pressures in children without medical conditions found a mean of 196 mm H2O, with the 90th percentile being 280 mm H2O (Avery, 2014). Pathologic elevations of the CSF pressure are discussed in Chapter 105. After the opening pressure has been recorded, CSF can be collected for analysis. Abdominal pressure or Valsalva maneuvers can be used to increase slow flow. In the case of very slow flow, gentle aspiration with a syringe may be attempted, although this may increase the risk of pulling a nerve rootlet or strand of arachnoid into the needle. At least 5 mL of CSF should be collected; the first three tubes of 1 to 2 mL are sufficient for routine studies: Gram stain, bacterial culture, cell count and differential, and glucose and protein concentrations. If the first tubes are grossly bloody, a fourth tube of at least 2 mL should be collected to aid in the differentiation of subarachnoid hemorrhage from a traumatic tap. This tube can also be held in reserve for additional studies, such as special microbiologic, immunologic, or metabolic tests. Replacing the stylet before withdrawing the spinal needle is recommended to avoid pulling a strand of arachnoid through the dura, creating a channel for continued CSF leakage and increasing the risk of postprocedural headache. In special situations, CSF can be obtained by ventricular shunt or by ventricular or cisternal puncture, usually with the assistance of a neurosurgeon.

Complications Transient complications during the procedure include pain and paresthesias in the distribution of a lumbar nerve root resulting from contact with the needle. The discomfort should subside with repositioning of the needle toward the midline, and permanent nerve injury is highly unlikely. More serious complications of LP do occur, although rarely. These mainly involve subarachnoid, subdural, and epidural hematomas resulting from a breach of the epidural venous plexus, radicular arteries, or radicular veins. Patients commonly have signs and symptoms of meningeal irritation or local pain. Severe symptoms, such as sensory, motor, or sphincter dysfunction, suggest the need for surgical hematoma evacuation. Infectious complications, including meningitis, epidural abscess, and osteomyelitis, can result from the use of incompletely aseptic technique. LP in the setting of bacteremia or active hematologic malignancy is not strictly contraindicated. The most common complications of LP are back pain and postprocedural headache. Postprocedural headache may occur within 72 hours of the puncture, may be worsened by an upright position and relieved by recumbency (orthostatic), and may be associated with neck stiffness, nausea, vomiting, and cranial nerve palsies. Pathologic reductions of the CSF pressure are discussed in Chapter 105. Several technical aspects and patient factors appear to lessen the incidence and severity of postprocedural headache in adults, including the use of small-diameter needles or atraumatic needles, low body mass index, male gender, and lack of a history of headache. Bed rest after LP has not been found to prevent headache, but it is effective in reducing pain after it has developed. Similarly, prophylactic epidural blood patches

11

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do not prevent headaches but are very successful in the treatment of refractory postprocedural headaches. Studies have been contradictory or negative regarding the use of steroids, hydration, or caffeine for the prevention or treatment of postprocedural headaches.

CEREBROSPINAL FLUID ANALYSIS Appearance Normal CSF is clear and colorless, indistinguishable from water when held up to white light in identical tubes. A cell count greater than 50 cells/mm3 can cause a snowy scattering of light, but the eye cannot easily distinguish between white blood cells (WBCs) and red blood cells (RBCs). With RBC counts between 500 and 6000 cells/mm3, the CSF color becomes pink or xanthochromic.

Cells Counting chambers can provide CSF WBC and RBC counts, with a pathologist reviewing a stained slide for confirmation. Normal values for infants have been difficult to obtain, in part because LP is rarely done without an indication such as fever, but also because many early studies had small samples and included children with conditions known to elevate CSF cell counts, such as viral meningitis (Chadwick et al., 2011). Older infants and children have normal values similar to those of adults (Table 11-2). Centrifugation and staining of the CSF are suitable for most clinical cytology. The WBCs found in normal CSF are typically 70% lymphocytes and 30% monocytes. An elevated WBC count or more than a few polymorphonuclear cells may indicate inflammation or infection within the CNS, but counts are not specific enough to allow ready differentiation, for example, of bacterial from viral meningitis. Neoplastic cells, plasma cells, stem cells, and eosinophils within the CSF are always considered abnormal. However, because cytologic analysis has such a low sensitivity, CSF testing for leptomeningeal metastasis of a systemic malignancy should be repeated multiple times and should employ large collection volumes. These points are examined in detail in Chapters 114 to 116, which discuss CNS infections, and Chapters 122 to 133, which discuss CNS malignancies. Excessive RBCs in CSF can be diagnostic of subarachnoid hemorrhage (SAH), but can also occur with a traumatic LP. TABLE 11-2  Total White Blood Cell Counts in the Cerebrospinal Fluid of Children without Central Nervous System Disease Age

N*

WBC Mean ± SD†

95th Percentile

Neonate   Premature (28-37 wk GA)   Term (38-42 wk GA)

38 25

5.1 ± 5.8 4.5 ± 3.6

16.7 11.7

Infant   25) in disorders of oxidative phosphorylation as compared with PDH complex disorders, in which the lactate:pyruvate ratio is usually normal. Clinical course may be benign in cases with only skeletal muscle involvement (benign infantile mitochondrial myopathy) or fatal in cases with intractable acidosis. Treatment options are limited and rely on supportive strategies to minimize catabolic stresses, and administration of cofactors (carnitine, nicotinamide, riboflavin). Diagnosis of primary genetic defects of mitochondrial function involving pyruvate metabolism and respiratory chain is difficult because of the extreme phenotypic and genotypic variability and because histologic and histochemical diagnostic techniques are difficult and not widely available. These conditions should be suspected in infants with persistent severe lactic acidosis combined with other organ disease, especially myopathy and/or cardiomyopathy. Confirmation and further biochemical definition of the diagnosis are complex and may require detailed biochemical studies to isolate the

functional defect, followed by identification of specific pathogenic gene mutations (Honzik et al., 2012).

Glutamine Synthetase Deficiency Glutamine synthetase (GS) plays a critical role in the brain to detoxify ammonia and regulate concentration and compartmentalization of neurotransmitter pools of glutamate and gamma-aminobutyric acid (GABA). GS deficiency is a rare autosomal-recessive condition manifest as profound neonatal encephalopathy with coma, quadriparesis, severe bulbar dysfunction, lissencephaly, and death shortly after birth as a result of multiorgan failure. Diagnosis in this clinical setting is suggested by moderate hyperammonemia with very low or absent glutamine concentration in blood, cerebrospinal fluid (CSF), and urine, and is confirmed by deficient enzyme activity in cultured fibroblasts. There are no effective treatments.

Fructose-1,6-Biphosphatase Deficiency Fructose-1,6-biphosphatase (FDPase) deficiency is an autosomal-recessive defect in gluconeogenesis. It presents as early infantile-onset severe acute encephalopathy, with fastinginduced lactic acidosis, ketoacidosis, and hypoglycemia, usually without other organ involvement, except hepatomegaly. The clinical and biochemical features should suggest the diagnosis, confirmed by enzyme assay on a liver biopsy specimen. Treatment is similar to that for type I glycogenosis, in addition to restriction of fructose and sucrose intake.

Fatty Acid Oxidation Defects Fatty acid oxidation disorders involve several enzymes in the degradation of lipids to fatty acids to acetyl-CoA or ketonebody production. These include carnitine palmitoyl transferase II (CPT II) deficiency, mitochondrial trifunctional protein deficiency (MTP), malonyl-CoA decarboxylase deficiency (MCD), multiple acyl-CoA dehydrogenase deficiency (MADD), and classic acyl-CoA dehydrogenase deficiencies (long-chain, or LCAD; medium-chain, or MCAD; short-chain, or SCAD). Although most of these present beyond the neonatal period, several have distinctive presentations in neonates, involving rapid onset of a fulminant metabolic encephalopathy with hypoglycemia, hyperammonemia, low or moderate ketonuria, and metabolic acidosis. Associated features include hepatomegaly, cardiomyopathy, and myopathy. Patients with MCD and MADD have cortical dysgenesis with pachygyria, whitematter atrophy, and gray-matter heterotopias. Characteristic clinical features should suggest the diagnosis, supported by decreased total plasma carnitine and elevated plasma acylcarnitine intermediates. Definitive diagnosis rests on measuring enzyme activity and genomic sequence analysis. Treatment involves supportive measures, glucose administration, carnitine supplementation, and modification of feeding schedules to minimize fasting states. Long-term outcome depends on the frequency and severity of decompensation. MTP deficiency predominantly presents in neonates, with rapid onset of depressed consciousness, heart failure, diffuse hypotonia and weakness with absent tendon reflexes, severe lactic acidosis, and death in a majority of patients as a result of heart failure. Multisystem involvement may include retinopathy, peripheral neuropathy, myopathy, cardiomyopathy, and liver disease. CPT II deficiency has several phenotypes presenting at different ages. The neonatal-onset form is the least common and most severe form and is almost always fatal. Affected infants have prenatally detected cerebral lesions and malformations. Neurologic symptoms appear shortly after birth, including seizures, depressed consciousness, hypotonia with myopathic



features, and cardiomyopathy leading to circulatory failure. Metabolic features are typical of fatty acid oxidation defects. Management is supportive and symptomatic, but ineffective in most cases. Definitive biochemical diagnosis is a prelude to confirmatory genetic testing.

Urea Cycle Disorders Neonates with urea cycle defects (UCDs) develop severe hyperammonemia, rapidly progressive lethargy, and vomiting, progressing to coma (Häberle et al., 2012). First-stage testing reveals no other major biochemical abnormalities. Diagnosis rests on plasma amino acid and urine organic acid and urinary orotate excretion profiles. Definitive diagnosis is confirmed by genetic testing. Elevated plasma glutamine levels are common to all of the UCDs. Transient hyperammonemia of the new­born resembles UCDs, featuring severe transient hyperammonemia associated with respiratory distress syndromes or herpes simplex infection. It differs from UCDs in its earlier onset (first 24 hours of life) and association with prematurity and pulmonary disease. Treatment includes discontinuing protein intake and administering intravenous dextrose and ammonia-scavenging drugs—sodium benzoate, phenylacetate, and arginine. Infants unresponsive to these measures or those presenting with coma may require hemodialysis. Long-term outcome is variable, with motor and cognitive deficits dependent on the severity and frequency of hyperammonemic decompensations.

Subacute Epileptic Encephalopathies Glycine Cleavage Defects Glycine cleavage defects are autosomal-recessive disorders causing glycine accumulation. The most common form is a neonatal-onset progressive encephalopathy with depressed consciousness, apnea, and seizures, usually myoclonic, and burst suppression on electroencephalogram (EEG). Lifelong severe cognitive and motor disabilities and intractable epilepsy are the rule among survivors. Factors predicting poorer outcome include early age of symptom onset, presence of cerebral dysgenesis, and degree of glycine elevation. Neuroimaging abnormalities include cerebral dysgenesis of prenatal origin, compounded by acute new foci of injury in acutely symptomatic neonates appearing as restricted diffusion in the posterior limbs of the internal capsule, lateral thalami, and dorsal midbrain and pontine nuclei, evolving to a progressive vacuolating myelinopathy in the postnatal period. Biochemical abnormalities are limited to elevated glycine levels in plasma and CSF, with CSF:plasma ratio less than 0.06. Definitive diagnosis rests on finding absent or very low activity of the glycine cleavage system enzyme in liver biopsy or autopsy, confirmed by genetic studies. Glycine cleavage defects differ from the hyperglycinemia that accompanies organic acidopathies in the presence of ketosis in the latter, and in characteristic organic acid excretion profiles. There are no proven therapies. Seizures are resistant to standard anticon­ vulsants. Treatment with dextromethorphan, ketamine, benzoate, and the ketogenic diet has been reported, with limited success.

Pyridoxine-Dependent and Pyridoxal PhosphateDependent Epileptic Encephalopathies Pyridoxine is the precursor for pyridoxal-5-phosphate (PLP), an essential cofactor for multiple enzymes in brain metabolism. Two enzyme defects with distinct gene mutations cause deficient PLP production: pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate-dependency disorder

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175

(Plecko, 2013). Pyridoxal phosphate-dependency disorder in­volves mutations in the gene for pyridox(am)ine-5′phosphate oxidase (PNPO), which converts pyridoxine to PLP. The spectrum of PDE includes gene mutations leading to partial loss of PNPO activity, presenting as pyridoxineresponsive neonatal-onset epilepsy with normal levels of PDE biomarkers. Affected infants present with prenatal- or neonatal-onset drug-resistant epilepsy and chronic encephalopathy, with no other metabolic abnormalities. EEG is severely abnormal, with several types of epileptiform patterns (hypsarrhythmia, burst suppression, generalized spike-wave). Diagnosis in PDE rests on finding elevated levels of α-aminoadipic semialdehyde and pipecolic acid in urine, blood, and CSF, confirmed by mutation analysis of the antiquitin gene. Diagnosis of PNPO deficiency should be considered in infants with the clinical features of PDE, but who are not fully responsive to pyri­ doxine, lack the confirmatory biochemical markers (elevated urinary alpha-aminoadipic semialdehyde dehydrogenase [AASA]), and respond to PLP. Genetic testing of the PNPO gene confirms the diagnosis. Folinic acid–responsive neonatal epileptic encephalopathy (FARNE) resembles PDE clinically and electrographically. Although FARNE is identical biochemically and genetically to PDE, these patients have a better response to either a combination of pyridoxine and folinic acid or folinic acid alone. Treatment in pyridoxine-dependency disorders includes supplementation with both pyridoxine and folinic acid because there is variable response to either agent alone. Dietary restriction of lysine has been suggested. Infants with clinical features PDE who are unresponsive to pyridoxine and folinic acid may be given pyridoxal supplementation while awaiting genetic testing for PNPO deficiency.

Sulfite Oxidase and Molybdenum Cofactor Deficiency Molybdenum cofactor (Moco) deficiency and isolated sulfite oxidase deficiency are related autosomal-recessive diseases affecting xanthine and sulfite metabolism. These defects share a similar clinical presentation that involves severe neonatalonset epileptic encephalopathy with diffuse severe cavitary leukomalacia (Schwarz, Mendel, and Ribbe, 2009). Infants are born at term uneventfully and develop seizures in the first week, followed by arrested development, acquired microcephaly, and early appearance of generalized hypertonicity. Clinical and radiographic features in the early stages mimic hypoxicischemic encephalopathy. Distinctive neuroimaging features include symmetric acute lesions affecting the globus pallidi and subthalamic regions coexisting with chronic-appearing cerebral infarction, pontocerebellar hypoplasia, and severe cavitary leukomalacia. There are no associated malformative anomalies, systemic metabolic perturbations, or abnormalities affecting other organ systems. Diagnosis is suggested by increased urinary excretion of sulfites, thiosulfate, S-sulfocysteine, and taurine. Patients with Moco deficiency have low serum and urinary uric acid levels and increased urinary xanthine and hypoxanthine levels. Patients with isolated sulfite oxidase deficiency have normal uric acid metabolite levels. Diagnosis may be confirmed by enzyme assay of biopsied liver or cultured skin fibroblasts. Treatment is supportive, with an emphasis on optimizing anticonvulsant therapy.

Serine Biosynthesis Defects Serine biosynthesis defects may present as neonatal-onset chronic encephalopathies with prominent refractory epilepsy, and most commonly result from 3-phosphoglycerate dehydrogenase deficiency. Affected infants are neurologically

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PART IV  Perinatal Acquired and Congenital Neurologic Disorders

abnormal at birth, with intrauterine growth retardation, congenital microcephaly, cataracts, seizures, and neurodevelopmental impairment. They have a distinctive leukoencephalopathy with hypomyelination, vacuolar changes, and gliosis, which may improve after treatment with serine and glycine supplementation. Diagnosis rests on finding low CSF concentrations of serine, glycine, and 5-methyltetrahydrofolate. This disorder is treatable with high-dose dietary supplementation of serine (500-700 mg/kg/day) and glycine (200 mg/kg/day).

Purine Biosynthesis Defects Purine biosynthesis disorders manifesting in the neonatal period involve adenylosuccinate lyase or riboside transformylase enzyme deficiencies (Jurecka, 2009). Affected infants are born uneventfully at term and develop severe neonatal encephalopathy with hypotonia and seizures. Neuroimaging may be normal initially, followed later by diffuse atrophy. These infants develop severe static encephalopathy with profound mental retardation, blindness as a result of optic atrophy, refractory epilepsy, and growth failure. The cardinal biochemical feature is elevated riboside metabolites 5-amino4-imidazolecarboxamide ribosiduria (AICA) and succinyl-5amino-4-imidazolecarboxamide ribosiduria (SAICA) in urine and CSF. Affected infants may have disturbed glucose and lipid metabolism as a result of impaired hepatic gluconeogenesis and fatty acid and cholesterol synthesis. Treatment with D-ribose and uridine supplementation has been shown to be of limited benefit. Management is symptomatic and supportive because there is no definitive or curative treatment.

L-Amino

Acid Decarboxylase Deficiency

L-amino

acid decarboxylase deficiency (L-ADD) is a defect of biogenic amine neurotransmitter metabolism that results in deficient brain dopamine, serotonin, norepinephrine, and epinephrine. Patients present in the first weeks of life with lethargy, hypotonia, dysphagia, and seizures, and sometimes with hypoglycemia and acidosis. Autonomic dysfunction leads to ptosis, hypotension, gastric and intestinal dysmotility, and impaired thermoregulation. Movement disorders are common, with dystonia, athetosis, oculogyric crises, and nonepileptic myoclonus. Diagnosis rests on finding increased L-DOPA and 5-hydroxytryptophan and decreased homovanillic acid (HVA) and 5-hydroxy-indole-acetic acid (5-HIAA) levels in CSF. Vanillactic acid (VLA) levels are elevated on urine organic acid profile. Management is symptomatic and supportive. Outcome is poor in most patients, who develop mixed severe motor and cognitive disability and chronic movement disorders that are refractory to symptomatic treatment.

Asparagine Synthetase Deficiency Asparagine modulates the cell cycle, cell proliferation, and neuronal hyperexcitability. Asparagine synthetase (AS) deficiency causes a progressive neonatal-onset encephalopathy featuring quadriplegia, profound intellectual disability, refractory epilepsy, and progressive diffuse cerebral atrophy. CSF levels of asparagine in affected patients are low compared with normal patients. Diagnosis is confirmed with molecular genetic analysis. Treatment rests on supportive and anticonvulsant therapies. Nutritional supplementation with asparagine has been suggested, with uncertain benefit.

Chronic Encephalopathies Without   Multiorgan Involvement Hyperphenylalaninemia Hyperphenylalaninemia causes a neonatal-onset chronic encephalopathy as a result of defects in phenylalanine metab-

olism, including phenylalanine hydroxylase (PAH) deficiency, tetrahydrobiopterin (BH4) synthesis deficiency, and GTP cyclohydrolase (GTPC) deficiency. In classical phenylketonuria (PKU) caused by PAH deficiency, plasma phenylalanine levels exceed 1000 µM, and PAH activity in liver biopsy is severely deficient. Non-PKU hyperphenylalaninemia is a milder form, with plasma phenylalanine less than 1000 µM and less severely deficient PAH activity. Clinical symptoms in untreated classical PKU include irritability, hyperkinesis, acquired micro­ cephaly, and severe cognitive deficiency. Infants with GTPC deficiency have a neonatal-onset chronic encephalopathy with severe hypotonia, bulbar dysfunction, and seizures. Treatment with L-DOPA has been beneficial in some patients. Diagnosis is made through newborn metabolic screening followed by quantitation of plasma phenylalanine and tyrosine and urinary and CSF biopterin metabolites. Treatment involves dietary restriction of phenylalanine, and folate and BH4 replacement in patients with BH4 disorders.

Succinic Semialdehyde Dehydrogenase Deficiency Succinic semialdehyde dehydrogenase deficiency is a defect of GABA degradation causing elevated brain GABA. Some patients present as neonates with a chronic encephalopathy and later develop diffuse hypotonia, neurodevelopmental impairment, and epilepsy. MRI finding of T2 hyperintensity in the globus pallidus may suggest the diagnosis, which rests on finding high levels of GABA in CSF and urine and elevated urinary 4-hydroxybutyric acid. Treatment with vigabatrin has been suggested, with variable results.

Glutaric Aciduria Glutaric aciduria (GA) is an autosomal-recessive defect in degradation of 2-keto-adipic acid, a metabolite in lysine and tryptophan degradation pathways. Neonatal and early infantile presentation occurs in type I GA, caused by glutaryl-CoA dehydrogenase deficiency. Affected infants have chronic progressive encephalopathy of neonatal or early infantile onset with macrocephaly, hypotonia evolving to rigidity and dystonia, developmental regression, and epilepsy. There may be episodic decompensations triggered by intercurrent illness, with vomiting, ketotic hypoglycemia, acidosis, hyperammonemia, hepatomegaly, and depressed consciousness. MRI shows frontotemporal atrophy with prominent extraaxial CSF collections and, in some cases, subdural hemorrhage. Metabolic crises are associated with acute bilaterally symmetric striatal necrosis, leading to permanent neuromotor disability. Diagnosis rests on finding elevated urinary glutaric acid and 3-OH-glutaric acid, confirmed by enzyme assay. Treatment involves dietary protein restriction, in particular L-lysine and tryptophan, and supplementation with L-carnitine and riboflavin. Type II GA involves multiple acyl-CoA dehydrogenase deficiencies, causing elevations of multiple organic acids. The clinical picture in neonatal-onset type II GA is severe, with nonketotic hypoglycemia, metabolic acidosis, vomiting, depressed consciousness, and multiorgan dysfunction.

Chronic Encephalopathies With   Multiorgan Involvement Congenital Disorders of Glycosylation Congenital disorders of glycosylation (CDGs) involve defective protein glycosylation, affecting cotranslational modification of numerous secretory and membrane-bound proteins (Funke et al., 2013). Type I involves oligosaccharide precursor assembly; type II involves oligosaccharide processing. A new classification system based on genetic and molecular features uses the gene symbol followed by the extension “CGD.” CDG



type Ia is the most common and has two presentation types: a neurologic and a multisystem pattern. The neurologic presentation involves chronic severe neurologic disability with prominent hypotonia and cerebellar dysfunction, punctuated by episodic acute deterioration resembling stroke. MRI shows cerebellar atrophy. Usually normal at birth, some patients present with hypotonia and oculomotor abnormalities, with later ataxic hypotonic motor impairment and severe cognitive deficiency, retinopathy, epilepsy, acquired microcephaly, thromboembolic strokes, and weakness resulting from polyneuropathy. Associated nonneurologic findings include growth failure, protein-losing enteropathy, obstructive cardiomyopathy, and nephrotic syndrome. Diagnosis rests on the measurement of transferrin isoelectric focusing (TIEF) and molecular genetic testing. Associated biochemical findings include elevated liver transaminases, low serum proteins, anemia, leukopenia, and low serum cholesterol. Treatment includes supplementation of mannose for MPI-CDG, fucose for SLC35C1-CDG, and butyrate for PIBM-CDG, with variable benefit.

Peroxisomal Disorders Peroxisomal disorders are progressive neurologic diseases with variable age of onset and severity. Neonatal forms with prominent neurologic involvement are autosomal-recessive disorders, including Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD). ZS involves multiorgan dysfunction, with typical facial dysmorphism, ocular anomalies (cataracts, glaucoma, pigmentary retinopathy), hepatic fibrosis, cystic kidney disease, subclinical adrenocortical insufficiency, and cardiac anomalies. Neurologic features include seizures, cranial nerve dysfunction, optic atrophy, and diffuse myopathic weakness. Survivors are profoundly handicapped. Neuroimaging and pathological studies reveal cortical and cerebellar migrational abnormalities and central white-matter demyelination. Biochemical studies reveal elevated very-longchain fatty acids (VLCFAs), phytanic acid, and pipecolic acids, and deficient synthesis of plasmalogens. Diagnosis can be confirmed by gene sequencing. NALD resembles ZS in many respects but is less severe. There are no proven treatments.

Cholesterol Biosynthesis Defects (Smith–Lemli–Opitz Syndrome) Smith–Lemli–Opitz syndrome is a disorder of cholesterol biosynthesis and presents in the neonatal period with multiple congenital anomalies and a chronic static encephalopathy, with hypotonia, sensorineural deafness, dysphagia, severe cognitive deficiency, microcephaly. Nonneurologic problems include abnormal facies with ptosis and micrognathia, genital anomalies, growth retardation, cataracts, congenital heart defects, digital anomalies, and cleft palate. Cerebral malformations (holoprosencephaly, agenesis of the corpus callosum, frontal hypoplasia, cerebellar hypoplasia) are common. Diagnosis is suggested by low serum cholesterol, confirmed by finding elevated serum 7-and 8-dehydrocholesterol. Treatment is supportive and symptomatic. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Ficicioglu, C., Bearden, D., 2011. Isolated neonatal seizures: when to suspect inborn errors of metabolism. Pediatr. Neurol. 45 (5), 283–291.

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Funke, S., Gardeitchik, T., Kouwenberg, D., et al., 2013. Perinatal and early infantile symptoms in congenital disorders of glycosylation. Am. J. Med. Genet. A 161A (3), 578–584. Häberle, J., Boddaert, N., Burlina, A., et al., 2012. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J. Rare Dis. 7, 32. Hoffman, G.F., Zschocke, J., Nyhan, W.L., 2010. Inherited Metabolic Diseases: A Clinical Approach. Springer, Heidelberg. Honzik, T., Tesarova, M., Magner, M., et al., 2012. Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. J. Inherit. Metab. Dis. 35 (5), 749–759. Jurecka, A., 2009. Inborn errors of purine and pyrimidine metabolism. J. Inherit. Metab. Dis. 32 (2), 247–263. Knerr, I., Weinhold, N., Vockley, J., et al., 2012. Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J. Inherit. Metab. Dis. 35 (1), 29–40. Plecko, B., 2013. Pyridoxine and pyridoxalphosphate-dependent epilepsies. Handb Clin Neurol 113, 1811–1817. Schwarz, G., Mendel, R.R., Ribbe, M.W., 2009. Molybdenum cofactors, enzymes and pathways. Nature 460 (7257), 839–847. Xue, Y., Ankala, A., Wilcox, W.R., et al., 2014. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/ genome sequencing. Genet. Med.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 23-2 Algorithm for evaluation of hypoglycemia in neonates. Fig. 23-3 Biochemical pathways affected by defects in branched-chain amino acid (BCAA) and organic acid metabolism. Fig. 23-4 Schematic of intermediate metabolism. Fig. 23-5 Schematic of intermediate metabolism showing the potential role of anaplerotic therapy for inborn errors of metabolism affecting cellular energetics. Fig. 23-6 Urea cycle defects. Fig. 23-7 Disorders of serine and glycine metabolism. Fig. 23-8 Pyridoxine dependency/deficiency. Fig. 23-9 Schematic of interrelationships between intermediate metabolism and the major neuronal neurotransmitters glutamate and GABA. Fig. 23-10 Defects in purine metabolism and sulfurcontaining amino acids. These are caused by the following deficiencies: 1, molybdenum cofactor (Moco) deficiency; 2, isolated sulfite oxidase deficiency. Fig. 23-11 Defects in purine biosynthesis. Fig. 23-12 Defects in biogenic amine neurotransmitter metabolism. Fig. 23-13 Defects in amino acid metabolism leading to hyperphenylalaninemia. Table 23-1 Neurologic Signs and Symptoms of Neonatal Metabolic Disease Table 23-3 Causes of Neonatal Hypoglycemia Table 23-4 Inborn Errors of Metabolism in Which Neonatal Hypoglycemia Is a Common Symptom Table 23-5 Clinical Neurologic Features of Neonatal Genetic Metabolic Encephalopathies Table 23-6 Nonneurologic and Metabolic Abnormalities in Neonatal Genetic Metabolic Disorders Table 23-7 Summary of MRI Findings in Neonatal Genetic Metabolic Encephalopathies Table 23-8 Biochemical Diagnosis of Organic Acidopathies

23

PART V

24 

Congenital Structural Defects

Overview of Human Brain Malformations William B. Dobyns, Renzo Guerrini, and A. James Barkovich

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION This section (Part V) on congenital structural defects reviews a large and growing number of complex developmental disorders of the brain, spinal cord, and skull. They represent the tip of the iceberg of developmental brain disorders more broadly, as they present with many of the same clinical features and involve many of the same molecular pathways— and sometimes the same genes—as more common and less specific disorders such as intellectual disability, early life epilepsy and autism. They collectively encompass a field of knowledge that has expanded dramatically over the past several decades. But the field has not expanded in isolation. Brain malformations: • Largely represent defects during the earliest stages of brain development, and thus reflect the underlying embryology and developmental genetics of the nervous system; • Provide an important window into normal brain development and into the genetic regulation of brain development and function; • Frequently co-occur with other diverse developmental brain disorders both with and without recognized structural defects; and • Are associated with a wide spectrum of functional deficits including intellectual disability (mental retardation), developmental language disorders, epilepsy, social and behavioral disabilities, numerous other specific learning disabilities, attention deficits, motor deficits associated with abnormal motor tone and posture or dyskinesias, and a host of problems associated with sleep, feeding, mood, hormonal and autonomic dysregulation. Thus an understanding of brain malformations is important in assessing almost all types of neurologic disorders in children. They are separated into disorders involving defects in development of primary brain stages and regions including neural tube (Chapter 25); forebrain (Chapter 26) and midhindbrain (Chapter 27) defects; malformations of cortical development involving brain size (Chapter 28) and other malformations of cortical development (Chapter 29); diverse disorders resulting in hydrocephalus (Chapter 30) or skull development (Chapter 31); and an important new chapter on clinically and genetically overlapping disorders without consistent brain malformations that we designate “developmental encephalopathies” (Chapter 32) with Angelman and Rett syndromes as paradigms. This section ends with a detailed look at prenatal diagnosis for this group of disorders (Chapter 33). In the sections that follow, brain malformations are reviewed including epidemiology, classification, clinical recog-

nition, relationship to other neurologic disorders and selected environmental factors, and genetic counseling.

EPIDEMIOLOGY The incidence of brain malformations has been estimated to be approximately 3.32 per 1000 and the prevalence approximately 2.21 per 1000 at age 14 years from studies of a 1-year birth cohort from northern Finland (Von Wendt and Rantakallio, 1986). These are much higher rates than were recognized in the era before MRI and recent increases in surgical treatment of hydrocephalus and epilepsy. Not surprisingly, the incidence is much higher in studies of children with cerebral palsy. This is an important point. To emphasize this, boy with apparent cerebral palsy attributed to prematurity at approximately 29 weeks gestation had a brain MRI that revealed mild callosal and cerebellar vermis hypoplasia, and chromosome microarray revealed a deletion 22q11.2, which implies either a genetic cause or possibly combined genetic and acquired pathogenesis.

CLASSIFICATION Although the chapters that follow review many different malformations, they are not complete as the number of recognized malformations continues to expand. Presenting these data is also complicated by the tendency for malformations to co-occur in some patients. For example, Figure 24-1 shows a striking example of a boy with malformations of the forebrain (agenesis of the corpus callosum), mid-hindbrain (severe cerebellar hypoplasia and mega-cisterna magna), brain size (megalencephaly), neuronal migration (periventricular nodular heterotopia), and cortical organization (polymicrogyria overlying the heterotopia). We have from time to time constructed flexible classification schemes for many of these malformations that primarily rely on traditional concepts such as embryology and anatomy with a contribution from genetic discoveries. Whereas recent discoveries lead to genes and gene pathways more than to embryology and anatomy, a more traditional classification scheme is listed in this and the following chapters. Outlines for brainstem and cerebellar (mid-hindbrain) malformations and for cortical malformations are shown in Boxes 24-1 and 24-2. Further details regarding most subgroups of malformations and the basis for the classification are given in the primary references (Barkovich et al., 2005; Barkovich et al., 2009). These schemes rely on—in decreasing order of priority—the underlying genetic basis when known, the

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A

B

C

D

Figure 24-1.  Brain images from a single patient showing multiple malformations. T1–weighted sagittal images demonstrate severe callosal hypogenesis with a small anterior remnant (angled arrow in A), very small cerebellar vermis (horizontal arrow in A) in an enlarged posterior fossa, extended Sylvian fissure with cortex connecting the perisylvian and superior parietal regions (angled arrow in B), and periventricular nodular heterotopia in the trigone (horizontal arrow in B). T2– and T1–weighted axial images show periventricular nodular heterotopia adjacent to the posterior portion of the lateral ventricles (horizontal arrows in C and D), and infolded gyri with mildly thick cortex overlying the heterotopia (angled arrows in C and D). (Courtesy of W.B. Dobyns, research subject LR00-086.)

BOX 24-1  Classification for Mid-Hindbrain Malformations I. Malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones A. Anteroposterior patterning defects 1. Gain, loss, or transformation of the diencephalon and midbrain 2. Gain, loss, or transformation of the midbrain and rhombomere 1 3. Gain, loss, or transformation of lower hindbrain structures B. Dorsoventral patterning defects 1. Defects of alar and basal ventricular zones 2. Defects of alar ventricular zones only 3. Defects of basal ventricular zones only II. Malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have pathogenesis at least partly understood) A. Developmental encephalopathies associated with MHM B. Mesenchymal-neuroepithelial signaling defects associated with MHM C. Malformations of neuronal and glial proliferation that prominently affect the brainstem and cerebellum D. Malformation of neuronal migration that prominently affect the brainstem and cerebellum 1. Lissencephaly with cerebellar hypoplasia 2. Neuronal heterotopia with prominent brainstem and cerebellar hypoplasia 3. Polymicrogyria with cerebellar hypoplasia

relevant embryology, brain imaging features, and miscellaneous other clinical features. Future revisions of these systems will rely more and more on the molecular pathways and genes.

Brain Imaging Recognition The improved quality of brain imaging studies, especially advances in MRI technology, has led directly to increased recognition and more accurate classification of brain malformations. Still, several recurrent types of classification errors continue to occur based on studies sent to the authors for review. First, pachgyria appears to be the best known of the severe cortical

4. Malformations with basement membrane and neuronal migration deficits E. Diffuse molar tooth type dysplasias associated with defects in ciliary proteins 1. Syndromes affecting the brain with low frequency involvement of the retina and kidney 2. Syndromes affecting the brain, eyes, kidneys, liver and variable other systems III. Localized brain malformations that significantly affect the brainstem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance) A. Multiple levels of mid-hindbrain B. Midbrain malformations C. Malformations of rhombomere 1 including cerebellar malformations D. Pons malformations E. Medulla malformations IV. Combined hypoplasia and atrophy in putative prenatal onset degenerative disorders A. Pontocerebellar hypoplasia B. Mid-hindbrain malformations with congenital disorders of glycosylation C. Other metabolic disorders with cerebellar or brainstem hypoplasia or disruption D. Cerebellar hemisphere hypoplasia (rare, more commonly acquired than genetic, often associated with clefts or cortical malformation)

malformations, and accordingly, all types of severe cortical malformations are often interpreted as “pachgyria.” The prime examples of malformations mistaken for pachgyria include severe congenital microcephaly (but here the cortex is usually thin rather than thick), tubulinopathies, polymicrogyria, and cobblestone malformations (for these, the cortex is moderately thick, but the surface and cortical-white matter interface are irregular rather than smooth). This unfortunately often leads to testing of the “lissencephaly” genes in patients with other cortical malformations, with negative results. Second, a thin corpus callosum may result from reduced volume of white matter due to abnormal development of white matter,



Overview of Human Brain Malformations

BOX 24-2  Classification for Malformations of Cortical Development MALFORMATIONS OF CORTICAL DEVELOPMENT I. Malformations due to abnormal neuronal and glial proliferation or apoptosis A. Decreased proliferation or increased apoptosis, or increased proliferation or decreased apoptosis 1. Microcephaly with normal to thin cortex 2. Microlissencephaly (extreme microcephaly with thick cortex) 3. Microcephaly with polymicrogyria 4. Megalencephaly B. Abnormal proliferation (abnormal cell types) 1. Nonneoplastic a. Cortical hamartomas of tuberous sclerosis b. Cortical dysplasia with balloon cells c. Hemimegalencephaly 2. Neoplastic (with disordered cortex) a. Dysembryoplastic neuroepithelial tumor b. Ganglioglioma c. Gangliocytoma II. Malformations due to abnormal neuronal migration A. Lissencephaly and subcortical band heterotopia spectrum B. Cobblestone malformation syndromes C. Heterotopia 1. Subependymal (periventricular) 2. Subcortical (other than band heterotopia) 3. Marginal glioneuronal III. Malformations due to abnormal cortical organization (including late neuronal migration) A. Polymicrogyria and schizencephaly 1. Bilateral polymicrogyria syndromes 2. Schizencephaly (polymicrogyria with clefts) 3. Polymicrogyria as part of multiple congenital anomaly/ mental retardation syndromes B. Cortical dysplasia without balloon cells C. Microdysgenesis IV. Malformations of cortical development, not otherwise classified A. Malformations secondary to inborn errors of metabolism 1. Mitochondrial and pyruvate metabolic disorders 2. Peroxisomal disorders B. Other unclassified malformations 1. Sublobar dysplasia 2. Others

progressive white matter dysgenesis, or white matter injury. However, this appearance is sometimes interpreted as agenesis of the corpus callosum. Next, diverse causes of cerebellar hypoplasia are often interpreted as Dandy-Walker malformation (when associated with a large posterior fossa and an enlarged fourth ventricle) or the so-called “Dandy-Walker variant” (equated with isolated cerebellar vermis hypoplasia). The latter is so overused and misapplied that the term should be abandoned. Finally, enlarged fluid collections below and especially behind the cerebellum are interpreted as arachnoid cysts or as “mega-cisterna magna” considering the latter a nonpathogenic variant. In our experience, mega-cisterna magna with fluid both below and behind the cerebellum sometimes represents a developmental disorder that belongs in the Dandy-Walker spectrum, and may be incorrectly interpreted as an arachnoid cyst.

181

Relationships to Other Neurologic Disorders The close connection between brain malformations and other classes of developmental disorders is conceptually important. A few examples include agenesis of the corpus callosum associated with nonketotic hyperglycinemia; cerebellar vermis hypoplasia or heterotopia with multiple acyl-CoA dehydrogenase deficiency known as glutaric aciduria type 2; cobblestone malformations and cerebellar hypoplasia with congenital disorders of glycosylation; pachygyria variants with severe peroxisomal disorders such as Zellweger syndrome; and cerebellar hypoplasia or agenesis of the corpus callosum with either autism or infantile spasms. Further, most malformations of cortical development are associated with epilepsy, which may be severe. Observations in these and many other disorders suggest that brain malformations represent the most severe expression or “tip of the iceberg” of a host of developmental brain disorders. One of the best examples involves disorders associated with mutations of the ARX gene, which can cause lissencephaly, agenesis of the corpus callosum, hydrocephalus, developmental encephalopathy with epilepsy (i.e., epileptic encephalopathy), or mental retardation with dyskinesia.

Relationship to Environmental Factors The genetic basis for many brain malformations has been known for years, and new genes are constantly being discovered. The question arises: are all brain malformations genetic? Although easy to overlook, substantial data exists to support environmental (extrinsic) causes for several brain malformations. Both microcephaly and hydrocephalus can result from numerous prenatal and early life diseases such as intraventricular hemorrhage in premature infants, other causes of intracranial bleeding, hypoxic-ischemic injury, central nervous system infections, and a host of other disorders reviewed throughout this text. Holoprosencephaly has been associated with pregestational diabetes and with structural analogs of cholesterol that interfere with cholesterol metabolism in humans and animals. Periventricular nodular heterotopia have been seen in mice and rats after prenatal exposure to high-dose ionizing radiation and possibly in humans as well. Schizencephaly and polymicrogyria, usually with microcephaly as well, have been associated with second trimester (13 to 21 weeks gestation) prenatal vascular disruption and with intrauterine cytomegalovirus infections. Numerous reports in the lay press from mid-2015 on, as well as one report of prenatal diagnosis have recently implicated the Zika virus as a cause of microcephaly, sometimes with additional evidence of prenatal brain injury. It has been blamed for a dramatic increase in the frequency of congenital microcephaly in Brazil and is rapidly spreading to other countries and regions.

GENETIC COUNSELING Although the genetic basis for more and more brain malformations and related syndromes are being uncovered, few studies examining the overall contribution of genetic disorders to brain malformations have been reported. Accordingly, only partial and selective information about the genetic recurrence risk for different brain malformations is available. However, some general guidelines are listed in Table 24-1. For example, the recurrence risk for holoprosencephaly reported in the literature is approximately 6%, but we have become aware of frequent mild expression or “formes fruste” of this malformation and, accordingly, suggest using a higher recurrence risk of 13% for isolated holoprosencephaly without

24

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PART V  Congenital Structural Defects

TABLE 24-1  Probable Genetic Recurrence Risks for Major Classes of Brain Malformations Pattern of Inheritance Malformation Groups

Sp

Ch

AD

AR

XL

Recurrence Risk Comments

FOREBRAIN MALFORMATIONS Holoprosencephaly Agenesis of corpus callosum Septo-optic dysplasia

++ ++ ++

++ ++ –

++ ± –

± ± ±

± ++ –

Risk is variable, may be high Risk is generally low Risk is very low, has occurred

MID-HINDBRAIN MALFORMATIONS Pontocerebellar hypoplasia Cerebellar hypoplasia (diffuse) Cerebellar hypoplasia (vermis) Dandy-Walker malformation Molar tooth malformation Rhombencephalosynapsis

– ++ ++ ++ – ++

– ++ ++ + – –

– ± ± ± – –

++ ++ + ± ++ –

– + + ± – –

Risk is 25%, all forms are AR Risk is variable, need diagnosis Risk is variable, need diagnosis Risk is very low, has occurred Risk is 25%, all forms are AR No recurrences reported

– ++ ++ ++ – ++ ++ ++

– ++ – ++ – ++ – ++

– + – – – + – ±

++ + – + ++ ± – ±

– + – ++ – ++ – +

++ ++ ++

– – –

– – –

± – –

– – –

Risk is 25%, most forms are AR Risk is variable, includes XL Risk is low (except for PTEN) Risk is variable, includes XL Risk is 25%, all forms are AR Risk is variable, may be high No recurrences reported Risk is low, XL may be important Risk is generally low Risk is very low, has occurred No recurrences reported No recurrences reported

CORTICAL MALFORMATIONS Microcephaly, congenital Microcephaly, postnatal Megalencephaly Lissencephaly and SBH Cobblestone malformation Heterotopia, periventricular Heterotopia, subcortical Polymicrogyria, perisylvian Polymicrogyria, other forms Schizencephaly Focal cortical dysplasias Hemimegalencephaly

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; Ch, chromosome imbalance; Risk, recurrence risk for siblings or other relatives; Sp, sporadic occurrence; XL, X–linked; ++, commonly observed; +, occasionally observed; ±, rarely observed and often poorly documented; –, never observed

known chromosome imbalances. For several malformations such as agenesis of the corpus callosum and polymicrogyria, single gene inheritance has been reported but only rarely and no formal studies are available. This implies a “generally low” risk and counseling with some uncertainty given that the experience is limited and exceptions occur. For some other malformations such as rhombencephalosynapsis and hemimegalencephaly, no examples of familial recurrence have ever been reported despite clinical recognition for decades. The first reports of familial focal cortical dysplasia have appeared, but this must be very rare, suggesting that the recurrence risk is very low. The most difficult malformations are those with significantly different recurrence risks for different subtypes and syndromes such as diffuse and vermis predominant cerebellar hypoplasia. These estimates are largely anecdotal in origin, so treating physicians and genetic counselors are encouraged to review information on the specific disorder at hand when counseling families.

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Barkovich, A.J., Kuzniecky, R.I., Jackson, G.D., et al., 2005. A developmental and genetic classification for malformations of cortical development. Neurology 65 (12), 1873–1887. Barkovich, A.J., Millen, K.J., Dobyns, W.B., 2009. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 132 (Pt 12), 3199–3230. von Wendt, L., Rantakallio, P., 1986. Congenital malformations of the central nervous system in a 1-year birth cohort followed to the age of 14 years. Childs Nerv. Syst. 2 (2), 80–82.

25 

Disorders of Neural Tube Development Nalin Gupta and M. Elizabeth Ross

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Neural tube defects (NTDs) are second only to congenital heart defects as the most common serious birth defect, affecting between 0.3 and 10 per 1000 live births, depending on geographic region. NTDs result from complex interactions of genes and environmental conditions. A significant proportion of NTDs may be preventable with measures such as prenatal maternal folic acid (FA) supplementation or by avoiding prenatal exposure to known teratogenic drugs or toxins. Here we discuss the NTD pathogenesis, risk factors, complications, and management.

ANATOMY AND EMBRYOLOGY Formation of the Neural Tube Among the earliest morphologic specializations in the embryo is the neural placode, followed by neural plate and then neural tube. In the late second gestational week, the human embryo is a bilaminar disc of epiblast cells overlying hypoblast cells. By the third week, the disc develops a midline groove, the primitive streak, in the caudal third (Fig. 25-1A), which marks the initiation of gastrulation and the formation of three germ layers—ectoderm (giving rise to skin and the nervous system), mesoderm (providing inductive signals to ectoderm and contributing to morphogenesis), and endoderm (giving rise to viscera). The primitive node at the cranial end of the streak contains cells that act to organize the embryonic axes (Fig. 25-1). At the same stage, thickening of the rostral ectoderm by the apical-basal elongation of cells into a pseudostratified columnar shape produces the neural placode that marks the initiation of neurulation (see Fig. 25-1B). Cells migrating through the primitive streak and node displace the hypoblast cells to form endoderm and subsequently middle layer mesoderm. Cells that migrate through the node in the midline form the prechordal plate and notochord, which are important for induction of the ventral CNS structures, starting with the neural plate. Neural plate formation is actually a default state of the ectoderm, and formation of epidermis involves the inhibition of bone morphogenetic protein (BMP) and the wingless (Wnt) signaling pathway. As the plate begins to emerge, morphogenesis, or shape changes, involving groups of cells in the neuroepithelium and surround, is essential to formation of brain and spinal cord. By 20 days of gestation, the neural plate appears indented in the midline, forming a groove or medial hinge region flanked by ridges–the neural folds. These folds elevate from the plane of the neural plate through the combined influences of proliferation of neural cells and underlying mesenchymal cells. Bending inward of the neural folds at the dorsolateral hinge points occurs through morphologic shape changes of the neural cells, which become radially elongated while their apical (luminal) poles constrict, through a combination of cell-cycle regulation that moves nuclei to the basal end of cells in the hinge region and actin-myosin contraction at the apical poles of cells in the hinge region, to bring the tips of the neural folds to touch. In the head region,

proliferation and movement of epidermis and mesenchyme cells also help to push the neural folds into apposition because at spinal levels, neighboring mesenchyme may be less critical to neural tube closure. In addition to cell elongation and proliferation, the shape changes in the neural plate are affected by cell motility in the form of convergent extension, in which laterally placed cells move to the midline and migrate rostrocaudally in a process that is mediated by noncanonical Wnt signaling (Fig. 25-4). Thus once elevation and bending of the neural folds occur, the lateral margins or tips of the folds join and then fuse in the midline to become the neural tube. In order to achieve this rising and bending inward of the neural folds, the cells of the neural plate must proliferate in an ordered manner, called interkinetic nuclear migration of progenitors, forming a pseudostratified epithelium in which S-phase occurs at the basal (outer) surface of the neural folds, mitosis (M-phase) occurs at the apical (central or luminal) surface, and G1 and G2 phase nuclei are positioned at intermediate locations. In addition, in the process of convergent extension, cells move medially and through the medial hinge region to migrate rostrocaudally and elongate the neuraxis, narrowing the ventral floor plate. If the floor plate is too wide or the neural folds fail to elevate and bend, the folds will not appose and NTDs will ensue (see Fig. 25-4). When apposition is successful, midline fusion of the neural folds, a process known as neurulation, occurs first at primary closure points and progresses by adding multiple closure points such as the teeth of a zipper to extend rostrally and caudally from each node to complete neural tube closure (Copp et al., 2003). In humans, the anterior neuropore, the region that will eventually give rise to the brain, closes approximately by day 26 of human gestation. The posterior neuropore, the region that will give rise to the caudal spinal column, closes approximately by day 29 of human embryogenesis. After the neural tube closes, it separates from the overlying ectoderm in a process termed dysjunction. Cells of the somitic mesoderm invade the space between the ectoderm and neural tube to form somites that eventually give rise to the posterior elements of the vertebral bodies and the paraspinal muscles. Specific neural cells at the tips of the folds are excluded from the neural tube; these cells form the neural crest, which is the anlage of the peripheral sensory and autonomic nervous systems and which also contributes the meninges and portions of the skull and face.

Molecular Patterning of the Neural Tube Work in animal models has identified a host of factors required for proper neurulation and neural tube closure. A key observation was that a small fragment of nonneural tissue (mesoderm), when transplanted, could duplicate the neural tube, indicating that secreted factors from mesoderm are sufficient to induce neurulation. These factors include chordin, noggin, sonic hedgehog (SHH), and several others, which are both necessary and sufficient for proper neurulation and control of the amount and fate of the neuroectoderm. In mammals, two distinct groups of nonneural cells appear to provide these early patterning signals: axial mesodermal cells of the

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PART V  Congenital Structural Defects

Neural fold Cut edge of amnion

Neural plate Neural groove Somite

Primitive node Primitive streak

A

18 days

Primitive streak

B

19 days

20 days

Figure 25-1.  Early stages of gastrulation and neurulation in human embryogenesis: views of the dorsal surface. A, The primitive streak emerges as a groove at the caudal pole of the embryo, with the primitive node at the cranial pole. Epiblast cells moving through the primitive streak and node form the three germ layers—ectoderm, mesoderm, and endoderm. B, A thickening of the ectoderm forms the neural plate, initiated at the cranial pole, whereas the primitive streak at the caudal end initiates gastrulation. By 20 days’ gestation, the neural folds have elevated from the neural plate, and tips of the folds are closing. Somites, comprised of mesoderm cells, support the elevation of the neural folds and are the precursors of vertebrae. (Adapted from Sadler, T.W., 2005. Embryology of neural tube development. Am J Med Genet C Semin Med Genet 135C, 2–8.)

Notochordal plate

A

Neural plate

Notochord

Node

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B

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Figure 25-4.  Cell movements affecting planar cell polarity (PCP) signaling in the early developing nervous system. A and B, Schematics showing cell movement toward the midline into the neural groove and longitudinally to narrow and elongate the embryo. C, This movement serves to narrow the ventral floor plate (red), facilitating median hinge-point bending and apposition of the neural folds. D, When PCP signaling is impaired, as in the looptail mouse-bearing mutation in Vangl2, the floor plate is wider (intervening cells remain in the floor plate region), which prevents the folds from meeting in the midline. (A, With permission from Ybot-Gonzalez, P., et al., 2007. Convergent extension, planar-cell-polarity signaling and initiation of mouse neural tube closure. Development 134, 789–799. B–D, With permission from Copp, A.J., et al., 2003. Dishevelled: linking convergent extension with neural tube closure. Trends Neurosci 26, 453–455.)

notochord, which underlie the midline of the neural plate; and the cells of the epidermal ectoderm, which flank its lateral edges. The notochord is the source of ventralizing inductive factor, and the epidermal ectoderm is the source of dorsalizing factors. Opposing actions of these two signals establish the identity and pattern of cell types generated along the dorsalventral axis of the neural tube.

The nervous system is organized in response to intrinsic patterning genes and critical embryonic signaling pathways involving secreted factors and cell-cell interactions. The homeotic, Hox, transcription factor genes provide a positional “address” or identity of spinal cord and hindbrain neurons. Fate determination along the dorsal-ventral axis also requires the action of three opposing signaling pathways:



1. Sonic hedgehog (SHH), produced ventrally by the notochord 2. Wnt, in which pathway different Wnts define dorsoventral regions of neural tube 3. Bone morphogenetic protein (BMP), in which pathway different BMPs are secreted by dorsally placed cells from the boundary of the neural and nonneural ectoderm In this model, SHH released by the notochord diffuses toward the ventral neural tube and induces the differentiation of the floor plate. The floor plate then produces additional SHH, which diffuses and establishes a gradient along the dorsalventral axis of the neural tube. Differentiation of cells in the dorsal half of the neural tube depends on signals such as BMPs provided by the lateral epidermal ectoderm. BMP4 and BMP7, released by the epidermal ectoderm, diffuse toward the dorsal neural tube and induce the differentiation of the roof plate. Regions of the spinal cord that are exposed to the highest concentrations of SHH and lowest concentrations of BMPs give rise to ventral motor neurons, whereas cells exposed to lowest SHH and highest BMP concentrations give rise to dorsal cells, such as commissural projection neurons. Rostrocaudally, the neural tube is regionalized into four major divisions: forebrain, midbrain, hindbrain, and spinal cord. Actions of FGF, Wnt, and retinoic acid (RA) pathways confer a caudal identity and also influence telencephalic patterning.

EPIDEMIOLOGY AND PATHOGENESIS Incidence Among live births, females are more affected by NTDs than males by 2 to 1. Additionally, the prevalence of NTDs varies across time, by region, and by ethnicity and approximates 0.5 cases per 1000 in the United States but 10 per 1000 in parts of China and India. FA fortification of the United States food supply and/or the availability of prenatal diagnosis and the elective termination has reduced NTD prevalence in the United States to 0.37 cases per 1000 reported. The twin concordance rate among same-sex twins (presumed monozygotic) is significantly increased (to 6.8%), supporting a genetic contribution. Furthermore, compared with an incidence in the general population of 1 per 1000, the risk of NTD recurrence in a family with one affected child increases to 1.8 per 100 but does not approach the 1 in 4 recurrence risk of an autosomalrecessive mutation with complete penetrance.

Complex Genetic Contributions The complexity of the genetic underpinnings of neurulation is reflected in the NTD-prone mouse lines, for which over 250 mutations have been associated with failure of neural tube closure (Harris and Juriloff, 2010). Despite this wealth of information, there is no single-gene polymorphism in the human homologs of these mouse genes that confers a robust, broadly reproducible enhanced risk of developing an NTD. This has led to the supposition that the genesis of NTDs requires the compounding of multiple gene polymorphisms. The several hundred genes that have been associated with NTDs in mouse models are beginning to provide insights into molecular networks that are critically important for neurulation and may become clinically useful (Ross, 2010). For example, just as mutation in Vangl2 renders the looptail mouse prone to NTD, polymorphisms in human Vangl1 and Vangl2 have been implicated in NTD patients. The complexity of the genetic underpinnings of NTD indicates that meeting the challenge for determining individual risk—and the optimal preventative therapy—will require evaluation of multiple genes (in signaling, metabolic, and transcriptional pathways)

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in a single person to detect compounding effects of gene polymorphisms that alone might not be significant. Advanced technologies for high-throughput genomic DNA sequencing and analysis and detection of the epigenome and perhaps the microbiome, as well as untargeted metabolomic screening, will all play a role in the clinical evaluation of individual patient assessments of NTD risk and prevention.

Gene-Environment Interactions in   Neural Tube Defects The environmental variables that have been implicated as risk factors for nonsyndromic forms of spina bifida are listed in Table 25-1. Risk factors include maternal diabetes, maternal obesity, and prepregnancy weight gain. Moreover, maternal periconceptional elevations in simple sugars that raise the glycemic index have been associated with increased NTD risk, even among nondiabetic women. In animal models, exposing rat embryos to a hyperglycemic environment induces dysmorphisms, accompanied by increases in biomarkers of oxidative stress and inositol depletion. Studies in the United Kingdom, later corroborated in Eastern Europe and elsewhere, indicated that the prevalence of NTDs could be reduced by 70% or more by prenatal supplementation with FA, even in the absence of maternal folate deficiency. However, some populations demonstrated only a small or no significant reduction in NTD rates with prenatal FA supplementation, suggesting that differences in genetic background, diet, or other environmental exposures could influence the efficacy of folate supplementation. Inadequate intake of natural folate before and during early pregnancy is associated with a 2- to 8-fold increased risk of MMC and anencephaly, as indicated by several series of casecontrolled, randomized clinical trials and community-based interventions.

Teratogens RA is a well-known teratogen when administered to nonhuman embryos, in which one of its many effects is to induce

TABLE 25-1  Risk Factors for Spina Bifida Risk Factor ESTABLISHED RISK FACTORS History of previous affected pregnancy with same partner Inadequate maternal intake of folic acid Pregestational maternal diabetes Valproic acid and carbamazepine SUSPECTED RISK FACTORS Maternal vitamin B12 status Maternal obesity Maternal hyperthermia Maternal diarrhea Gestational diabetes Fumonisins Paternal exposure to Agent Orange Chlorination disinfection byproducts in drinking water Electromagnetic fields Hazardous waste sites Pesticides

Relative Risk (-Fold Increase) 30 2–8 2–10 10–20 3 1.5–3.5 2 3–4 NE NE NE NE NE NE NE

NE, not established. (With permission from Mitchell, L.E. et al., 2004. Spina bifida. Lancet 364, 1885–1895.)

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NTDs, including spina bifida, exencephaly, and anencephaly in several different species. Most, if not all, antiepileptic drugs (AEDs) are known teratogens. Different AEDs, however, are associated with different constellations of malformations. An increased risk of MMC is associated with in utero exposure to valproic acid or carbamazepine alone, or in combination with other AEDs. In infants exposed to valproic acid or carbamazepine, the risk of MMC can be as high as 1% to 2% (Wlodarczyk et al., 2012). The mechanisms by which valproic acid and carbamazepine increase the risk of NTD have not been established, but there is general consensus that genetic predisposition to its teratogenic effect is required for valproate to promote NTDs. Folate administration does not appear to protect against the effects of valproic acid or carbamazepine on neural tube closure.

CLASSIFICATION OF NEURAL TUBE DEFECTS Nomenclature Broadly speaking, it is useful to separate those anomalies that arise from an early failure of neural tube formation and those that arise from defects in subsequent developmental steps. MMC refers to the commonest form of spina bifida, which comprises a flat neural placode, the unfolded derivative of the neural plate, elevated above a sac containing cerebrospinal fluid and continuous with the skin. Neural tube closure is required for subsequent steps, including formation of mesodermal structures (e.g., dura, posterior spinal elements, and muscle). Milder NTDs often result in near-normal formation of mesodermal structures and closure of the overlying skin. This basic difference, the presence or absence of skin, has led to the designation of spina bifida into open forms, spina bifida aperta, or closed forms, spina bifida occulta. Spina bifida occulta is a confusing term because it can refer to either a broader group of anomalies that have normal skin overlying the spinal defect or a specific anomaly that indicates a lack of fusion of the spinous processes in the lumbar area and has limited clinical significance

A

B

(see later in this chapter). Fortunately, both of these terms are not common in current use.

Embryologic Classification of   Neural Tube Defects Neurulation is first visible as ectodermal thickening into the neural plate and proceeds in steps outlined previously. The commonly encountered NDs may be classified on the basis of the embryologic anomalies due to: • Defects of neural folding and formation—myelomeningocele and anencephaly • Disordered postneurulation development—encephaloceles • Incomplete dysjunction—dermal sinus and associated dermoid and epidermoid tumors • Premature dysjunction—spinal cord lipomas • Disorders of gastrulation—split cord malformation, neurenteric cysts • Disordered secondary neurulation—thickened filum terminale, myelocystocele • Failure of caudal neuraxial development—sacral agenesis

MYELOMENINGOCELE Myelomeningocele (MMC), the most complex of congenital spinal deformities, involves all tissue layers dorsal to and including the neural tube (i.e., spinal cord, nerve roots, meninges, vertebral bodies, skin). The dysplastic neural tube observed in newborns with MMC is a flat, disorganized segment of tissue located at the middle and most superficial portion of a cerebrospinal fluid-containing sac (Fig. 25-14).

Antenatal Diagnosis Maternal serum α-fetoprotein (AFP) determination and ultrasound examination are used to identify fetuses that have or are likely to have spina bifida or anencephaly. Elevated amniotic AFP concentrations correlate with open NTDs, whereas

C

Figure 25-14.  Lumbar meningocele in a newborn. A, External appearance of the skin. B, Midline sagittal view from a fetal T2-weighted MRI study depicts a fluid-filled cystic lesion. Note homogeneous water signal within the lesion, suggesting the diagnosis of meningocele, rather than meningomyelocele. C, Midline sagittal T2-weighted image from the postnatal MRI showing the fluid-filled sac and the spinal cord within the spinal canal.



closed lesions usually do not lead to increased AFP concentration. Detection of NTDs correlates with the magnitude of increase in the amniotic fluid AFP level; NTDs are associated in a minority of pregnancies with mildly elevated AFP levels, in a majority of those with moderately elevated levels, and overwhelmingly in those with very elevated AFP levels. Sonography can differentiate between ventral wall defects and NTDs and can identify additional structural malformations that are characteristic of fetuses with chromosomal abnormalities. It is 60% accurate in low-risk pregnancies, which is equivalent to the accuracy of serum AFP screening (64%), 89% accurate in high-risk pregnancies, and 100% accurate for women referred for confirmation of a suspected spina bifida by another ultrasonographer. The data indicate that neither sonography nor AFP screening alone provides sufficient sensitivity or specificity but that, when these studies are used together, the predictive value is much higher.

Clinical Features The mortality rate for MMC is approximately 50% in the absence of therapy. The primary goal of surgery for closure of the lumbosacral defect is to prevent meningitis. The location and extent of the defect determine the nature and degree of neurologic impairment; rating scales attempt to standardize the evaluation of affected children. Lumbosacral involvement is most common. Thoracic defects are the most complex and frequently are associated with serious complications. Cervical cord involvement is different from MMC of the lower spine and can be differentiated into two types: 1. Myelocystocele herniating posteriorly into a meningocele 2. Meningocele with or without an underlying split cord malformation Varying degrees of leg paresis, usually profound, and sphincter dysfunction are the major clinical manifestations. Congenital dislocation of the hips or deformities of the feet such as clubbing may also occur. Severe sensory loss and accompanying trophic ulcers may complicate the condition. Occasionally, only sphincter disturbances are present. Hydrocephalus is present in about 70% to 85% of patients with MMC and occurs most frequently with thoracolumbar lesions, which accounts for 90% of patients. Most persons with spina bifida have normal intelligence, but specific cognitive disabilities and language difficulties are common and can adversely affect educational and occupational achievements and the ability to live independently.

Secondary Abnormalities Central Nervous System Complications Seizures have been reported in up to 17% of patients with MMC and almost always occur in those with shunted hydrocephalus. Additional CNS abnormalities seen in these patients may underlie seizures and include encephalomalacia, previous stroke, malformations, and intracranial calcifications. Seizures may be difficult to control, and frequently, seizure exacerbation is associated with shunt malfunction or ventriculitis.

Bladder and Bowel Dysfunction Bladder dysfunction and urinary incontinence pose major management problems and may be present at birth in the form of hydronephrosis. Interruption of sacral nerve roots and fiber connections between the brainstem and sacral cord causes the dysfunction. Loss of sphincter tone, overflow

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incontinence, sacral and rectal loss of sensation, and loss of detrusor activity on cystometry are seen. Normal bladder control occurs in 10% of children with MMC. Prevention of bladder infection requires intermittent catheterization to maintain low residual urine volumes and prophylactic antibacterial drugs. Vesicoureteral reflux often develops during the second and third years of life, and assessment for this problem must be ongoing.

Orthopedic Problems Orthopedic defects associated with this paralysis, muscle imbalance, and accompanying regional spasticity may be severe and necessitate early intervention. Severe foot deformities afflict 80% of children and are treated with splinting or casting. Sensory deficits of the casted skin areas increase risk of skin ulcers. Physical therapy may help to preserve and extend the range of motion of the joints. Progressive leg or foot deformity, weakness, pain, or deterioration of gait or bladder function implies restricted growth or tethering of the spinal cord. Cord tethering affects many older children with spina bifida who are neurologically stable. Surgical repair of a worsening tethered spinal cord and shunting or fenestration of syringomyelia can prevent decline of function.

Chiari II Malformation Classification.  Multiple hindbrain malformations are associated with congenital hydrocephalus. Four types of Chiari malformation have been characterized. Chiari I malformation is a downward displacement of the cerebellum and cerebellar tonsils. Chiari II malformation is a complex malformation that includes downward displacement of the cerebellar vermis and tonsils and is encountered almost exclusively in patients with MMC. Chiari III is an encephalocervical meningocele, and Chiari IV refers to hypoplasia of the cerebellum. The major features of the Chiari II malformation include: 1. Inferior displacement of the medulla and the fourth ventricle into the upper cervical canal 2. Elongation and thinning of the upper medulla and lower pons, persistence of the embryonic flexure of these structures, and the appearance of a “beaking” of the tectum 3. Inferior displacement of the lower cerebellum through the foramen magnum into the upper cervical regions 4. A variety of bone defects of the foramen magnum, occiput, and upper cervical vertebrae Hydromyelia and syringomyelia of the cervical spinal cord occur in 20% to 50% of patients. Clinical Features.  The symptoms associated with Chiari II malformations include apnea, swallowing difficulties, and stridor in the newborn and headache, quadriparesis, scoliosis, and balance and coordination difficulties in the older child; they are present in up to one-third of persons with the disorder (Box 25-1). It is often difficult to differentiate between symptoms related to the hydrocephalus versus cerebellar malformation, but many symptoms are directly referable to cerebellar, brainstem, and cranial nerve dysfunction. More than onethird of affected infants display feeding disturbances with reflux and aspiration. Vocal cord paralysis with stridor and abnormalities of ventilation, including both obstructive and central apnea may occur. The causes of the clinical abnormalities of brainstem function are threefold. First, they relate in part to the brainstem malformation, which involves cranial nerves and other nuclei, present in most cases. Second, compression and traction of the anomalous caudal brainstem by hydrocephalus and

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BOX 25-1  Clinical Manifestations of Chiari II Malformation • Apnea • Tongue fasciculations • Stridor • Facial palsy • Gastroesophageal reflux • Swallowing difficulties • Poor feeding • Ataxia • Hypotonia • Upper extremity weakness • Hydrocephalus • Syringomyelia • Attention deficit • Seizures • Extraocular movement abnormalities • Nystagmus • Increased mortality (With permission from McLone, D.G., Dias, M.S., 2003. The Chiari II malformation: cause and impact. Childs Nerv Syst 19, 540–550.)

increased intracranial pressure also may play a role, especially in the vagal nerve disturbance that results in vocal cord paralysis and stridor. Third, ischemic and hemorrhagic necrosis of the brainstem often is present also and may be secondary to the disturbed arterial architecture of the caudally displaced vertebrobasilar circulation.

Management Management of MMC requires multidisciplinary efforts involving many specialists. Treatment includes surgical reduction and other associated defects such as syringomyelia, prevention of infection, covering of the MMC, control of hydrocephalus, management of urinary dysfunction, and treatment of the paralysis and abnormalities of the hips and feet.

Fetal Repair of Myelomeningocele Compared with historical controls, infants given treatment in utero have a lower incidence of moderate to severe hindbrain herniation and hydrocephalus requiring shunting. A randomized, prospective clinical trial examined the efficacy of fetal repair of MMC between 22 and 26 weeks gestational age compared with standard postnatal repair. After inclusion of 183 subjects and analysis of 158 children at 12 months of age, the study was closed because of demonstrated benefit in the fetal treatment arm (Adzick et al, 2011; Gupta et al, 2012). In particular, there was a reduced rate of hydrocephalus requiring shunting, an improvement in motor function, and an improvement in hindbrain herniation in the group who underwent fetal repair. These benefits were balanced by the increased risk of preterm delivery and a number of maternal risks. The long-term outcomes are still undefined, but the patients recruited for the study described previously are being evaluated.

Management in the Newborn Period Standard treatment includes closure of skin lesions overlying MMCs and treatment of hydrocephalus. The value of immediate correction of the defect within 48 hours of birth is widely

accepted. Even when cerebrospinal fluid leakage occurs, however, a delay in closure for up to 48 hours does not increase the risk of infection or worsen the neurologic deficit. In such cases, the patient is given antibiotics, and the exposed placode is kept clean and moist. Ultrasonography and urodynamic studies should be carried out to assess the status of the urinary tract and provide a baseline for continuing assessment. At this age, bowel function is usually not difficult because affected infants have the gastrocolic reflex and pass stools with most feedings. The decision to give vigorous therapy for the most severely affected infants with MMC is beset by moral and medical considerations; restricted therapy often is associated with survival but poor outcome.

Treatment of Chiari II Malformation Evaluation with MRI is the procedure of choice to evaluate a Chiari II malformation. Before considering surgical decompression of the posterior fossa, it is important to treat hydrocephalus if present. A properly functioning ventricular shunt often can obviate the need for decompression of hindbrain herniation. Many patients will resolve brainstem symptomatology with shunting. Significant improvement in the size of an accompanying spinal syrinx may occur after ventriculoperitoneal shunting or shunt revision. Suboccipital craniectomy may be warranted to decompress neural and vascular structures.

Outcome Short-term and long-term survival of patients with spina bifida has increased with improvements in medical and surgical management. Patients with MMC are at substantial risk for leg weakness and paralysis, sensory, bowel and bladder dysfunction, and orthopedic abnormalities (e.g., clubfoot, contractures, hip dislocation, scoliosis, kyphosis). In general, the functional level corresponds to the anatomic level of the bony spinal defect. Patients with MMC also develop symptoms from associated malformations of the CNS, including hydrocephalus, syringomyelia, and Chiari II malformations.

ANENCEPHALY Anencephaly is a congenital malformation in which both cerebral hemispheres are absent. Most anencephalic infants are stillborn, and those infants born alive die shortly after birth. Epidemiologic studies demonstrate a striking variation in prevalence rates. The highest incidence is in Great Britain and Ireland, and the lowest incidence is in Asia, Africa, and South America. In the past two decades, prenatal screening with ultrasound examination during the first trimester, which is nearly 100% accurate, and maternal AFP determinations have resulted in earlier detection of anencephaly. Earlier detection has resulted in a dramatic decrease in the average gestational age at birth, from 35.6 weeks in the 1970s to 19.6 weeks in 1988 to 1990, with virtually no term liveborn anencephalic infants born after 1990 in those pregnancies in which a prenatal diagnosis of anencephaly had been made (Drugan, 2001).

Pathogenesis The causes of anencephaly remain unknown; however, of importance, they mirror the causes of spina bifida, and similarly, folate has reduced the incidence of disease significantly. Indeed, both spina bifida and anencephaly can occur in the same family, reflecting the stochastic nature of where and



when neural tube closure may fail. Risk factors discussed previously apply to both spina bifida and anencephaly.

Differential Diagnosis In anencephaly, the absence of the brain and calvaria can be total or partial. Acrania is defined as congenital partial or total absence of the skull. Craniorachischisis is characterized by anencephaly, accompanied by a contiguous bony defect of the spine and exposure of neural tissue. In iniencephaly, dysraphism in the occipital region is accompanied by severe retroflexion of the neck and trunk, with three cardinal features: deficiency of the occipital bone; cervicothoracic spinal retroflexion; and rachischisis. Iniencephaly differs from anencephaly in that the cranial cavity is present and skin covers the head and retroflexed region. A majority of the patients also have visceral and other severe CNS malformations. In encephalocele, the brain and meninges herniate through a defect in the calvaria.

Pathology The cranial vault is defective over the vertex, exposing a soft, angiomatous mass of neural tissue covered by a thin membrane continuous with the skin. The cranial abnormality may extend inferiorly to the cervical region, with formation of a complete spina bifida. The extremely thin and flattened spinal cord is readily observed. The optic globes usually are protuberant because of inadequate bony orbits.

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Severe intellectual and motor delays typically occur in association with microcephaly; motor delay is accompanied by weakness and spasticity. Intellectual impairment is more prevalent in patients with posterior encephaloceles than in those with anterior encephaloceles. Some patients, however, may have fairly normal development. When the deformity extends into the ventricle, hydrocephalus is almost inevitable.

Management Prenatal diagnosis of encephaloceles may be established with determination of increased amniotic AFP content and ultrasound studies. Surgical correction of all but the smallest encephaloceles is necessary. Accompanying hydrocephalus may require ventriculoperitoneal shunting. Associated systemic abnormalities are present in approximately half of the patients, depending on the syndromic nature of the condition. A full battery of endocrinologic screens should be performed to evaluate basal encephaloceles.

OCCULT FORMS OF SPINAL DYSRAPHISM

An encephalocele is a herniation of intracranial contents through a midline skull defect. Also known as cephaloceles, these lesions are classified by their contents and location. Cranial meningoceles contain only leptomeninges and cerebrospinal fluid, whereas encephaloceles also contain brain parenchyma. The incidence of cephaloceles is approximately 0.8 to 5 per 10,000 live births, with encephaloceles being the most common form. Encephaloceles occur in the occipital (75%) or frontal areas (25%). Basal and transsphenoidal encephaloceles are rare; they may appear between the ethmoid and sphenoid bones and extend into the upper pharynx. Encephaloceles extending from the orbit, nose, or forehead are termed sincipital encephaloceles; those in the occipital region are termed notencephaloceles.

The spectrum of occult spinal dysraphism includes anomalies in which the overlying skin is mostly normal and covers the underlying NTD. These anomalies include distortion of the spinal cord or roots by fibrous bands and adhesions, intraspinal lipomas, dermoid or epidermoid cysts, fibrolipomas, spinal cord lipomas, lipomyelomeningocele, and split cord malformations. Symptoms of occult spinal dysraphism may be absent, minimal, or severe, depending on the degree of neural involvement. The patient may exhibit static or slowly progressive weakness, spasticity, or sensory loss in the legs or feet, gait difficulty, and foot deformity. Bowel and bladder dysfunction such as incontinence, repeated bladder infection, and enuresis also may occur. Common findings include diminished Achilles tendon reflexes, contracted heel cords, high arches, equinovarus deformity of the feet, decreased rectal sphincter tone, unequal leg or foot length, scattered sensory loss, Babinski signs, and trophic ulcers. Ultrasonography and MRI have greatly facilitated the diagnosis and management of these occult lesions. A tethered spinal cord, lipoma, or fatty filum terminale can be detected without invasive myelography. Ultrasonography can demonstrate a poorly pulsatile, low-lying, or thickened conus medullaris in infants. The decision to proceed to surgery is based on progressive symptomatology.

Etiology

Spinal Cord Lipoma

The etiology of encephaloceles is likely is multifactorial. Studies have indicated that consumption of FA during the periconceptional period can reduce the risk of anencephaly, as well as spina bifida. A similar protective effect, however, has not been noted for encephalocele.

Spinal cord lipomas are developmental anomalies that range from a small fatty mass attached to the distal spinal cord to very complex anomalies that involve all spinal structures. In some cases, the lipoma is entirely intraspinal and extends through a limited defect in the posterior elements of the spine into the subcutaneous tissues. When involving subcutaneous tissues along with a cerebrospinal fluid-containing space, this is usually referred to as a lipomyelomeningocele. Spinal cord lipomas are considered more complex forms of spinal dysraphism. Despite this, they can present with either no symptoms or symptoms over long periods of time. If untethering of the spinal cord can be accomplished with low morbidity, then a surgical procedure should be considered early in life. For large and complex lesions, particularly in patients with normal function, serious consideration should be given to observation, as deficits can evolve slowly.

ENCEPHALOCELE

Clinical Characteristics A fluctuant, round, balloon-like mass that protrudes from the cranium, usually posteriorly, is the most typical manifestation of encephaloceles. The mass may pulsate and be covered by an erythematous, translucent, or opaque membrane, or by normal skin. The amount of compromised and deformed neural tissue and the degree of resultant microcephaly determine the extent of cerebral dysfunction. Brain tissue not extending into the encephalocele (i.e., retained within the intracranial cavity) may be deformed and functionally impaired.

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Dermal Sinus Tract Recurrent meningitis from external contamination of cerebrospinal fluid may result from occult congenital malformations along the spinal canal and neuraxis such as dermal sinus tracts. From an embryologic perspective, sinus tracts consist of epithelial-lined canals that probably represent persistence of an ectodermal-derived pathway from the skin to the CNS. In most cases, the spinal cord appears largely normal, implying that neural tube formation is complete but a persistent communication is still present. Dermal sinus tracts are seen in approximately 1 in 2500 live births. An MRI scan should be obtained, followed by surgical treatment to eliminate this connection and remove the risk of meningitis.

as hairy patch, dimple, hemangioma, subcutaneous mass, or teratoma. A progressive myelopathy with deformities of the feet, scoliosis, kyphosis, or discrepancy in leg length may develop. The intervening mesenchymal elements appear to contribute to progressive neurologic, urologic, and orthopedic deterioration from spinal cord tethering. Resection of the spur should be performed in patients who have progressive neurologic manifestations; those without worsening symptoms should be observed until progression occurs and then resection performed.

DISORDERS OF SECONDARY NEURULATION Fibrofatty Filum Terminale

Spina bifida occulta, a confusing term, is defined as a defect in the posterior bony components of the vertebral column without involvement of the cord or meninges. It occurs in at least 5% of the population but most often is asymptomatic. The presence of a cutaneous lesion, tuft of hair, or a cutaneous angioma or lipoma in the midline of the back, is associated with spina bifida occulta in only approximately 10% of cases, although the percentage increases to approximately 50% when two or more skin lesions are present.

The filum terminale is the nonfunctional continuation of the end of the spinal cord. It usually consists of fibrous tissue without functional nervous tissue. Although its embryologic origin is unclear, it probably represents the termination of the neural tube and its most caudal link to the rest of the embryonic tissues. The filum can be enlarged either with fibrous tissue only or with fat. A thickened or fatty filum terminale may be associated with a low conus and a spectrum of clinical findings, including bladder dysfunction, leg numbness and weakness, and scoliosis. In the presence of neurologic findings and a fatty filum, an untethering procedure may be considered.

Meningocele

Sacral Agenesis

Meningocele, a protrusion of meninges without accompanying nervous tissue, is not associated with neurologic deficit. The mass usually is evident as a fluid-filled protrusion covered by skin or membrane in the midline. An MRI is essential to determine the contents of a mass along the spine and in differentiating meningocele from MMC (Fig. 22-14). Very small subcutaneous lesions may remain undetected for prolonged periods and typically require no specific treatment. When careful examination of patients with suspected meningocele reveals significant neurologic abnormality (e.g., equinovarus deformity, gait disturbance, abnormal bladder function), the diagnosis of MMC is appropriate. These patients likely have entrapped nerve roots within the defect that can be identified during surgery.

Sacral agenesis is a congenital absence of all or part of the sacrum. In its classic form, often described as the caudal regression syndrome, malformations of most or all structures derived from the caudal region of the embryo, including the urogenital system, the hindgut, caudal spine, spinal cord, and the lower limbs, may be seen. Approximately 15% to 25% of mothers of these children have insulin-dependent diabetes mellitus.

Spina Bifida Occulta

Split Cord Malformations Embryology In split cord malformations, previously known as diastematomyelia, a midline septum divides the spinal cord longitudinally into two, usually unequal portions extending up to 10 thoracolumbar segments. The septum may span the entire width of the spinal canal and is anchored to the ventral dura mater on the posterior aspect of the vertebral bodies. Split cord malformations can be divided into two different types. In type I, present in 50% of cases, a split spinal cord is surrounded by a normal undivided arachnoid-dural sleeve without a septum. In type II, present in the other 50%, each hemicord is invested by a separate dural sleeve, divided by a fibrous, cartilaginous, or bony septum.

Clinical Characteristics Patients with split cord malformations present with a congenital scoliosis, hydrocephalus, or cutaneous lesion such

REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Adzick, N.S., Thom, E.A., Spong, C.Y., et al., 2011. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N. Engl. J. Med. 364, 993–1004. doi:10.1056/NEJMoa1014379. Copp, A.J., Greene, N.D., Murdoch, J.N., 2003. The genetic basis of mammalian neurulation. Nat. Rev. Genet. 4, 784–793. Drugan A, Weissman A, Evans MI. Screening for neural tube defects. Clin Perinatol 2001;28:279–87, vii. Gupta, N., Rand, L., Farrell, J., et al., 2012. Open fetal repair for myelomeningocele. J. Neurosurg. Pediatr. 9, 265–273. Harris, M.J., Juriloff, D.M., 2010. An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res. A. Clin Mol. Teratol. 88, 653–669. Ross, M.E., 2010. Gene-environment interactions: folate metabolism and the embryonic nervous system. Wiley Interdiscip. Rev. Syst. Biol. Med. 2 (4), 471–480. Wlodarczyk, B.J., Palacios, A.M., George, T.M., et al., 2012. Antiepileptic drugs and pregnancy outcomes. Am. J. Med. Genet. A 158A, 2071–2090.



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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 25-2 Cross-sections through the primitive streak. Fig. 25-3 A coronal cross-section through the cranial neural folds as they come together in the midline. Fig. 25-5 Examples of myelomeningocele lesions. Fig. 25-6 A T2-weighted magnetic resonance image of a 22-week-old fetus with an open neural tube defect and cerebellar tonsils descended into the upper cervical canal. Fig. 25-7 A postnatal sagittal T2-weighted magnetic resonance image of a child with a Chiari II malformation. Fig. 25-8 Postnatal magnetic resonance images of a child who underwent fetal repair of a myelomeningocele. Fig. 25-9 A typical occipital encephalocele. Fig. 25-10 Prenatal and postnatal images of the patient shown in Figure 25-9.

25 Fig. 25-11 A typical spinal cord lipoma. Fig. 25-12 A dermal sinus tract. Fig. 25-13 A typical bifid spinous process that is usually termed spina bifida occulta. Fig. 25-15 A type II split cord malformation. Fig. 25-16 A fibrofatty filum terminale extending from the end of the conus to the end of the thecal sac. Fig. 25-17 Partial sacral dysgenesis, or Currarino syndrome. Fig. 25-18 Partial absence of distal sacrum (black arrows) and abrupt wedge-shaped truncation of the tip of the conus (white arrows). No tethered cord is noted. Table 25-2 Classification of Chiari Malformations Table 25-3 Selected Syndromes Associated with Encephaloceles

26 

Disorders of Forebrain Development Elliott H. Sherr and Jin S. Hahn

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION The prosencephalon forms at the end of primary neurulation as one of three principal vesicles: the hindbrain, the midbrain, and the forebrain (prosencephalon). The major disorders of prosencephalic formation, holoprosencephaly, agenesis of the corpus callosum, and septooptic dysplasia, are discussed in the next sections, after a brief introduction to prosencephalic development.

Prosencephalon Patterning Prosencephalic development occurs by inductive interactions from the prechordal mesoderm. The peak time period of development is the second and third months of gestation. Prosencephalon development occurs as three sequential events: prosencephalic formation, prosencephalic cleavage, and midline prosencephalic development (Fig. 26-1). Prosencephalic formation segments this structure into three prosomeres (P1–P3). P1 becomes the pretectum, P2 the thalamus, and P3 the prethalamus. More rostral brain regions, including the telencephalon, are also divided into prosomeric boundaries. The neocortex itself exhibits regionally restricted gene expression; however, data argue against anatomically and regionally restricted boundaries because cell lineage experiments demonstrate that sibling cells can occupy multiple nuclei throughout the anteroposterior axis.

Prosencephalic Cleavage Prosencephalic cleavage occurs in the fifth and sixth weeks of gestation and includes three basic cleavages: 1. Horizontal, to form the paired optic vesicles, and olfactory bulbs and tracts 2. Transverse, to separate the telencephalon from the diencephalons 3. Sagittal, to form the paired cerebral hemispheres, lateral ventricles, and the basal ganglia from the telencephalon Three crucial thickenings or plates of tissue become apparent around the end of the second month; these are the commissural, the chiasmatic, and the hypothalamic plates. These structures are important in the formation, respectively, of the corpus callosum, anterior commissure and septum pellucidum, the optic nerve chiasm, and the hypothalamic structures. Disorders associated with abnormal development of the prosencephalon are outlined in Table 26-1.

HOLOPROSENCEPHALY Holoprosencephaly (HPE) is a complex brain malformation characterized by a failure of the forebrain (prosencephalon) to separate completely into two distinct cerebral hemispheres,

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a process normally complete by the fifth week of gestation. HPE is typically associated with midline facial anomalies.

Epidemiology HPE is the most common developmental defect of the forebrain and midface in humans and occurs in 1 in 250 pregnancies, but because only 3% of the fetuses with HPE survive to delivery, the incidence in live births is only approximately 1 in 10,000. There also appears to be a slight female preponderance in some case series. A few studies of limited size suggest a higher than average prevalence of HPE in Far East Asians and Filipinos.

Definition and Subtypes of Holoprosencephaly The sine qua non of HPE is incomplete cleavage of midline structures involving the telencephalon and diencephalon. HPE typically is divided into three main subtypes and distinguished by the degree of separation of the cerebral hemispheres (Fig. 26-2). In the most severe type, alobar HPE, nearly complete lack of separation of the cerebral hemispheres is characteristic, with a single midline ventricle very often communicating with a dorsal cyst. The interhemispheric fissure and corpus callosum are completely absent. In the intermediate form, semilobar HPE, the anterior hemispheres are not separated, but some degree of separation of the posterior hemispheres is seen. Similarly, the genu and body of the corpus callosum are absent, but the splenium is present. The frontal horns of the lateral ventricles are not developed, but the posterior horns are present. The mildest form, lobar HPE, is characterized by lack of separation of the most rostral and ventral aspects of the cerebral hemispheres. The splenium and body of the corpus callosum are present, but the genu is absent. Rudimentary frontal horns may be present. In addition to these types, another subtype is identifiable: the middle interhemispheric variant. In this variant, the midportion of the cerebral hemispheres is continuous across the midline, with absence of the corpus callosum seen only in this region. There is separation of the anterior frontal lobes, basal forebrain, and occipital lobes. Evidence for this malformation being a subtype of HPE is bolstered by mutation of the ZIC2 gene, which has been implicated in causing the classic forms of HPE. Failure of separation also is common in the hypothalamic, caudate, lentiform, and thalamic nuclei. About one fourth of patients have some degree of midbrain nonseparation. Occasionally, isolated neuronal heterotopias are seen, particularly in the middle interhemispheric variant. The gyri often are normally developed, although in alobar and semilobar HPE, the gyri may be excessively smooth or broad. Although for discussion HPE is divided into subtypes, the degree of



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DORSAL

26

Epiphysis Diencephalic roof Lamina terminalis Commissural primordium

ROSTRAL

Chiasmatic primordium

Olfactory bulb

CAUDAL

Hypothalamus

Hypophysis Optic vesicle BASAL Figure 26-1.  Prosencephalic midline development. The prosencephalic midline is presented by a series of independent but closely related segments. Note particularly the commissural, chiasmatic, and hypothalamic primordia or plates. The proximity of these structures in the developing brain and their derivation from a common primordium explain the spectrum of midline defects associated with septooptic dysplasia, which include optic nerve hypoplasia and hypothalamic and corpus callosum defects. (With permission from Leech RW, Shuman RM. Holoprosencephaly and related midline cerebral anomalies: A review. J Child Neurol 1986;1:3.)

malformation occurs along a spectrum, and individual patients do not fall neatly into categories.

Etiology Multiple environmental and genetic factors have been implicated in causing HPE. Prenatal exposures to a variety of toxins, medications, and infections also have been reported. The strongest teratogenic evidence exists for maternal diabetes and exposure to alcohol and retinoic acid. A diabetic mother’s risk of having a child with HPE is approximately 1%, a greater than 100-fold increase over the general population. A recent population study confirmed the risks of preexisting maternal diabetes and salicylates (aspirin) but also noted an increased risk with artificial reproductive therapy. Some teratogens are thought to produce HPE via interference with the sonic hedgehog gene signaling pathways, or cholesterol biosynthesis. Approximately 30% to 50% of live births with HPE have chromosomal abnormalities, but this is likely an overestimation based on underreporting of milder cases. HPE can be seen in association with trisomy 13, trisomy 18, or triploidy. Various deletions or duplications of chromosomal regions have also been associated with HPE. HPE is also seen in single gene syndromes, such as Pallister-Hall syndrome, RubinsteinTaybi syndrome, Smith-Lemli-Opitz, and Goldenhar syndromes. An updated list of genetic disorders associated with HPE can be found on the online Mendelian Inheritance in Man (OMIM) website (http://www.ncbi.nlm.nih.gov/omim). In nonsyndromic and nonchromosomal HPE, autosomaldominant and autosomal-recessive pedigrees have been reported. At least nine genes have been associated with HPE, including: SHH (7q36); ZIC2 (13q32); SIX3 (2p21); TGIF (18p11.3); PATCHED-1 (9q22); GLI2 (2q14); DISP1 (1q24); NODAL (10q); and FOXH1 (8q24.3). Of these genes, the four most commonly affected (SHH, ZIC2, SIX3, and TGIF) account for only 25% of the cases of HPE with normal chromosomes and approximately 5% to 10% of all HPE patients (Roessler and Muenke, 2010). SHH (sonic hedgehog) was the first identified HPEassociated mutated gene, and the SHH protein is a secreted

intercellular signaling molecule involved in establishing cell fates at several points during development. SHH is expressed early in development in the ventral forebrain and is critical for ventral patterning of the developing neural tube. Disruption of SHH signaling in animal models mimics the brain and facial malformations in HPE. The SHH signaling network is the common pathway through which multiple environmental and genetic influences interact to cause HPE. For example, PTCH is a receptor for SHH, and GLI2 is a mediator of SHH target gene transcription. Environmental influences link the SHH signaling network with hypocholesterolemia. For example, maternal hypocholesterolemia has been implicated in HPE. Also, HPE is seen in Smith-Lemli-Opitz syndrome, which is due to a defect in 7-dehydrocholesterol reductase, the final enzyme in cholesterol synthesis.

Clinical Manifestations and Outcomes Along with the midline brain malformation seen in HPE, a corresponding midline facial malformation may be present. In its most severe and usually lethal form, cyclopia with the presence of a single midline eye and a proboscis (rudimentary single-nostril nose) above the eye can be present. Survivors may have hypotelorism, a flattened nasal bridge, median cleft lip and palate, or a single median maxillary central incisor. The oft-quoted statement “the face predicts the brain” refers to the observation that the degree of facial malformation frequently reflects the degree of brain malformation. This was amended later to “the face predicts the brain approximately 80% of the time,” in recognition of individuals with alobar HPE with a normal facial appearance, as well as cases of milder brain malformation associated with abnormal facies. Previous studies indicated that children with HPE do not survive beyond early infancy. This may have been due to the identification of only the most severe cases. Early death is typical for most cytogenetically abnormal children and those individuals with the most severe facial features (cyclopia or ethmocephaly). In children without these risk factors, more

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recent studies have indicated that long-term survival is not uncommon. In one series of 104 HPE patients, the mean age at the time of study was 4 years, and 15% were between 10 and 19 years of age. When death did occur, causes included brainstem dysfunction, pneumonia, dehydration from diabetes insipidus, and rarely, intractable seizures. Children with HPE may experience a variety of medical and neurologic problems. A significant proportion develops hydrocephalus, with 60% of alobar and 8% of semilobar requiring a VP shunt. As in children with other midline brain defects, endocrinologic problems are very common. Diabetes insipidus is particularly frequent, growth hormone deficiency, hypocortisolism, and hypothyroidism also may occur. The endocrinopathies may be due to midline defects involving the hypothalamus and are rarely due to a dysgenetic (e.g., hypoplastic or ectopic) pituitary gland. Approximately half of the children with HPE have epilepsy, and the likelihood of developing seizures does not correlate with the severity of the brain malformation. The most common seizure type is complex partial seizures, with or without secondary generalization, but seizures can include generalized tonic-clonic, tonic, atonic, myoclonic, or infantile spasms. In 50% of affected children, the seizures are relatively easy to control with antiepileptic medication but with increased risk associated with cortical dysplasia. Feeding problems and swallowing dysfunction are common in children with HPE and are correlated with the severity of the brain malformation. Two thirds of patients with alobar and semilobar HPE require gastrostomy tubes. Developmental disability affects nearly all patients with HPE. The severity of the brain malformation determines the degree of delay and neurologic impairments (including hypotonia and spasticity). Severe developmental delay is present in alobar HPE. There is no reported case of a child with alobar HPE who is able to sit independently. In lobar HPE, approximately 50% of children ambulate (with or without assistance), use their hands functionally, and have some verbal communication. Neuropsychologic evaluation in HPE demonstrates relative strengths in receptive language and socialization and weaknesses in visual reasoning and nonverbal problem skills. In the middle interhemispheric variant, the incidence of endocrinopathies is much lower than has been attributed to the more normally separated hypothalamus seen on MRI. The degree of motor complications (hypotonia evolving into spasticity and dystonia) and developmental dysfunction is similar to that seen in lobar HPE.

Management Children with alobar HPE, a dorsal cyst, or normocephaly or macrocephaly should be closely observed for the development of hydrocephalus and perhaps shunting early given the high risk, as hydrocephalus can lead to progressive head enlargement and greater difficulty in caring for the child. Electrolyte screening should be performed for diabetes insipidus surveillance. Screening for other endocrine abnormalities should be considered, including assays of cortisol, thyroid-stimulating hormone, free thyroxine, and insulin-like growth factor-1 (IGF-1). If seizures develop, the possibility of acute reactive seizures should be evaluated for and a serum sodium level checked. MRI also should be considered to evaluate for focal heterotopia. Gastrostomy tubes often are necessary to address the complex management issues of ensuring adequate calories related to feeding dysfunction and delivery of adequate free water necessary for management of diabetes insipidus. Motor difficulties and dystonia may be partially responsive to trihexyphenidyl. This agent may improve upper extremity and

oromotor function. Motor dysfunction, including hypertonia and dystonia, is common and may require physical, pharmacologic, or surgical therapies.

Prenatal Diagnosis and Imaging The first-trimester ultrasound can detect alobar HPE but may be much less sensitive in detecting milder cases. The presence of large dorsal cysts, hydrocephalus, or midline craniofacial defects may provide clues that eventually lead to the recognition of the associated HPE. Fetal MRI has been used to diagnosis a range of HPE. Other midline anomalies, such as agenesis of the corpus callosum, absence of the septum pellucidum, and hydrocephalus with communication of the lateral ventricles, are sometimes misdiagnosed prenatally as HPE (Fig. 26-3).

Genetic Counseling and Testing The recurrence risk of isolated HPE is estimated to be 6%. Special attention should be given to the family history to identify “microforms” such as anosmia or a single central incisor. Such a finding indicates higher recurrence risk. Genetic sequence analysis is commercially available and should be considered. Prenatal testing for HPE risk genes is possible by means of amniocentesis or chorionic villus sampling. The gene tests, in conjunction with fetal MRI, have been found to be helpful in prenatal diagnosis and counseling in a series of pregnancies. High-resolution cytogenetic analysis can detect abnormalities in 24% to 45% of all individuals with HPE. Chromosomal microarray has a higher yield in detecting chromosomal deletions, duplications, and unbalanced rearrangements and is the preferred chromosomal test in fetuses and newborns suspected of having HPE.

AGENESIS OF THE CORPUS CALLOSUM The corpus callosum forms between the 8th and 14th weeks of fetal development. Nearly 200 million axons course through this structure and innervate opposing hemispheres in a homotopic manner; that is, each axon innervates structures in the mirror location in the opposing hemisphere. Absence or diminution of this structure is found in 1 in 3000 live births and is the most common birth defect of the central nervous system after spina bifida. Callosal abnormalities are frequently seen with other malformations of brain development but can present in an isolated manner (Fig. 26-4). Many cases are also associated with birth defects in other organ systems and can be caused by chromosomal disorders. There is also recognition that subtle chromosomal copy number variants (CNVs) play a critical role in the etiology of ACC (Sajan et al., 2013). Single-gene mutations and metabolic disorders can also disrupt callosal development. Fetal alcohol syndrome, the best-known and most studied environmental cause of ACC, can also result in a significant reduction in whitematter volume. There is a great diversity of clinical outcomes for patients with ACC. Many individuals with ACC have deficits in social cognition, even with a normal IQ. Many of these individuals carry clinical diagnoses that place their phenotype on the autism spectrum. In children with ACC and associated brain anomalies, many have seizures and more significant developmental impairment, including intellectual disability and cerebral palsy. In some individuals with ACC due to chromosomal, metabolic, or single-gene disorders, the outcome can be quite severe, including a significantly shortened life expectancy.



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26

A

B

C

D

Figure 26-3.  Fetal magnetic resonance imaging in holoprosencephaly. A and B, Fetal MRI (single-shot fast spin echo) of a 21-week- and 5-day-old fetus with alobar HPE. The thalami, basal ganglia, and midbrain structures are incompletely delineated on the midline sagittal image (A). A large dorsal cyst (dc) communicates with the monoventricle (asterisk). The hemispheres are not separated, resulting in a holosphere (B). C and D, Fetal MRI of a 26-week gestational age fetus with trisomy 13 and semilobar HPE. The HASTE fetal sequence in the midsagittal plane (C) shows a monoventricle (asterisk), a moderate size dorsal cyst (dc), and inferior cerebellar vermis hypoplasia (Dandy-Walker complex). On the axial image (D), the thalami and basal ganglia appear fused, whereas the posterior hemispheres are separated. (With permission from Hahn JS, Barnes PD. Neuroimaging advances in holoprosencephaly: refining the spectrum of the midline malformation. Am J Med Genet Part C 2010;154C:120–132.)

Epidemiology Population studies suggest a birth incidence for ACC of 1 in 3000 (Glass et al., 2008). Like many birth defects, the incidence rate of ACC is higher in births from mothers over age 40, with a nearly three-fold increased risk compared with women in their 20s. There is also a slightly higher prevalence in children born to older fathers, as has also been reported recently for autism. Babies with ACC are nearly four times more likely to be born prematurely than the general population. It should be noted that detection of ACC occurs more commonly with better ultrasound surveillance, and its detection in utero may alert physicians to the increased probability of premature birth (Glass et al., 2008). In addition, identifying ACC should also alert the clinician to screen for other

organ malformations, including musculoskeletal, renal, and gastrointestinal.

Prenatal Diagnosis and Prediction of Outcomes The majority of information on the epidemiology of callosal agenesis comes from studies of postnatally diagnosed cases. However, in the studies that investigated all types of ACC in large fetal cohorts, approximately 70% of individuals had other associated anomalies in the central nervous system, including white matter deficits, cortical malformations, cysts, and posterior fossa abnormalities (Hetts et al., 2006). Isolated ACC only accounted for approximately 30% of the total number of cases. In these cases of prenatally detected, isolated ACC, approximately 50% show neurologic impairment in the

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first few years of life, and many of the remainder show cognitive and behavioral deficits during school years. Current standard ultrasonography can reliably detect callosal agenesis at 22 weeks’ gestation; however, many pregnant women receive a single ultrasound at 18 weeks to evaluate fetal anatomy as part of standard prenatal care. There are recommendations within the obstetric community to perform two ultrasounds, one transvaginally at 14 weeks to assess nuchal translucency and other early visible anatomic changes and a second study at 20 to 22 weeks to better visualize later-developing structures, such as the corpus callosum.

Development of the Corpus Callosum The corpus callosum is the largest white-matter tract in the brain, with over 190 million axons crossing the midline to innervate principally homotopic structures. The disproportionate increase in white-matter volume in mammalian and, specifically, in primate evolution points to the importance of long-range connectivity (particularly of the frontal lobes) in brain evolution and function. The first callosal fibers can be seen crossing the midline around the 14th week of gestation. The midline is composed of a number of structures that likely assist in guiding these callosal fibers, including the glial wedge, midline zipper glia, glial sling, and indusium griseum glia (Fig. 26-5). The full complexity of molecular and cellular events necessary for callosal development is not yet known, but these events can be seen within a general framework of developmental steps that include: birth and specification of commissural neurons; guidance of these neurons to the midline; midline fusion and development of key midline structures (as outlined in Fig. 26-5); and axonal crossing of the midline with guidance of crossed neurons to the final site of connectivity. In patients with ACC, it can be difficult to determine which one of these steps is altered. However, in one group, patients with microcephaly and absent Probst bundles, there are likely defects in the initial birth and specification of commissural neurons. In contrast, it is more likely that patients who have Probst bundles (and normal or near-normal cerebral white-matter volume) have deficits in axonal guidance or midline fusion.

Imaging and the Corpus Callosum Imaging of children and adults with ACC has shown that the missing corpus callosum is frequently only one component of the spectrum of brain malformations found in an individual patient. In a retrospective study of 142 cases of callosal agenesis, only five had truly “isolated” ACC, whereas over half had malformations of cortical development, one third had cerebellar malformations, and one fourth had brainstem anomalies. Advanced techniques such as diffusion tensor imaging (DTI) have demonstrated that the ventral cingulum bundle (CB) is smaller and has lower fractional anisotropy in ACC patients, which may explain the behavioral deficits observed in ACC.

Etiology Genetic Many molecular and cellular processes are necessary for normal callosal formation. As such, many single-gene recessive disorders can be associated with callosal agenesis (Table 26-2). Whole exome sequencing has accelerated this discovery and new genes such EPG5 for Vici syndrome, C12orf57 for Temtamy syndrome, and GPSM2 for Chudley-McCullough syndrome were recently discovered. Autosomal dominant disorders associated with callosal agenesis and dysgenesis,

such as mutations in the DEAD-box gene DDX3X were also recently identified (Snijders Blok et al., 2015). In many disorders, the degree of callosal dysgenesis can be quite variable as in Sotos syndrome, in which complete ACC is present in a minority of cases, but other versions of callosal dysgenesis are prevalent in these patients (Schaefer et al., 1997). There is also evidence that de novo chromosomal disorders play a significant role in callosal dysgenesis. A recent publication cataloged de novo deletions and duplications at recurrent genetic loci from nearly 400 ACC patients. These include regions in 1p36, 1q4, 6p25, 6q2, 8p, 13q, and 14q. A subsequent publication suggested that over 15% of ACC patients have a large de novo CNV that may be causative. Although the initial presumption has been that most cases of ACC have a genetic etiology, it is possible that nongenetic causes may play an important etiologic role.

Nongenetic The best example of environmental causes of ACC is fetal alcohol syndrome (FAS). Despite this linkage, there is clearly variability in the expression of callosal deficits in fetal alcohol syndrome. The cell surface molecule L1, which is involved in both axon guidance and fasciculation, is a proposed target for alcohol toxicity and signaling through this pathway may explain the variable expressivity of fetal EtOH exposure. There are a few reports of heavy metal toxicity and ACC, but without many reports, it is difficult to attribute a significant percentage of ACC cases to these causes.

Clinical Manifestations Association of Agenesis of the Corpus Callosum With Autism and Related Neurodevelopmental Disorders A wide range of clinical deficits can be seen in individuals with callosal agenesis including autism, intellectual disability, epilepsy, and cerebral palsy. However, it is difficult to know the precise prevalence of these associated features because most individuals with ACC are evaluated specifically because of their clinical difficulties, introducing ascertainment bias. With that limitation in mind, many studies have reported that patients with ACC have significant cognitive and neuromotor impairment. Epilepsy is common and is more prevalent in patients who have other associated brain malformations. Autistic features are present in approximately 40% of patients with ACC who have normal IQs, and a more detailed analysis shows that high-functioning ACC individuals also have problems with social cognition, paralinguistic communication, and executive function skills. Thus they have difficulties holding down jobs, finding partners, and living independently, even though they may have normal intelligence.

Management Currently, the mainstay of management for patients with ACC includes symptomatic measures that may include use of antiepileptic drugs for epilepsy, physical and occupational therapy for hypotonia and cerebral palsy, and speech therapy. Patients with ACC, including apparently high-functioning individuals, often have difficulty with more complex cognitive and behavioral tasks and need explicit behavioral training and education, which is often lacking in school settings. Anecdotal reports suggest that these individuals do better with therapy targeted at simplifying these tasks, providing repetition, and supporting a slower learning pace. Although many individuals with ACC have social deficits, they generally desire social



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consistently reported include maternal smoking and low socioeconomic status. Two genes were initially found in association with SOD, the homeobox gene, HESX1, and the transcription factor gene, SOX2. Chromosomal changes also have rarely been reported in SOD cases. More recently, data suggested an overlap between Kallmann syndrome and SOD. Thus most patients with SOD are hypothesized to result from a combination of genetic and environmental factors, recognizing that other mechanisms are yet to be discovered.

Clinical Manifestations

Figure 26-8.  Septooptic dysplasia. In this brain of a newborn, note corpus callosum thinning (short arrow), absent septum pellucidum (long arrow), hypothalamic hypoplasia (double arrows), and optic nerve hypoplasia (asterisk).

interactions. With recent reports of the potential benefits of intranasal oxytocin treatment for autistic individuals with social deficits, some have hypothesized that similar approaches may have long-lasting benefits in ACC patients. This approach remains to be formally tested.

SEPTOOPTIC DYSPLASIA The constellation of symptoms that comprise septooptic dysplasia (SOD) is presumed to result from failure of formation of the optic nerves, septum pellucidum, pituitary gland, and all midline structures within the prosencephalon (Fig. 26-8). Patients typically present with pituitary hormone abnormalities that can result in hypoglycemia or microphallus at birth or growth failure and other endocrine manifestations throughout childhood. It is a rare condition, with an estimated incidence of 1 to 10 in 100,000; known genetic etiologies contribute to only a small percentage of cases. Also, data suggest that young maternal age contributes to the risk of developing SOD. SOD is better viewed as a complex (SOD complex), with variable etiology and clinical presentation.

SOD can present at birth with manifestations of pituitary insufficiency, including hypoglycemia, hypogonadotropic hypogonadism, and midline birth defects, including cleft lip and palate, as well as other brain malformations such as a thin corpus callosum. SOD patients are also at risk for adrenocorticotropic hormone, thyroid-stimulating hormone, and growth hormone deficiency. As with HPE and ACC, many patients with SOD have developmental delay and cerebral palsy.

Management Symptom management is essential in individuals with SOD, and careful attention should be paid to the heterogeneity of this complex disorder. Any child presenting with nystagmus should be evaluated for optic nerve involvement, and if ONH is detected, the patient should be assessed for anterior pituitary hormone deficiency. Additionally, many children with SOD can have developmental delay and seizures and should be evaluated for these possible concerns. Because children are at risk for adrenocorticotropic hormone, thyroid-stimulating hormone, and growth hormone deficiency (as well as hypothalamic dysfunction and poor production of the posterior pituitary hormones, antidiuretic hormone and oxytocin), they can present with hypoglycemia, diabetes insipidus, and poor thermoregulation. Multiple case reports of sudden death in SOD patients have described these complications (Kauvar and Muenke, 2010). REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES

Definition and Subtypes There are three cardinal features of SOD: optic nerve hypoplasia, pituitary abnormalities, and midline brain defects (involving primarily the septum pellucidum and, at times, the corpus callosum). The diagnosis of SOD is typically made when two of the three features are present; however, given the heterogeneity intrinsic to this constellation of symptoms, most investigators have initiated their analysis by ascertaining patients with optic nerve hypoplasia (ONH) and then grouping those that had both pituitary dysfunction and absence of the septum pellucidum. From a clinical perspective, those that had ONH and pituitary anomalies but a normal septum pellucidum will have similar management issues. In contrast, those that have ONH and an absent septum pellucidum without pituitary abnormalities often have other brain malformations and likely represent a separate group.

Etiology SOD and ONH have been associated with primiparous birth and young maternal age. Additional risk factors that have been

Glass, H.C., Shaw, G.M., Ma, C., et al., 2008. Agenesis of the corpus callosum in California 1983–2003: a population-based study. Am. J. Med. Genet. A 146A (19), 2495–2500. Hetts, S.W., Sherr, E.H., Chao, S., et al., 2006. Anomalies of the corpus callosum: an MR analysis of the phenotypic spectrum of associated malformations. AJR Am. J. Roentgenol. 187 (5), 1343– 1348. Kauvar, E.F., Muenke, M., 2010. Holoprosencephaly: recommendations for diagnosis and management. Curr. Opin. Pediatr. 22 (6), 687–695. Roessler, E., Muenke, M., 2010. The molecular genetics of holoprosencephaly. Am. J. Med. Genet. C Semin. Med. Genet. 154C (1), 52–61. Sajan, S.A., Fernandez, L., Nieh, S.E., et al., 2013. Both rare and de novo copy number variants are prevalent in agenesis of the corpus callosum but not in cerebellar hypoplasia or polymicrogyria. PLoS Genet. 9 (10), e1003823. Schaefer, G.B., Bodensteiner, J.B., Buehler, B.A., et al., 1997. The neuroimaging findings in Sotos syndrome. Am. J. Med. Genet. 68 (4), 462–465. Snijders Blok, L., Madsen, E., Juusola, J., et al., 2015. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. Am. J. Hum. Genet. 97 (2), 343–352.

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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 26-2 Subtypes of holoprosencephaly. Fig. 26-4 Agenesis of the corpus callosum without other associated central nervous system malformations. Fig. 26-5 Corpus callosum development. Fig. 26-6 Q-ball tractography of subjects with partial agenesis of the corpus callosum.

Fig. 26-7 T1-weighted anatomic images and diffusion tensor imaging tractography of six subjects. Fig. 26-9 Septum pellucidum defect. Table 26-1 Disorders of Midline Prosencephalic Development Table 26-2 Disorders Associated with Agenesis of the Corpus Callosum*

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Disorders of Cerebellar and Brainstem Development Dan Doherty and Andrea Poretti

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Advances in brain imaging, neuropathology, clinical phenotyping, genetics, and developmental biology have markedly improved the diagnosis of patients with structural disorders of the cerebellum and brainstem (SDCB) (Barkovich et al., 2009; Doherty et al., 2013; Robinson et al., 2014). It is now possible to recognize dozens of specific conditions by their clinical and imaging features, facilitating the identification of genetic and environmental (nongenetic) causes (Table 27-1). SDCB include malformations (genetic) and disruptions (acquired due to prenatal infection, hemorrhage, or ischemia). The differentiation between a malformation (genetic) and a disruption (acquired) implies a huge difference in the recurrence risk with implications for genetic counseling and family planning (Poretti et al., 2009). The majority of disruptions are acquired lesions without recurrence risk; however, a genetic predisposition to disruptive lesions may be present in some cases, such as dominant mutations in COL4A1. In addition to specifying recurrence risk, precise diagnosis is essential for providing accurate prognostic information and guiding surveillance for associated medical issues, supportive therapies, genetic testing, and emerging gene-specific therapies. Furthermore, a specific diagnosis can relieve parental guilt and allow families affected by rare disorders to connect with each other for support.

CLINICAL FEATURES The clinical features of SDCB are usually nonspecific and include hypotonia, motor delay, ataxia, and abnormal eye movements (Table 27-2). Cognitive impairment is common, but the range is broad (Bolduc et al., 2011). Although characteristic clinical features help identify patients with posterior fossa abnormalities, clinical features point to a specific diagnosis only in a minority (e.g., “figure-of-eight” head-shaking pattern for rhombencephalosynapsis). In the majority of patients, identifying the final diagnosis requires integration of history, clinical examination, neuroimaging, and laboratory testing.

APPROACH TO NEUROIMAGING Magnetic resonance imaging (MRI) is the neuroimaging tool of choice (Jissendi-Tchofo et al., 2015). Evaluation in multiple imaging planes and familiarity with the normal agedependent anatomy of the pediatric mid-hindbrain is essential (Table 27-3). Advanced neuroimaging techniques may be useful in selected cases. Susceptibility-weighted imaging (SWI) is highly sensitive for blood products and calcifications and is helpful in disruptive lesions. 1H-MR spectroscopy can be useful in the diagnosis of mitochondrial and other metabolic disorders. Diffusion tensor imaging (DTI) provides information about the microarchitecture of cerebellar structures, the course of cerebellar white matter tracts, and their connections with other brain structures. In addition, DTI may reveal new diseases due to axon guidance defects that are not detectable by

conventional structural MRI. Functional MRI (task-based and resting state) remains largely a research tool but shows promise for improving diagnostic specificity, guiding treatment, and monitoring treatment response.

APPROACH TO GENETIC TESTING Given the incredible advances in sequencing technologies and other methods for identifying mutations across the entire genome, clinical genetic testing is very much a moving target. The different SDCB can be caused by large chromosome abnormalities, as well as recessive and dominant simple nucleotide variants. The importance of de novo and mosaic dominant mutations has only recently been appreciated. Repeat expansion has only been described in the spinocerebellar ataxias (rare in children), and imprinting defects have not been shown to cause SDCB.

DISORDERS PRIMARILY AFFECTING CEREBELLUM Cerebellar Hypoplasias Primarily   Affecting Vermis Dandy-Walker Malformation Clinical characteristics: Dandy-Walker malformation (DWM, OMIM 220200) is the most prevalent human cerebellar malformation (about 1 in 30,000 live births). The majority of children present prenatally or during the first year. Macrocephaly affects 90% to 100% of children during infancy. The outcome is variable and at least one third of patients have normal cognitive function, but the risk of abnormal neurodevelopmental outcome is increased in patients with extra-CNS abnormalities. Differential diagnosis and evaluation: The diagnosis of DWM is based on the neuroimaging findings: 1) hypoplasia and anticlockwise rotation of the cerebellar vermis on sagittal view; and 2) cystic dilation of the fourth ventricle, filling nearly the entire posterior fossa. In most patients, the tentorium is elevated, the posterior fossa is enlarged, and the cerebellar hemispheres are hypoplastic and splayed. Frequently, hydrocephalus is also present, whereas brainstem hypoplasia and other malformations (e.g., callosal dysgenesis and migrational abnormalities) are less common. Abnormal vermian lobulation and additional brain malformations may be associated with poorer cognitive outcome. Additional terms such as “Dandy-Walker variant,” “DandyWalker complex,” or “Dandy-Walker spectrum” have been variably used to refer to related constellations of imaging findings. If full criteria for DWM are not met, a detailed anatomic description (e.g., inferior cerebellar vermis hypoplasia or global CH) should be used, and nonspecific terms such as Dandy-Walker variant should be abandoned. DWM can be distinguished from other posterior fossa cystic malformations through detailed neuroimaging assessment. Blake’s pouch cyst (BPC) is characterized by an infraretrocerebellar cyst that communicates with an enlarged fourth

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TABLE 27-1  Typical Clinical, Imaging, and Genetic Characteristics of Midbrain and Hindbrain Malformations Involving the Cerebellum Disease

Clinical Features

DISORDERS PRIMARILY AFFECTING THE CEREBELLUM Dandy-Walker Macrocephaly common, malformation variable intellectual disability, systemic involvement possible Joubert syndrome Hypotonia, ataxia, alternating apnea and tachypnea (improves with age), intellectual disability, retinal dystrophy, coloboma, nephronophthisis, liver fibrosis, polydactyly

Rhombencephalosynapsis

X-linked intellectual disability with cerebellar hypoplasia

Alopecia, trigeminal anesthesia (GLH), head shaking (figure-of-eight pattern), hyperactivity and impulsivity, VACTERL features ( 75% of Brains by MRI

Present in > 75% of Brains by Ultrasound

22–23

18

29

18

22–23

20

22–23

18

Callosal sulcus

14

22–23

18

Calcarine fissure

16

22–23

20

24–25

22

Cingular sulcus

18

22–23

20

24–25

24

Central sulcus

20

24–25

26

27

28

Postcentral sulcus

25

27

28

28

30

Precentral sulcus

24

26

28

27

30

Superior temporal sulcus

23

26

28

27

30

Inferior temporal sulcus

30

30

28

33

30

Superior frontal sulcus

25

24–25

28

29

30

Inferior frontal sulcus

28

26

28

29

30

Secondary cingular sulcus

32

31

30

33

32

34–35

33

30

34

32

Secondary occipital sulcus

34

32

26

34

30

Olfactory sulcus

16

Insular sulcus

Marginal sulcus

24 22–23

The primary fissure is observed between 27 and 30 weeks of pregnancy. Some degree of differentiation between lobules is possible, starting from 30 to 32 weeks of gestation. The fourth ventricle is uniformly observed as a triangular structure anterocaudal to the vermis. The cerebellar vermis is best assessed by MRI on direct midline sagittal images and on coronal images. The cerebellar hemispheres are best assessed on axial and coronal views. Fetal MRI shows gestational age-specific changes in signal intensity in the normal development and maturation of the cerebellar hemispheres and brainstem. The cerebellar cortex, dentate nucleus, tectum, dorsal pons, and medulla are T1-hyperintense and T2-hypointense. By 26–27 weeks of gestation, a three-layered pattern is noted in the cerebellar hemispheres. Fetal brain MRI can show the fissures of the cerebellum, depending on the gestational age. The primary fissure is identified on sagittal images at 22 weeks but the cerebellar surface is smooth. From 24 to 29 weeks, foliation of the vermis and posterior lobes of the cerebellum is seen on sagittal images. The convoluted pattern of the cerebellum is well identified from 30 weeks on and is always seen beyond 33 weeks (Fogliarini et al., 2005a).

PRENATAL DIAGNOSIS OF VENTRICULOMEGALY Assessment of the width of the atria of the lateral cerebral ventricles is recommended as part of the routine anomaly scan. The lateral ventricle should be measured by US in the axial plane, at the level of the frontal horns and cavum septi pellucidi, with the calipers positioned at the level of the internal margin of the medial and lateral wall of the atria. Ventriculomegaly is defined as a lateral ventricular width ≥10 mm. Fetal ventriculomegaly may be classified as mild

26

30 27

30

when the lateral ventricular width is between 10 and 15 mm, and severe when larger than 15 mm; it may be unilateral or bilateral. Ventriculomegaly is defined as isolated if there is no additional evidence of associated malformations or markers of aneuploidy. Mild ventriculomegaly represents a diagnostic and counseling difficulty, as it can be an apparently benign finding, but can also be associated with chromosomal abnormalities, congenital infection, cerebral vascular accidents, and other fetal cerebral and extracerebral abnormalities; it may also have implications regarding long-term neurodevelopmental outcome (Melchiorre et al., 2009). Therefore, upon confirmation of ventriculomegaly, a complete search for associated central nervous system (CNS) and non-CNS anomalies should be attempted, including a study of the brain in a multiplanar approach. The investigation should also include screening for in utero infection, amniocentesis, and fetal echocardiography. MRI can add important information to that obtained by US imaging. Information relevant enough to modify obstetric management can be obtained in 10% of cases. Follow-up examinations at 3- to 4-week intervals are indicated to assess progressive enlargement of ventricles or to diagnose associated pathologies not previously detected. When mild ventriculomegaly is isolated, the outcome is usually good. The risk for abnormal outcome increases when there are associated anomalies, the atrial width is greater than 12 mm, or there is a progressive increase of the lateral ventricular width. The outcome of severe ventriculomegaly depends mainly on the presence of associated pathologies. When associated pathologies are diagnosed, the prognosis is usually poor unless the cause is intraventricular hemorrhage. Even when isolated, the risk of perinatal death or severe neurologic sequelae is in the range of 50% of survivors.



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A

B

C

D

E

F

G

H

Figure 33-6.  A–D, Maturation of the normal fetal cortex by ultrasound. Coronal slices at 23 (A), 27.5 (B), 31.5 (C), and 35 (D) weeks. E–H, Maturation of the normal fetal cortex by magnetic resonance imaging (MRI) (note opercularization). Coronal T2-weighted slices at 23 (E), 27 (F), 31 (G), and 35 (H) weeks. (A–D: Courtesy of Dr. Zvi Leibovitz.)

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PRENATAL DIAGNOSIS OF ABNORMALITIES OF THE CORPUS CALLOSUM Developmental abnormalities of the corpus callosum include agenesis, hypogenesis (or partial agenesis), dysgenesis, hypoplasia, and secondary destruction. Agenesis of the corpus callosum (ACC) can be detected prenatally by routine sonography, for which the important signs include absence of the cavum septum pellucidum, colpocephaly, high-riding third ventricle, widening of the interhemispheric fissure, and radiating medial hemispheric sulci. US can also depict an abnormally thick corpus callosum, which may signify a poor prognosis. Fetal MRI is clinically helpful in suspected cases of ACC because it can confirm the absence of the corpus callosum and diagnose associated anomalies. ACC is rarely isolated. Additional abnormalities occur frequently (46%). The most common findings are sulcation and posterior fossa abnormalities. Abnormal sulcal morphology can be detected as early as 19 gestational weeks. The gyral abnormalities include polymicrogyria, lissencephaly, pachygyria, and schizencephaly. Interestingly, in 10% of fetuses with ACC, there may be evidence of destructive changes in the brain parenchyma, suggesting either an acquired etiology or a genetic/metabolic abnormality (Prasad et al., 2009).

PRENATAL DIAGNOSIS OF MALFORMATIONS OF CORTICAL DEVELOPMENT Although the migration process terminates around the end of the first half of pregnancy, malformations of cortical development are seldom diagnosed in utero, possibly because the time of appearance of significant morphologic changes is beyond the recommended time of the anatomic scan (19 to 23 weeks), and because US evaluation of the brain is often limited to visualization of the lateral ventricles and cerebellum. Abnormal sulcation landmarks have been observed as early as the 22nd week of gestation in fetuses suffering from lissencephaly. In fetuses with migration disorders, US usually demonstrates one of the following patterns: delayed or premature appearance of sulcation, a thin and irregular cortical mantle, wide abnormal overdeveloped or underdeveloped gyri, wide opening of isolated sulci, nodular bulging into the lateral ventricles, cortical clefts, and intraparenchymal echogenic nodules (Malinger et al., 2007). A definitive diagnosis is hard to reach prenatally; US can identify abnormal migration but cannot definitively differentiate between different pathologies. MRI can identify cortical malformations more accurately, particularly late in pregnancy. The imaging signs suggestive of abnormal sulcation are: mild ventriculomegaly associated with delayed cortical development; dysgenesis of the sylvian fissure; delayed or abnormal sulcal appearance; callosal abnormality; cortical thickening; heterotopias; absence or abnormal appearance of fissures; irregular, abnormal, asymmetric gyri; and noncontinuous cortex in schizencephaly (Fogliarini et al., 2005b). When the operculum is abnormally formed, the prognosis is usually poor and an underlying malformation of cortical development can be detected. An underdeveloped operculum for gestational age is usually associated with an abnormal head circumference or other brain anomalies. When it is an isolated finding, it may represent a metabolic disease, chromosomal anomaly, or benign delayed maturation of the operculum, usually associated with macrocephaly and enlargement of the subarachnoid spaces (Prasad et al., 2009).

Prenatal Diagnosis of Lissencephaly Type I Fetuses with lissencephaly type 1 can be diagnosed after 27 to 30 weeks of gestation when most of the primary sulci are already present, either by detailed neurosonography or by MRI, by demonstration of dysgenesis of the sylvian fissure, delayed sulcal appearance, callosal abnormality, and cortical thickening. Sometimes, zones of normal cortex and zones of pachygyric or agyric cortex alternate. The bilateral opercular dysplasia is responsible for a figure-eight-shaped brain. Fetuses with Miller–Dieker syndrome have abnormal parieto-occipital and sylvian fissures by the time of the secondtrimester US examination.

Prenatal Diagnosis of Cobblestone Complex Findings suggestive of cobblestone complex are early en­­ largement of the lateral ventricles, abnormal sulcation, abnormal vermis, a Z-shaped brainstem, retinal detachment, and cataract. MRI can better visualize the posterior fossa, brainstem, and gyration pattern (Fogliarini et al., 2005b).

Prenatal Diagnosis of Complex Cortical Malformations Mutations in tubulin genes cause complex cortical malformations. Three subtypes of cortical malformations have been described in fetuses: microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum; lissencephaly, either classical or associated with cerebellar hypoplasia, with corpus callosum agenesis; and polymicrogyria-like cortical dysplasia with inconstant corpus callosum agenesis and hypoplastic brainstem and cerebellum.

Prenatal Diagnosis of Periventricular Nodular Heterotopia Periventricular nodular heterotopia should be considered when US depicts an irregular lateral ventricular wall with indentations of periventricular tissue and a signal similar to that of the cortex. The sonographic diagnosis is difficult, particularly when the lateral ventricle width is normal. MRI demonstrates multiple small nodular subependymal foci of low signal intensity, isointense to the germinal matrix, located in the margins of the lateral ventricles. They cannot be distinguished reliably from the subependymal nodules seen in tuberous sclerosis; therefore, it is important to search for other manifestations of tuberous sclerosis. A posterior fossa cyst, which can be seen in females with filamin A mutations, may be the initial abnormality and, in association with periventricular nodules, may suggest the prenatal diagnosis. Heterotopia may go unrecognized when the nodules are small or subcortical.

Prenatal Diagnosis of Polymicrogyria The cortical changes of polymicrogyria take place late in pregnancy and appear as localized and/or generalized absence of normal sulcation with multiple abnormal infoldings of the affected cortex. It is more apparent on MRI than on US. In young fetuses (24 weeks), the identification of the cortical malformation is quite difficult, and the manifestations in both US and MRI are subtle (Adamsbaum et al., 2005). They include presence of sulci that are not as expected, according to the gestational age; an irregular surface of the brain; and absence of the normal signal of the cortical ribbon. Late in



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pregnancy, the MRI features are similar to what is known in the postnatal period: packed and serrated microgyri, irregular cortex–white-matter junction, and an aberrant and asymmetric sulcal pattern (Fogliarini et al., 2005b). Because the MRI pattern of polymicrogyria changes with increasing gestational age, it is important to follow young fetuses and repeat the US and MRI examinations in order to confirm the diagnosis.

associated with callosal anomalies, fenestration of the falx, and cortical malformations. The cisterna magna is obliterated by a low-lying torcula, vermian herniation through the foramen magnum, and a small slitlike fourth ventricle. The herniated cerebellum often degenerates. The cerebellum is banana shaped because of the herniation and small posterior fossa. The fetus may demonstrate a lemon-shaped skull.

Prenatal Diagnosis of Schizencephaly

Prenatal Diagnosis of Dandy–Walker Malformation

Prenatal US enables diagnosis of schizencephaly, although prenatal MRI is more specific in detection of the gray matter lining the defect, communication with the ventricle, and other associated structural abnormalities. The prenatal diagnosis of schizencephaly depends on the extent of cleft separation; closed-lip and open-lip variants with a very small gap remain undiagnosed. The prenatal diagnosis of schizencephaly has been described as early as 21 weeks. Neurosonography demonstrates bilateral or unilateral open-lip wedge-shaped defects, usually in the parietotemporal regions, frequently accompanied by absence of the cavum septum pellucidum. Fetal MRI shows schizencephalic clefts extending from the pial surface to the ventricle lined with gray matter, which is seen as a lowsignal-intensity line covering the edge of the remaining brain parenchyma. This finding allows differentiation of the defect from porencephaly (Fogliarini et al., 2005b).

PRENATAL DIAGNOSIS OF POSTERIOR FOSSA ANOMALIES Infratentorial anomalies are usually diagnosed in utero when associated with enlarged posterior fossa fluid spaces, with or without an abnormal fourth ventricle. The suspicion of abnormal cerebellar development is usually raised after the visualization of a small cerebellum or a large communication between the fourth ventricle and the cisterna magna, using the transcerebellar axial plane. Severe anomalies, such as Arnold– Chiari malformation type 2, Dandy–Walker malformation, and cerebellar hypoplasia, are usually detected during routine second-trimester US examinations. Particular care should be taken in order to differentiate between the vermis and the cerebellar hemisphere in cases of suspected vermian agenesis or hypoplasia. Visualization of the normal triangular shape of the fourth ventricle, and of the primary vermian fissure, facilitates exclusion of vermian pathologies. The in utero diagnosis of the pontocerebellar hypoplasias necessitates measurements of the pons diameter in addition to the cerebellar dimensions. It is important to note the relationship of the size of the midbrain to pons and medulla. In cases of diagnostic uncertainties, a follow-up examination is pertinent, because a false-positive diagnosis of partial vermian agenesis may be made before 24 weeks of pregnancy, because of delayed closure of the fourth ventricle owing to a persistent Blake pouch cyst, and cerebellar hypoplasia may be missed early in pregnancy because the arrest of growth occurs later. A dysplastic cerebellum, which refers to disorganized development, such as an abnormal folial pattern or the presence of heterotopic nodules of gray matter, is rarely diagnosed in utero, even with MRI, because it does not produce signal abnormalities.

Prenatal Diagnosis of Chiari Type II Malformation The posterior fossa is relatively small in Chiari II malformation, and spinal neural tube defects are present with variable hindbrain herniation. The Chiari II malformation may be

Prenatal diagnosis of Dandy–Walker malformation is usually possible during the second trimester; midsagittal planes enable visualization of the abnormal vermis, the communication between the fourth ventricle and the enlarged cisterna magna, and the elevated torcula and tentorium. It should not be confused with partial vermian agenesis. Dandy–Walker malformation may be associated with other CNS anomalies, such as callosal dysgenesis, occipital encephalocele, polymicrogyria, or heterotopias. Hydrocephalus may develop only late in pregnancy or postnatally. The prognosis after a prenatal diagnosis of Dandy–Walker malformation is variable; however, the prognosis is worse when there are associated brain anomalies (Bolduc and Limperopoulos, 2009).

Prenatal Diagnosis of Mega Cisterna   Magna, Posterior Fossa Arachnoid Cyst,   and Blake’s Pouch Cyst Isolated enlargement of the posterior fossa is frequently diagnosed by fetal US or MRI. It may be seen in three situations: mega cisterna magna, posterior fossa arachnoid cyst, and Blake’s pouch cyst. The prognosis in all three entities is usually good. In mega cisterna magna, the posterior fossa depth is greater than 10 mm, but the vermis and torcula location are normal. The term has been loosely applied to a large-appearing retrocerebellar cerebrospinal fluid space with a normal vermis and cerebellar hemispheres. It is usually an incidental finding, but it can be associated with other anomalies. Mega cisterna magna can be difficult to distinguish from an arachnoid cyst, as both are anechoic fluid spaces. Congenital arachnoid cysts are extraaxial, and 10% to 45% occur in the posterior fossa. They present on US as anechoic avascular cysts with mass effect on the cerebellum or internal table of the skull. Associated congenital anomalies are rare. Blake’s pouches have the same radiographic appearance as do arachnoid cysts, with the exception that, in some cases, the choroid plexus can be identified, as it extends through the median aperture along the superior cyst wall, carrying the anterior lip of the median aperture far up the vallecula. Blake’s pouches communicate with the fourth ventricle and may or may not produce mass effect on the cerebellum. Occasionally, there is the appearance of compression or absence of the inferior vermis. It may be hard to differentiate between inferior vermis hypoplasia and a Blake’s pouch cyst.

Prenatal Diagnosis of Vermis   Hypoplasia/Agenesis The term Dandy–Walker variant has been used to describe a heterogeneous group of disorders with different degrees of cerebellar vermis agenesis, slight or absent upward rotation of the vermis, and variably sized posterior fossa fluid collections,

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PART V  Congenital Structural Defects

but without enlargement of the posterior fossa. However, in recent years, it has been strongly advocated that the term be abandoned altogether, given its multiple and variable definitions. The terms hypoplasia and agenesis are used interchangeably in the literature on fetal vermian abnormalities, but the definitions of these entities are completely different. Vermian agenesis means either complete or partial absence of the vermis. In partial vermian agenesis, part of the vermis is absent and the remaining part is anatomically of normal volume. Because of the craniocaudal development of the vermis, partial agenesis involves its inferior part. Vermian hypoplasia means a small but complete vermis with congenital volume diminution. Vermis agenesis is associated with CNS and non-CNS anomalies in up to 71% of children, with the most common being ventriculomegaly and agenesis of corpus callosum. Extra-CNS anomalies have also been reported in up to 65%, with cardiac, renal, extremity, and facial anomalies occurring most frequently (Bolduc and Limperopoulos, 2009). Vermian development is assessed in the midline sagittal view from the caudal extent of the inferior vermis over the fourth ventricle. The diagnosis of inferior vermis agenesis is made when there is partial absence of the inferior portion of the cerebellar vermis with normal- or near-normal-shaped cerebellar hemispheres, a normal-sized posterior fossa without obvious cystic lesions, and normal supratentorial structures. The normal proportion of anterior vermis to posterior vermis (1 : 2) is lost. A correct diagnosis of inferior vermian agenesis is difficult and, even with MRI, there is a false-positive rate of 32%. Inferior vermian agenesis should be differentiated from failure of “closure” of the vermis with normal morphology and biometry; this probably represents isolated elevation or rotation of the vermis because of a persistent Blake’s pouch. Failure of “closure” seems to result from two potential processes: arrest of vermian development so that it does not cover the fourth ventricle at its inferior extent, or failure of adequate fenestration of the fourth ventricular outflow foramina, leading to a secondary elevation of an otherwise normal vermis. The prognosis in these situations is completely different.

Prenatal Diagnosis of Cerebellar Hypoplasia Cerebellar hypoplasia implies abnormal development rather than atrophy. Diagnosis is made by measurement of the transverse cerebellar diameter. Severe cerebellar hypoplasia is easily identified in utero after 22 weeks as a very small cerebellum associated with a shallow brainstem and absence of the anterior bulging of the pons, resulting in pontocerebellar atrophy/hypoplasia of extremely poor prognosis. Isolated cerebellar hypoplasia is more challenging, and difficulty in distinguishing malformation from necrosis can occur, especially in unilateral hypoplasia. An intact cerebellar cortex is most likely seen in cerebellar hypoplasia, as opposed to cerebellar necrosis, in which the cortical ribbon is usually absent (Fogliarini et al., 2005b).

Prenatal Diagnosis of Rhombencephalosynapsis The diagnosis of rhombencephalosynapsis is raised, after demonstration of a small transcerebellar diameter. US and MRI both demonstrate a hypoplastic, single-lobed cerebellum

with fused cerebellar hemispheres, no vermis, and transverse folia. Associated cerebral abnormalities are usually found. Coronal and axial planes are superior for diagnosis of rhombencephalosynapsis, because a midline sagittal cut through the cerebellum can be mistaken for a vermis.

Prenatal Diagnosis of Molar Tooth-Related Syndromes The diagnosis of the molar tooth (deep interpeduncular fossa, thick and elongated superior cerebellar peduncles, vermian agenesis) is difficult to visualize in utero. However, the prenatal diagnosis of Joubert syndrome or related disorders usually follows a positive family history and the finding of abnormal posterior fossa anatomy on fetal ultrasonography or the presence of associated suggestive features, such as kidney anomalies, polydactyly. The molar tooth features can be visualized in the axial plane, including the interpeduncular fossa, cerebellar peduncles, and brainstem.

Prenatal Diagnosis of Brainstem Anomalies Brainstem malformations are usually described in utero when they are associated with cerebellar and cerebral anomalies. Fetuses with cobblestone malformations show a prominent elongation of the tectum, a thin pons, a small dysplastic vermis, and a kinked brainstem. Fetuses with pontocerebellar hypoplasia demonstrate a reduction of all midbrain and hindbrain measurements in addition to a short transcerebellar diameter. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Adamsbaum, C., Moutard, M.L., Andre, C., et al., 2005. MRI of the fetal posterior fossa. Pediatr. Radiol. 35, 124–140. Blaas, H.G., Eik-Nes, S.H., 2009. Sonoembryology and early prenatal diagnosis of neural anomalies. Prenat. Diagn. 29, 312–325. Bolduc, M.E., Limperopoulos, C., 2009. Neurodevelopmental outcomes in children with cerebellar malformations: a systematic review. Dev. Med. Child Neurol. 51, 256–267. Cohen-Sacher, B., Lerman-Sagie, T., Lev, D., et al., 2006. Sonographic developmental milestones of the fetal cerebral cortex: a longitudinal study. Ultrasound Obstet. Gynecol. 27, 494–502. Fogliarini, C., Chaumoitre, K., Chapon, F., et al., 2005a. Assessment of cortical maturation with prenatal MRI. Part I: normal cortical maturation. Eur. Radiol. 15, 1671–1685. Fogliarini, C., Chaumoitre, K., Chapon, F., et al., 2005b. Assessment of cortical maturation with prenatal MRI. Part II: abnormalities of cortical maturation. Eur. Radiol. 15, 1781–1789. Garel, C., Chantrel, E., Brisse, H., et al., 2001. Fetal cerebral cortex: normal gestational landmarks identified using prenatal MR imaging. Am. J. Neuroradiol. 22, 184–189. Malinger, G., Kidron, D., Schreiber, L., et al., 2007. Prenatal diagnosis of malformations of cortical development by dedicated neurosonography. Ultrasound Obstet. Gynecol. 29, 178–191. Melchiorre, K., Bhide, A., Gika, A.D., et al., 2009. Counseling in isolated mild fetal ventriculomegaly. Ultrasound Obstet. Gynecol. 34, 212–224. Prasad, A.N., Malinger, G., Lerman-Sagie, T., 2009. Primary disorders of metabolism and disturbed fetal brain development. Clin. Perinatol. 36, 621–638.



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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 33-1 Ultrasound: axial sections of the fetal brain at 16 weeks of gestation. Fig. 33-2 Ultrasound: coronal sections of the fetal brain at 25 weeks of gestation. Fig. 33-3 Ultrasound. Fig. 33-4 High-resolution transvaginal ultrasound (12 MHz probe). Fig. 33-5 Magnetic resonance imaging at 23 weeks demonstrates 5 layers. Fig. 33-7 Ultrasound: ventriculomegaly. Fig. 33-8 Magnetic resonance imaging: complete agenesis of the corpus callosum.

33 Fig. 33-9 Ultrasound findings in fetuses with malformations of cortical development. Transvaginal parasagittal views. Fig. 33-10 Magnetic resonance imaging: lissencephaly type 1 at 33 weeks of gestation. Fig. 33-11 Magnetic resonance imaging: Walker–Warburg syndrome. Fig. 33-12 Periventricular heterotopias at 25 and 32 weeks. Fig. 33-13 Unilateral perisylvian polymicrogyria. Fig. 33-14 Magnetic resonance imaging. Fig. 33-15 Magnetic resonance imaging. Fig. 33-16 Ultrasound and MRI of anomalies of the posterior fossa, midsagittal planes. Fig. 33-17 Magnetic resonance imaging: rhombencephalosynapsis. Fig. 33-18 Magnetic resonance imaging of Joubert syndrome.

PART VI

34 

Genetic, Metabolic and Neurocutaneous Disorders

Neurogenetics in the Genome Era Kelly McMahon, Alex R. Paciorkowski, Lauren C. Walters-Sen, Jeff M. Milunsky, Alexander Bassuk, Benjamin Darbro, Jullianne Diaz, William B. Dobyns, and Andrea Gropman

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION TO THE HUMAN GENOME The human genome consists of approximately 3.08 billion base pairs of deoxyribonucleic acid (DNA) divided into 22 numbered chromosomes and two sex chromosomes (X, Y). Nearly 3% of the genome is protein coding, or exonic, and has come to be termed the exome. This coding region is responsible for some 20,000 genes, the primary units of heredity. The remainder of the genome (approximately 97%) is comprised of regions of repeats and segmental duplications (50%), and some highly conserved regulatory regions. Compared with many other organisms, the genome of Homo sapiens is modest in size, and the diversity of protein products in humans is greatly increased through the process of alternative splicing. Chromosomes reside in the cell nucleus in a threedimensional structure called a fractal globule with important consequences for short-range and long-range regulation of gene expression. The nucleotide sequence of the genome is the principle determinant of gene activity, but chromosomes are comprised of DNA upon a protein scaffold, the combination of which is termed chromatin. The proteins within chromatin include histones, which are strongly evolutionarily conserved DNA-associated proteins. Chromatin that is less condensed is termed euchromatin and contains coding DNA. The more condensed heterochromatin contains noncoding DNA. Epigenetic factors, defined as factors independent of the nucleotide sequence that affect gene expression, include methylation of DNA and histone acetylation. Taken together, the journey from primary DNA sequence to biological effect is a complex one with numerous opportunities for the introduction of pathology. The numbered chromosomes are referred to as autosomes and exist in pairs in every cell, each member of the pair being derived from a parent. Chromosome X and Y have pseudoautosomal regions with distinct recombinatory properties. Through the process of X-inactivation, women selectively inactivate one X chromosome in every cell, leading to the observation that in this sense all females are mosaic. In addition to the nuclear genome, cells have an additional mitochondrial genome that resides in those organelles and whose division and replication are regulated semiautonomously. The mitochondrial genome comprises 14 genes, and several well-characterized human disorders are associated with mutations in those genes. Many of the genes encoded in the mitochondrial genome produce proteins essential for function of the electron transport chain. Due to the lack of mitochondria in paternal sperm, an individual’s mitochondrial genome is generally derived maternally. Mutations within the

mitochondrial genome can occur somatically with the result that any one cell may host several copies of that genome, some with mutations and some without, a phenomenon called heteroplasmy.

Genomic Variation The terminology used to describe genomic variation can be complex, and a glossary of terms is included in Table 34-1.

Chromosomal Structural Rearrangements A variety of chromosomal structural rearrangements has been known to geneticists for many decades and includes translocations of part of one chromosomal arm onto another. Translocations are often visible on karyotype and are classified as balanced or unbalanced, depending on whether or not they result in net loss or gain of genomic material. On the whole balanced translocations are generally regarded as nonpathogenic, unless the translocation disrupts a critical locus. Balanced translocations can, however, result in chromosomal breakage and can mediate a chromosomal deletion or duplication in an offspring—for example Robertsonian translocations as a cause of Trisomy 21. These examples change recurrence risk inform the need to perform karyotypes in parents of children with chromosomal abnormalities.

History of Cytogenetics The origins of human cytogenetics can be attributed to Walther Flemming, who first described human chromosomes in the early 1880s. Improvements in technology in the early 20th century led to research into the number of human chromosomes and the configuration of sex chromosomes between males and females. However, it was not until the accidental “discovery” of hypotonic treatment in the early 1950s that the diploid complement of chromosomes was set at 46. This key step, which caused the cells to swell and allowed chromosomes to separate, was necessary to fully visualize each homolog pair. At the same time, the use of colchicine to destroy the mitotic spindle permitted scientists to view the chromosomes at the stage of maximal contraction. This combined hypotonic/ colchicine technique led to the modern field of cytogenetic analysis that we know today (Gerson and Keagle, 2013). With accurate visualization of chromosomes, various defects in chromosome number and structure were discovered. The first such discovery was made by Lejeune and colleagues in 1959 with the observation of an additional chromosome in the fibroblasts of patients with Down

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TABLE 34-1  Glossary of Ferms Used to Describe Genomic Variation Term

Definition

Aneuploidy

A chromosomal numerical abnormality, such as a trisomy or monosomy

Balanced translocation

A type of chromosomal structural rearrangement where there is no apparent loss or gain of genetic material

Heteroplasmy

Presence of more than one mitochondrial genome within a cell

Indel

An insertion or deletion of DNA.

Missense mutation

A coding single nucleotide variant that results in a change in amino acid sequence; a type of nonsynonymous variant

Mosaic

Presence of more than one populations of cells with different genotypes within an organism.

Mutation

A genetic variant that causes abnormal biologic function and is pathogenic, disease-causing; this can include any pathogenic genetic variant but is most commonly used to refer to pathogenic single nucleotide variants

Nonsense mutation

A coding variant that results in the premature introduction of a stop codon

Nonsynonymous variant

A coding variant that results in a change in amino acid sequenc.

Regions of homozygosity

Chromosomal regions where the pattern of DNA polymorphisms indicates decreased genetic diversity

Segmental duplication

Genomic sequences sharing >90% similarity over >1 kb with another genomic location

Short tandem repeats

Tracks of tandemly repeated short (1–6 bp) DNA sequence motifs; also called microsatellites

Single nucleotide polymorphism

Single nucleotide variant that is found in the general population and is considered benign; a type of single nucleotide variant

Single nucleotide variant

A single change in the nucleotide sequence that may be benign (polymorphism) or pathogenic (mutation)

Somatic mosaic

A form of mosaicism that occurs due to mitotic errors after fertilization

Structural rearrangements

Deletion, duplication, or translocation of chromosomal material

Synonymous variant

A coding variant that does not result in a change in amino acid sequence. Can affect exon splicing

Unbalanced translocation

A type of chromosomal structural rearrangement where there is loss or gain of genetic material

Uniparental disomy

The inheritance of both copies of a chromosome, or a chromosomal region, from one parent only

Variant of unknown significance

A variant whose pathogenicity is unknown

syndrome, later identified as chromosome 21. The sex chromosome abnormalities of Turner syndrome, Klinefelter syndrome, and Triple X syndrome were also defined in 1959, by Ford and colleagues, Jacobs and Strong, and Jacobs and associates, respectively. The next year brought the description of Patau syndrome and Edwards syndrome, later defined as trisomy 13 and trisomy 18, respectively. No additional advances in the field could be made until improvement in staining techniques. When methods for examining chromosomes under the microscope were first developed, individual chromosomes could not be identified because of solid staining. Instead, they were separated into seven groups (A to G), based on their length and centromere position. Although not ideal, this was suitable for the analysis of simple monosomies and trisomies. However, the discovery of quinacrine mustard staining by Caspersson and colleagues in 1971 allowed the identification of individual chromosomes, the foundation of the numbering system in use today. The ability to positively identify a chromosome, along with the possibility of visualizing “bands” within each homolog, led to an explosion of defined chromosomal syndromes, including deletions, duplications, inversions, translocations, and other rearrangements. The field has expanded, with development of new technologies that allow even finer resolution of the chromosomal complement. Several of these techniques use molecular genetics methodologies as discussed further in this chapter. Thus the distinction between cytogenetics and molecular genetics has become blurred. In general, traditional cytogenetic analyses examine large regions of the genome such as chromosomes or regions of chromosomes, whereas standard molecular genetics

methods focus on smaller regions of the genome, from single nucleotides to genes and gene regions. However, even in this era of nucleotide-level resolution, traditional cytogenetics remains critical for the study of rearrangements not routinely detected by new technologies, most importantly balanced rearrangements that disrupt crucial genes in development. A uniform system of human chromosome classification and nomenclature is used to describe abnormalities. This system was developed at a series of international conferences and was most recently revised in 2013. In this system, the chromosomes are separated into bands, which are placed into regions defined by landmarks. As resolution increases, bands can be subdivided into subbands, which are designated with a decimal point. All bands are described in relation to the centromere, with higher region and subband numbers corresponding with more telomeric positions. The four required components of a band description are: (1) chromosome number; (2) arm symbol (p for short arm or q for long arm); (3) region number; and (4) band number within the region. Thus the designation 17p13.3 (read as “17-pone-three-point-three”) corresponds to chromosome 17, short arm, region 1, band 3, subband 3. The use of this standardized system allows consistent description of chromosomal abnormalities regardless of the laboratory performing the analysis. As with any technique, there are limitations to traditional cytogenetic analysis. Even with high-resolution banding techniques genomic imbalances smaller than three megabases cannot be visualized. In addition, cryptic rearrangements involving bands of similar size and staining density may not be recognized. On the other hand, polymorphic variations in banding, aside from common sites, can be confused for pathogenic changes if not further explored through family



studies. Mosaicism for multiple cell lines may not be recognized if the level of the secondary cell line is low (typically lower than 20%). Finally, the genetic composition of chromosomal material of unknown origin, either in the form of markers or material added on to existing chromosomes often cannot be confirmed through standard analysis. Additional techniques, such as fluorescent in situ hybridization (discussed later in this chapter) or microarray analysis, are often necessary to fully elucidate the genomic origin of such material (Haines et al., 2012).

Fluorescence in Situ Hybridization Fluorescence in situ hybridization (FISH) is a technique used to detect specific chromosomes or chromosomal regions through hybridization (attachment) of fluorescently labeled DNA probes to denatured chromosomal DNA. Examination under fluorescent lighting detects the presence or absence of the hybridized fluorescent signal (and hence presence or absence of the chromosome material). Described as a “molecular cytogenetic” technique, FISH has been accepted as the standard-of-care for a variety of chromosomal aberrations. These abnormalities are too small to be visualized using standard cytogenetic techniques and too large to be analyzed with standard DNA sequencing. FISH studies can be performed on metaphase chromosomes or interphase cells, depending on the type of abnormality being considered and the probe type being used. Probes can be divided into three major categories: repetitive sequence, whole chromosome, or unique sequence. Repetitive sequence probes include those covering the alpha satellite regions at the centromeres of chromosomes. These probes can be used to detect aneuploidy in both metaphase and interphase cells. Whole chromosome probes, or chromosome painting probes, are comprised of both unique and mildly repetitive sequences covering the entire length of a particular chromosome. These are most often used in metaphase cells for the study of structural abnormalities. The most widely used probe type, unique sequence, is used to study a particular genomic region, ranging in size from 1 kb to larger than 1 Mb. These probes can be used in interphase or metaphase cells to detect deletions, duplications, or other abnormalities. However, in contrast with metaphase FISH, interphase FISH does not permit visualization of the actual chromosomes; therefore most types of structural rearrangements cannot be reliably detected. An additional type of unique sequence probe that is commonly used is telomerespecific probes. These probes correspond to the telomeres of all of the chromosomes and are used to detect abnormalities at the ends of chromosomes that are not visible by routine chromosome analysis. The previous utility of these probes has now generally been replaced by microarray analysis or MPLA analysis (see later section). Most FISH analyses examine one to two chromosomal regions at once, although it is possible to multiplex probes with special fluorescent markers to increase the number of regions that can be assayed. FISH analyses are also used in conjunction with microarray studies that have identified copy number variations. Although microarrays can provide the highest resolution of genomic gains and losses, FISH analysis is still necessary to identify the underlying mechanism of the genomic alteration. For example, FISH studies can discriminate between tandem duplication and duplication due to an unbalanced rearrangement. Even though the outcome of the two abnormalities is the same (gain of a particular region), the mechanism of the abnormality could have a substantial influence on family planning. In addition, FISH analysis is often less expensive and faster than additional microarray studies when determining the

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inheritance pattern of a microarray abnormality. This can lead to a more rapid clinical assessment of the patient, given the possible pathogenicity of a de novo variant versus a likely benign familial copy number change.

Copy Number Variations The completion of the draft human genome sequence in 2000 inaugurated a new era of appreciation for the patterns of genomic variation. It was soon discovered that the human genome contains numerous areas of segmental duplication, which are nucleotide sequences sharing greater than 90% similarity over larger than1 kb in size with another genomic location. There are over 1400 copy number variable regions in the human genome (about 12% of the entire genome), and 25% of these copy number variable regions are associated with segmental duplications. Segmental duplications are therefore an important mechanism mediating copy number variation. Copy number variants range in size from small insertions or deletions of single nucleotides, through duplication or deletion of chromosomal regions hundreds of kilobases (kb) in size or larger, all the way to include trisomies (duplications of entire chromosomes) or monosomies (loss of entire chromosomes). However, most copy number variants are benign and number in the hundreds of kb in size (Cooper et al., 2011; Kearney et al., 2011).

Indels Among genomic variants, insertions/deletions (indels) are the second most common type and the most common type of structural variant. Collectively, between 1.6 and 2.5 million indel polymorphisms are present in the human population, with approximately 0.4 million short indels (1 to 16 bp) present per individual. The presence of an indel may be associated with disease, particularly if the inserted or deleted nucleotides result in a frameshift in a coding region. In contrast, the biological function of indels located within noncoding regions, intragenic regions, introns, and untranslated regions are more likely to be benign variants.

Short Tandem Repeats Short tandem repeats (STRs), or “microsatellites,” are tracks of tandemly repeated short (1 to 6 bp) DNA sequence motifs. STRs may occur in both intergenic and intragenic regions, including within genes, and account for approximately 3% of the human genome. Some microsatellites are highly mutable and show both sequence and length polymorphism whereas others are more conserved and can be informative markers in population genetics, mapping, and linkage studies. A specific subclass of trinucleotide repeats are combinations of nucleotides arranged repetitively (i.e., CAG or CGG repeats).

Mutations, Single Nucleotide Variants, and Single Nucleotide Polymorphisms A word regarding nomenclature is important at the outset here. For geneticists, there are important distinctions between mutations, single nucleotide variants, and single nucleotide polymorphisms. All refer to alterations in a single nucleotide. The term mutation is best reserved for nucleotide changes that are clearly associated with a deleterious biological effect or a disease. Single nucleotide variants (or SNVs) are those nucleotide changes not clearly associated with abnormal biology or disease but not clearly benign population variants either. SNVs therefore may be understood to include variants of unknown significance. Finally, single nucleotide polymorphisms (or SNPs) are a special group of common nucleotide

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variants present in a significant (generally greater than 0.05%) percentage of the human population and are widely understood not to be associated with abnormal biology or disease. SNPs that have been documented in the general population will have catalog numbers (beginning with “rs”) and will be present in the Database of Single Nucleotide Polymorphisms (dbSNP; http://www.ncbi.nlm.nih.gov/SNP/), often with an associated mean allele frequency. Single nucleotide variants are the most common form of genomic variation, with 3 million SNVs typically present per individual. Of these, nearly 20,000 are located within coding regions. When SNVs located within coding regions do not result in a change in the amino acid sequence encoded, they are termed synonymous variants. There have usually no identifiable biological effects of synonymous SNVs except when they are located in splice regions at the exon-intron boundaries. When an SNV results in a change in the amino acid encoded, it is referred to as a nonsynonymous variant. These variants that alter the amino acid sequence may prove to be pathogenic if the change significantly affects the conformation or biological activity of the protein. Methods of General Mutation Detection DNA Sequence Analysis Sanger Sequencing.  DNA sequence analysis is the most sensitive and direct method to detect mutations at the level of individual nucleotides. The most widely used method of DNA sequencing is the Sanger method, also known as dideoxy sequencing or chain termination. It is based on the use of synthetic nucleotide analogs—2, 3-dideoxynucleoside triphosphates (ddNTPs). Dideoxy NTPs differ from nucleotides found in natural DNA in that they lack the 3’-hydroxyl group. When integrated into a sequence, they prevent the addition of further nucleotides as phosphodiester bonds cannot form between a dideoxynucleotide and the next incoming nucleotide. Thus the DNA chain is terminated. DNA sequencing most commonly is performed by the method of cycle sequencing, in which the DNA region to be sequenced (which is first generated by PCR) is denatured, and a short oligonucleotide is annealed to one of the template strands. DNA synthesis occurs in the presence of DNA polymerase, ddNTPs, and normal (deoxy) nucleotides and starts from the 3’ end of the annealed oligonucleotide. As the DNA is synthesized, nucleotides are added on to the growing chain by the DNA polymerase; however, on occasion, a ddNTP is incorporated into the chain in place of a normal nucleotide, resulting in a chain-terminating event. At the end of the sequencing reaction, multiple DNA molecules are present such that, at each nucleotide position, a proportion of molecules are terminated because of the incorporation of a ddNTP. These products are separated by size on capillary or polyacrylamide gel electrophoresis systems, and the fluorescently labeled ddNTPs are detected. Each ddNTP is labeled with a different fluorophore. Shorter DNA molecules migrate faster than longer molecules on electrophoresis, and by analyzing the different fluorescent signal of all of the different-sized molecules, the DNA sequence can be determined. For example, ddCTP is labeled with a blue fluorophore. Everywhere a G residue exists in the template DNA, either a dCTP or a ddCTP will be incorporated into the synthesized strand. For every G residue in the template DNA, a proportion of molecules with a ddCTP at that site will be present. Each of these molecules will be of a different size, depending on where a G residue resides in the sequence and will be distinguished by electrophoresis. The same applies for the other ddNTPs. Specialized DNA sequencing software exists that can convert the different fluorescent signals to different-color peaks that constitute a DNA sequence chromatogram.

After performing the necessary laboratory techniques, the sequence is analyzed by a trained molecular technician. Computer programs are used to facilitate the comparison of generated sequence with the reference sequence for the region of interest. If differences are discovered, they should ideally be confirmed. Such differences are then described using both nucleotide and amino acid designations in the standardized fashion. The nucleotide change is defined as the position in the coding sequence, with the adenine nucleotide of the initiator ATG designated as the first base, followed by the nucleotide change, all beginning with a “c” identifier. For example, a guanine to cytosine change at the fiftieth nucleotide in the coding sequence would be defined as “c.50G>C.” The amino acid change is then defined as the original amino acid (either three letter or single letter code), the numerical identifier of the amino acid in question, and the new amino acid, all beginning with a “p” identifier. For example, using the previous nucleotide change, the seventeenth codon changes from CCA to CGA, which results in a change from proline to arginine; this would be defined as “p.Pro17Arg” (alternatively “p.P17R”). The next stage of analysis involves bioinformatics techniques. The variant identified through sequencing may be a known population polymorphism, a known pathogenic mutation, a completely novel variant, or a reported variant without clear phenotypic consequences. In order to determine which class contains the identified variant, a molecular geneticist queries public databases such as dbSNP, ClinVar, or HGMD. If the pathogenicity of the variant is unknown, this aspect can be explored using web-based prediction programs, such as PolyPhen, SIFT, MutPred, Condel, or FATHMM. However, it should be remembered that these are predictions only and are not definitive evidence of the functional effect of a given variant. A sequence variant is typically reported as pathogenic, of uncertain significance, or benign, and the final report should include all pertinent information regarding this designation. The use of the Sanger technique to study the sequence of a genomic region of interest is limited only by the ability of the user to design appropriate oligonucleotides, or primers, to be used in PCR amplification and subsequent sequencing. However, several limitations exist for this technique and must be taken into account. First, as the Sanger technique relies on an initial PCR amplification, it is subject to PCR errors. These events are rare, but they can cause significant problems in final analysis if they occur early in the PCR cycling process. Second, Sanger sequencing is not well-adapted to analyzing mosaicism, again due to the initial PCR step. This is not a quantitative method, and a target sequence in a smaller proportion can be overwhelmed by another sequence present in the template. Third, care must be taken in the design of primers to ensure that the proper target is amplified, which is especially vital when considering genes with closely related pseudogenes. Finally, Sanger sequencing can only detect changes in sequence, not changes in copy number. If one allele carries a deletion or duplication, it will not be detected; the final chromatogram will be consistent with two homozygous alleles. These caveats must be considered when using Sanger sequencing. Deletion/Duplication Analysis.  The most common method of deletion/duplication analysis is Multiplex Ligation-dependent Probe Amplification, or MPLA. MLPA is used to detect copy number changes of small DNA fragments. This technique is most often used to assay individual exons of genes but can also be used to study the subtelomeric regions of chromosomes or multiple regions of specific chromosomes to detect aneuploidy. In this technique, special MLPA probes are hybridized to the ends of sequences under study; if both ends are present, the probes are ligated together. Only then can PCR be used to



amplify the complete sequences. The unique MLPA probes are comprised of a sequence compatible to the target sequence, a stuffer sequence for size variation, and a common PCR primer sequence. The combination of variable size products and a single set of PCR amplification primers allow this technique to assay up to fifty separate targets in a single reaction. MLPA utilizes the same laboratory equipment as PCR-based Sanger sequencing, specifically a thermocycler and a fluorescent capillary electrophoresis system. MLPA is often the first-tier test in disorders primarily caused by exon or gene deletions/duplications, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMN1), and Charcot-Marie-Tooth neuropathy (PMP22). In addition, the use of MLPA in conjunction with traditional gene sequencing can increase the rate of detection of pathogenic variants, typically up to an additional 10%. MLPA is advantageous in that it can detect very small imbalances, to the level of 50 to 75 nucleotides, which is much smaller than the resolution of oligonucleotide microarrays or FISH analysis. In addition, the exact location of the imbalance does not need to be known a priori, as is required with standard PCR-based methods of deletion/duplication analysis. However, kits are only available commercially for defined genomic locations, without the ability to study less commonly affected regions. In addition, care must be taken when interpreting results that are indicative of deletions. Sequence variation within the probe target site can either abolish or reduce probe binding, which would generate an electrophoretic profile consistent with a deletion. As such, results must be considered in conjunction with clinical information, and ideally all results should be confirmed with a separate methodology. Methylation Studies.  Methylation of cytosine is a DNA modification associated with several biological processes, including imprinting, X chromosome inactivation, and silencing of repetitive DNA sequences. The most recent studies suggested approximately 151 genes in the mouse genome were subject to imprinting, and a similar number estimated for the human genome, despite some recent methodological controversy. Of these, the 15q11q13 region, associated with the Angelman, Prader-Willi, and Duplication of Maternal 15q11q13 syndromes is most notable. These are imprinting disorders, in which the phenotype is determined by the pattern of parental methylation of 15q11q13. Individuals with loss of the paternal methylation pattern present with Prader-Willi syndrome, whereas those with loss of the maternal methylation pattern present with Angelman syndrome. This may occur through a number of molecular mechanisms, and for Angelman syndrome includes de novo deletion of 15q11q13 (70% to 75% of individuals) uniparental disomy for chromosome 15 (2% to 3% of individuals), imprinting center mutations (3–5% of individuals), or mutations in UBE3A (5% to 10% of individuals) a gene on 15q11q13 whose expression is directed by parent-of-origin allele-specific methylation. Therefore the best first test for diagnosis of Angelman syndrome is bisulfide methylation sensitive polymerase chain reaction (PCR), which will detect any of the methylation defects, whether caused by chromosomal deletion, uniparental disomy, or imprinting center mutation. Chromosomal microarray will only detect 15q11q13 deletions, will miss approximately 25% of Angelman patients and should not be used as the first diagnostic test. In individuals with normal 15q11q13 methylation studies, but who have a phenotype consistent with Angelman syndrome, UBE3A sequencing should be the second test sent. Chromosomal Microarray.  Copy number variants (CNVs) are identified by array-based methods that use comparative genome hybridization (CGH). CGH determines copy number of genomic DNA sequencing using varying intensity patterns

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between hybridized patient and control DNA. Control DNA used in microarray either represents the whole genome or contains cloned fragments (targeted microarray) from the genome. Bacterial artificial chromosomes (BAC) probes are approximately 75,000 to 150,000 base pairs in length whereas oligonucleotide probes, used for oligonucleotide and singlenucleotide polymorphism (SNP) arrays, are approximately 50 to 60 base pairs in length, allowing for increased breakpoint specificity and improved accuracy of copy number variants. The resolution of the array depends on the number and types of probes used and whether the probes are targeted or cover the whole genome (Manning and Hudgins, 2010). SNP arrays can detect copy number neutral regions of homozygosity that can be associated with uniparental disomy or consanguinity by comparing reference DNA to hybridized patient DNA. Identifying a copy neutral region of homozygosity may suggest an autosomal recessive disease in the patient. Typically, clinical chromosomal microarrays can detect chromosomal imbalances of 20 to 50 kb in targeted regions. Copy number variants (CNVs) are classified as either pathogenic/abnormal, variant of unknown significance (VUS), or likely benign. It should be kept in mind when interpreting results that the estimated mean number of benign CNVs per individual is 800 or more. When a copy number variant is identified by chromosomal microarray, fluorescence in-situ hybridization (FISH) studies to confirm the finding in the patient, parental FISH studies, clinical genetic evaluation, and genetic counseling are recommended. In general, when a CNV is found to be inherited from a healthy parent, is gene poor, or is a duplication with no known dosage-sensitive genes involved, this indicates that the variant is likely benign. Likely pathogenic CNVs include those which are inherited from an affected parent, are gene rich, or overlap a genomic coordinates for a known genomic-imbalance syndrome. Several studies have validated chromosomal microarray as a first tier test, over G-banded karyotype, in the evaluation of developmental delay, intellectual disability, autism spectrum disorders, and multiple congenital abnormalities. In a study of 21,698 patients with developmental delay, intellectual disability, autism spectrum disorders, or multiple congenital abnormalities, chromosomal microarray was found to have a diagnostic yield of 12.2%. Pathogenic CNVs have been shown to play a role in the etiology of epilepsy, providing evidence to support that chromosomal microarray be a part of the diagnostic evaluation for patients with unexplained epilepsy. It is estimated that up to 40% of epilepsies have a genetic component. Chromosomal microarray can identify recurrent CNVs for epilepsy “hotspots,” deletions, or duplications in known epilepsy genes, or nonrecurrent CNVs involving epilepsy genes. Chromosomal microarray has an even higher diagnostic yield in individuals with epilepsy and additional findings such as intellectual disabilities, dysmorphic features, malformations, developmental delay, and autism spectrum disorders. In a study of 102 patients with different types of epilepsy, either isolated or with intellectual disability/developmental delay, dysmorphic features, autism or other neurologic signs, 10 of 102 (9.8%) were found to have pathogenic CNVs associated with epilepsy. Limitations of chromosomal microarray include poor detection of low-level mosaicism, balanced rearrangement, and, in some arrays, polyploidy. Chromosomal microarray should not be used when a rapid turnaround time is needed, when a chromosomal trisomy such as Trisomy 21 is suspected, or when a well-described syndrome is suspected as a diagnosis. Southern Blot.  The Southern blot is a technique that uses gel electrophoresis combined with labeled probes for a DNA sequence of interest that allows for the detection of repeat expansions within specific genes. The technique is used to

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detect the triplet repeat expansions seen in neurologic diseases such as myotonic dystrophy, fragile X syndrome, and many spinocerebellar ataxias. Despite advances in sequencing technologies, this technique remains the standard for direct molecular diagnosis of these disorders. Next-Generation Sequencing.  The term “next-generation sequencing,” or “high-throughput sequencing,” has become synonymous with the most recent appearance on the clinical and research scene of massively parallel sequencing of regions of interest. In 2009 the first use of next-generation sequencing, specifically whole-exome sequencing, as a proof-of-principle to confirm mutations in MYH3 as the causative gene for Freeman-Sheldon syndrome. Soon after, a similar technique was employed to identify DHODH as the causative gene for Miller syndrome, followed by the identification of MLL2 as the first causative gene for Kabuki syndrome. Of note, the identification of MLL2 highlighted the challenging bioinformatics aspects of next-generation sequencing analysis, as several iterations of analysis were required before mutations were found. In the years since those findings, an evolution of the technological platforms for next-generation sequencing has occurred, with the Illumina platform producing 100 bp paired-end reads, currently the most prevalent in research and clinical diagnostic settings, although alternatives exist. Next-generation sequencing involves the targeted capture of defined genomic regions of interest. At the most narrow— for example, those available in disease gene panels such as epilepsy or intellectual disability panels—the region of interest may be the coding exons of several dozen genes. Larger regions of interest such as the exome include the coding regions of all genes. Variability in the percentage coverage of each gene is a factor in the capture of regions of interest and should be taken into account during the selection of a sequencing method. The bioinformatics analysis of nextgeneration sequencing data has emerged as a new field within genomics, and changes in best practices occur quickly.

RESOURCES FOR INTERPRETING GENOMIC TESTING A constant feature of current genomic testing is the rapid introduction of new technologies and, along with them, new methods to allow their interpretation. In an ideal setting, close collaboration exists with genetics colleagues who maintain currency with this evolving field. However, appropriate expertise may not be readily available in all of the settings where child neurologists evaluate individuals with neurodevelopmental disorders. A summary of the tools discussed here is found in Table 34-2. CNVs for which no literature exists to help interpretation can be evaluated using DECIPHER (https://decipher.sanger .ac.uk/), and the Database of Genomic Variants (http:// dgv.tcag.ca/dgv/app/home). Most genomic variants that are causative of neurodevelopmental diseases are rare, not present in the general population, and in the case of relatively common disorders such as autism and epilepsy (Epi4K Consortium), are often but not always due to de novo mutations that are not inherited from the parents. Other disorders are autosomal recessive or X-linked, in which case a disease causing variant may be present in one (usually the mother in the case of X-linked) or both parents (in the case of autosomal recessive). Several online resources provide expert-curated gene-phenotype associations relevant to child neurology (Table 34-5). Finally, the Developmental Brain Disorders Database (DBDB; https://www.dbdb.urmc .rochester.edu/home) provides a repository of genes, phenotypes, and syndromes specifically targeted at neurodevelopmental disorders.

TABLE 34-2  Glossary of Terms Used for Genomic Diagnostic Technologies and the Genomic Variations They Detect Diagnostic Technology

Genomic Variation Detected

Karyotype

Aneuploidy (trisomy, monosomy), structural rearrangements including balanced translocations, deletions and duplications >5 Mb.

Fluorescence in situ hybridization(FISH)

Specific deletions or duplications.

Methylation studies

Abnormal parental methylation patterns.

Chromosomal microarray (CMA)

Copy number variations (deletions, duplications) >50-100 kb. SNP arrays can detect loss of heterozygosity (regions of homozygosity), uniparental disomy.

Sanger sequencing

Single nucleotide variants, small frameshift indels

Multiplex ligation probe amplification

Exon-level deletions or duplications

Southern blot

Triplet repeat expansions

Next-generation sequencing

Massively parallel detection of single nucleotide variants, small indels in many genes simultaneously across targeted region of interest

Recently a statistical approach was proposed to determine whether or not variants in a given gene are likely to be disease causing based upon the prevalence overall of common variation in that gene, with the hypothesis that some genes are more tolerant of variation whereas others are not. The proposed residual variance intolerance score (RVIS) is derived from the regression of common coding variants in a gene upon all variants in that gene. A value lower than the 25th percentile is taken as a cutoff higher than which a gene is said to “tolerate” variation and therefore is unlikely to be a disease gene; indeed, many known neurodevelopmental disease genes fall lower than this percentile. A difficulty with this approach, however, is that it treats all variation as equal when clearly this is not the case. Null mutations anywhere in a gene may be deleterious, even in a gene with many common sequence variants. Likewise, specific amino acid substitutions at biologically critical loci within a gene (whether or not variations in the gene overall are frequent) can also cause disease. Although the use of whole-exome sequencing for clinical diagnostics has resulted in the identification of causative mutations in many individuals, the overall diagnostic yield of 25% has not been as impressive as initially hoped. It is suggested that adoption of whole genome sequencing able to identify both CNVs and SNVs will increase the diagnostic yield of next-generation sequencing to over 40%.

Somatic Mosaicism and Challenges of Tissue of Origin for DNA DNA isolated from patient leukocytes has been the traditional source for diagnostic genetic testing, including in neurologic disorders. However, a spectrum of disorders has been identified in which the causative mutations are present in affected brain tissue in a somatic mosaic manner. This observation began with the identification of “second-hit” somatic mutations in TSC1/2, in neurons of individuals with tuberous sclerosis complex, and in germline mutations in the same gene. Then, mosaic mutations were identified in a spectrum



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TABLE 34-5  Summary of Online Tools Involved in Analysis of Genomic Diagnostic Testing Tool and URL

Use Case

Database of Genomic Variants (DGV) http://dgv.tcag.ca/dgv/app/home

Evaluation of copy number variants

DECIPHER https://decipher.sanger.ac.uk/

Evaluation of copy number variants

Human Gene Mutation Database (HGMD) http://www.hgmd.cf.ac.uk/ac/index.php

Evaluation of known mutations in known disease genes

SIFT http://sift.jcvi.org/

Prediction of effect of amino acid substitution on protein function

PolyPhen http://genetics.bwh.harvard.edu/pph2/

Prediction of effect of amino acid substitution on protein function

Ensembl’s Variant Effect Predictor (VEP) http://grch37.ensembl.org/Homo_sapiens/Tools/VEP

Allows batch annotation of genomic variants for SIFT, PolyPhen, dbSNP membership, and other annotations

dbSNP http://www.ncbi.nlm.nih.gov/SNP/

Evaluation of single nucleotide polymorphisms for population frequency

UCSC Genome Browser http://www.genome.ucsc.edu/

Allows visualization of a range of genomic regions of interest and multiple annotations

Eukaryotic Linear Motif server (ELM) http://elm.eu.org/

Evaluation of amino acids within functional protein domains

Exome Variant Server (EVS) http://evs.gs.washington.edu/EVS/

Allows search for variants in >6500 other whole exomes

Exome Aggregate Consortium browser (ExAC) http://exac.broadinstitute.org/

Allows search for variants in >63,000 whole exomes

GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1116/

Expert curated chapters on well-described single gene syndromes

Online Mendelian Inheritance in Man (OMIM) http://www.ncbi.nlm.nih.gov/omim/

Expert curated information on a broad range of genetic syndromes

Developmental Brain Disorders Database (DBDB) https://www.dbdb.urmc.rochester.edu/home

Expert curated gene-phenotype-syndrome associations specific to neurodevelopmental disorders

of megalencephaly polymicrogyria syndromes, hemimegalencephaly, and focal cortical dysplasia type II, with the mutations documented at varying levels in blood, skin, brain, and saliva-derived DNA. Clearly, blood-derived DNA may not be the most informative in these disorders, an issue now being addressed by diagnostic testing laboratories. Determining an etiology for a child’s developmental delays/ intellectual disability or autism spectrum disorders may influence a child’s treatment. In a survey of 48 patients with positive chromosomal microarray results, physicians noted a direct effect on the family in 70% of cases. The most beneficial effect to families was the ability to provide recurrence risks, providing access to educational and insurance services, avoiding other tests to determine a diagnosis, and helping target additional medical referrals such as to a cardiologist or ophthalmologist. Failure to diagnose a genetic disease can have negative effects for both the family, including lack of potential treatments, clinical trials, or recurrence risks, and for society as continued genetic testing or therapies increases medical expenditures. A three-generation family pedigree should be recorded at the initial patient visit and should be periodically updated. There are several methods of gathering family history information, including physician-directed questions or a questionnaire given before the patient’s visit. Factors to consider when assessing a family pedigree for patterns of inheritance include the possibilities of variable expressivity, age related penetrance, gonadal mosaicism, and incomplete penetrance. Next generation sequencing panels and whole-exome sequencing are becoming more popular testing options and increase the complexity of the genetic counseling process.

Pretest counseling for whole-exome sequencing should include a formal consent process by a medical geneticist or genetic counselor and should include the expected outcomes of testing, likelihood and type of incidental findings, and what results will or will not be disclosed (ACMG Board of Directors). Patients should be informed of the possibility that incidental or secondary findings, as defined by the minimum list of incidental findings recommended by the American College of Medical Genetics, that are unrelated to the patient’s symptoms, but may influence medical care may be detected on clinical whole-exome sequencing) and the patient should be given the option to opt-in or opt-out of this additional information (Allyse and Michie, 2013). Patients should be counseled regarding alternatives to testing and informed consent should be included with written documentation (ACMG Board of Directors, 2013). Pretest counseling should also include a description of the differences between research and clinical whole-exome sequencing. It is important for healthcare providers to include the detailed family pedigree, information on physical examination, and previous laboratory tests with the patient’s sample to assist with interpretation of results. Results of clinical whole-exome sequencing may include pathogenic variants known to be associated with the phenotype, variants of uncertain significance in genes possibly related to the patient’s phenotype, and medically actionable pathogenic variants not related to the patient’s phenotype (ACMG Board of Directors, 2013). Interpreting results of whole-exome sequencing should be done in the context of the patient and family history and requires an understanding of a range of inherited conditions. Candidate variants in genes suspected to be related to the

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patient’s phenotype are often identified and require further studies to determine its role in disease, but a variant of uncertain significance should not be used in the patient’s medical decision making. It is strongly recommended to include parental sample with the proband to help in interpretation of variants. The majority of variants for autosomal dominant diseases can be ruled out with parental samples if either of the parents carry the same variant and are unaffected. In addition to information directly related to the patient’s phenotype, additional information from whole-exome sequencing may include carrier status of a disease that may influence reproductive decisions and disease susceptibility or predisposition.

Standards of Genomic Care The recent advances in genomic medicine have brought new recommendations about best practices in the evaluation of individuals who may have genomic-mediated disorders. Arriving at a molecular genetic diagnosis may have care related consequences for affected individuals and may include recommendations for surveillance for known complications, in addition to affecting decisions about choice of medications. The difficulty is there are now so many characterized disorders and the spectrum of presenting symptoms can be so varied that any one practitioner is unlikely to be able to rule out a specific genetic syndrome solely on clinical grounds. Identification of a genetic diagnosis also allows affected individuals to participate in clinical trials and/or natural history studies that may be available for that disorder. An accurate molecular diagnosis is usually an inclusion criterion for participation. Although it should be noted that insurance providers are not in the business of paying for diagnostic testing for the purpose of enabling participation in a clinical trial, it is still within the purview of the physician to provide optimal care to their patients, and this should include making families aware of the availability of clinical trials and/or natural history studies. Funding agencies are unlikely to provide resources to pay for genetic tests that are clinically available. This is one aspect of the current tension surrounding the best practices of care for children with developmental disorders. It should be noted that much of the medical surveillance recommendations for conditions such as MECP2-related disorder come in part from the results of natural history studies. The ability to identify individuals made possible the

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recent treatment trials for fragile X syndrome and Duchenne muscular dystrophy.

LOOKING TOWARD THE FUTURE Genomic medicine as it applies to child neurology has undergone dramatic changes in the past decade. The advent of new molecular diagnostic technologies has meant that children once diagnosed with “developmental delay,” “epilepsy,” and “intellectual disability” now have access to much more specific molecular diagnoses. In many cases, more specific diagnoses now have specific health surveillance and treatment recommendations. Just one exciting example is the discovery of the molecular basis underlying focal cortical dysplasia and hemimegalencephaly and their associated intractable epilepsy, which means that new avenues of treatments that are based on biological pathways are now investigation. The technology to assay the human genome will continue to mature, as will the computational algorithms to identify pathogenic variation. New methods are in development to address gaps in next-generation sequencing analysis, in particular structural rearrangements, copy number variants, repeat expansions, and large indels. Many of these mutational classes will be addressed through new targeting chemistries, longer read sequencing, and novel analysis techniques. Still, the current gaps mean that chromosomal microarray, Southern blot, MLPA, Sanger sequencing, as well as karyotype will continue to have their place in clinical diagnosis.

EXAMPLE OF PRINCIPLES IN PRACTICE Patient AB is a 3-year-old with a history of progressive complex partial seizures. Onset of seizures began approximately 5 weeks ago. Her mother describes AB as “blanking out and staring into space” during a seizure episode. Episodes usually last less than 2 minutes and are not followed by a prolonged postictal period. After diagnosis of her seizures, she was placed on Keppra; however, her seizures continued and changed in nature. Her seizures are now accompanied by lip smacking and stiffening, occurring up to 20 times a day. A brain MRI was normal. EEG activity appeared focal during seizures and best described as complex partial with a tonic component. A microarray was ordered (Fig. 34-9).

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Figure 34-9.  CMA result from the short arm of chromosome 20 in the case patient.



Clinical interpretation of CNVs requires knowledge of several factors including: 1. Performance characteristics of the chromosomal microarray being used for testing 2. Frequency of CNV in databases of both control individuals as well as individuals with disease 3. Gene content of the CNV 4. Deletion versus duplication status 5. Inheritance of the phenotype/disease under consideration and disease genes within the CNV 6. De novo or inherited status and cosegregation with disease phenotype in a family The evaluation of a clinical CMA test begins with knowledge of the microarray platform being used. The ACMG recommends that CMA platforms should be able to detect genome-wide CNVs of at least 400Kb at 99% analytical sensitivity (with a lower limit at the 95% confidence interval greater than 98%) and a false-positive rate of less than 1% (Cooper et al., 2011). This is the minimum standard clinical CMA platforms must meet; however, most clinical laboratories offering CMA today use platforms that allow for the reliable detection of much smaller CNVs—typically on the order of 50 to 100kb. In the above referenced clinical case, the CMA platform used was able to detect CNVs as small as 50kb in size. The first challenge in interpreting a clinical CMA test is determining which of the myriad of CNVs detected are benign and thus not needing of additional consideration as an underlying cause of disease. Several publically available databases exist to aid in this task, including the Database of Genomic Variants. The Database of Genomic Variants (DGV) is a comprehensive collection of curated structural variation found in the genomes of control individuals from numerous studies and multiple ethnicities. It is important to note that data from control individuals is not precisely the same as data from healthy, “unaffected” individuals. Many of the control individuals with data in DGV were not screened for the myriad of neurodevelopmental or psychiatric conditions that are often times a part of the clinical phenotypic spectrum of patients being evaluated by CMA testing. However, despite this limitation, the copy number variants deposited within DGV have other associated information that makes them suitable for the interpretation of potential pathogenicity. As with SNVs, one of the most consistently used pieces of data is the frequency at which a particular region of the genome is found to be copy number variable in control populations. Different clinical laboratories will often have different frequency thresholds but they are typically in the range of 1% to 5% variant frequency. Furthermore, it is also recommended that, before a CNV be considered benign, it also be found at a relatively high frequency in more than one study deposited in DGV and in studies with a sufficient number of individuals. Lastly, given the rapidly evolving rate of both microarray and sequencing technologies, it is important to place higher confidence on those studies that used a CNV detection platform consistent with the one being used clinically. In addition to DGV, there are other clinical databases that can be used to help interpret the likely pathogenicity of CNVs, including the ClinGen Structural Variant database (formerly the International Standards for Cytogenetic Arrays Consortium, or ISCA) and Database of Chromosomal Imbalance and Phenotype in Humans (DECIPHER) (http://clinicalgenome.org/ and (Zarrei et al., 2015). Lastly, each clinical laboratory should maintain a database of their own to identify both recurrent CNVs that may have disease significance but also those that are seen frequently enough to warrant exclusion as benign. Once all likely benign CNVs have been removed, it is important to perform additional analysis to interpret those

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remaining CNVs as either variants of unclear clinical significance or likely pathogenic. If a CNV is detected that is a well-established, disease-associated variant, such as a 22q11.2 deletion and DiGeorge syndrome or a 7q11.23 deletion and Williams syndrome, it can be interpreted fairly quickly and accurately. If, however, a CNV does not fall within one of these well-known disease loci, additional steps are necessary. First, does the CNV contain any genes? If no genes are located within the CNV, interpretation of its potential clinical significance is very difficult. Only 2% to 3% of the genome is known to code for protein and, as such, is the portion of the genome most easily interpreted in a clinical sense. If a CNV contains no genes there is very little confident information that can be conveyed about its potential effect on disease or human phenotypes. Such CNVs are typically not mentioned in clinical reports. Gene content of a CNV, as opposed to simply size, appears to be a larger determinant of phenotypic significance. Additionally, deletions tend to disrupt gene function more often than duplications that, when they do, exert a phenotypic effect can be via several different mechanisms. Deletions naturally cause haploinsufficiency of dosage sensitive genes. Most importantly, interpretation of the clinical significance of a CNV requires knowledge of any disease-associated genes within the CNV as well as the inheritance pattern of the disease in the family under investigation. A thorough family history and creation of a pedigree is highly recommended before any type of genetic testing is ordered. If the condition being investigated has a clear inheritance pattern, interpretation of CMA results can be much more accurate. The majority of conditions diagnosable by CMA are autosomal dominant or X-linked recessive in nature as the vast majority of lesions identified by CMA are single allele deletions or duplications. Genes known to only cause disease in a recessive fashion are less likely to be of clinical significance in the interpretation of a CNV and typically require sequencing of the other allele to determine the status of the other gene copy. This is not the case, however, if a homozygous deletion is detected. Knowledge of other affected individuals within the family is very important as cosegregation of a CNV with disease can contribute to an interpretation of likely pathogenicity. If a potentially disease-associated CNV is found in a proband and is also found to be inherited from an unaffected parent, the likelihood of that CNV being the sole cause of the proband’s condition is greatly reduced. In contrast, if such a CNV is found to be de novo in the proband and not found in either biological parent, then that increases the probability of pathogenicity. Parental testing should be considered to help refine the interpretation of CNVs of unclear clinical significance, however, it is likely to have a higher probability of being meaningful if other features of the CNV suggest pathogenicity (such as gene content, disease-associated genes of appropriate inheritance patterns, deletion status, and absence or rarity in control and/or clinical CNV databases). In the present case, after benign CNVs have been excluded only two remained that were higher than the size threshold of 50kb. Microarray results showed a 540kb deletion at 20p13 followed by 216kb duplication immediately adjacent. There are no identical or very similar deletions or duplications within the DGV or other clinical databases; however, both ClinGen and DECIPHER do list patients with deletions and/or duplications that cover the region of the genome. The deletion contains 14 genes and the duplication contains four genes. Within the deletion interval there are two disease-associated genes: RBCK1 and TBC1D20. RBCK1 is implicated in polyglucosan body myopathy 1 with or without immunodeficiency, an autosomal recessive condition, and TBC1D20 is implicated

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Figure 34-10.  Karyotype result exhibiting a ring chromosome 20 in the case patient.

in Warburg micro syndrome 4, also an autosomal recessive syndrome. Neither of these conditions is a good phenotypic fit for the patient under consideration nor would a single copy loss be expected to result in an autosomal recessive phenotype. One gene within the duplication interval is listed as a disease-associated gene with the OMIM database: SLC52A3. This gene is implicated in the conditions Brown-Vialetto-Van Laere syndrome 1 and Fazio-Londe disease. Both of these conditions are autosomal recessive and unlikely to result from a duplication (gain of copy number) of the associated gene. Thus on the basis of the CMA data only, these CNVs would best be classified as variants of unclear clinical significance. However, in this case, convention chromosome analysis was also ordered and a ring chromosome 20 was discovered (Fig. 34-10). This case illustrates one of the most important limitations of CMA: the inability to detect balanced structural rearrangements. Whereas in this case the formation of the ring chromosome 20 did involve the loss and gain of DNA sequence and was thus detectable by CMA, the true nature of this lesion was only elucidated by chromosome analysis. The ring chromosome 20 syndrome, also referred to as R(20) syndrome, is a rare chromosomal disorder associated with refractory epilepsy. The seizures in this condition are typically partial complex in nature and can be difficult to control. It is interesting and relevant to a discussion of CNVs that, whereas most patients with R(20) syndrome are mosaics with nearly completely balanced chromosomal rearrangements, those patients that are not mosaic, as was the case in Patient AB, typically do have small deletions or duplications identified that are associated with the ring. As is the case with Patient AB, the onset of seizures is typically in childhood and the seizures are typically partial complex in nature. Staring episodes along with automatism and focal motor symptoms are also common. Thus the phenotype described for R(20) syndrome very closely

matches that of Patient AB suggesting the etiology of her seizure conditions has been elucidated. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES ACMG Board of Directors, 2013. Points to consider for informed consent for genome/exome sequencing. Genet Med. 15, 748–749. Allyse, M., Michie, M., 2013. Not-so-incidental findings: the ACMG recommendations on the reporting of incidental findings in clinical whole genome and whole-exome sequencing. Trends Biotechnol. 31 (8), 439–441. Cooper, G.M., Coe, B.P., Girirajan, S., et al., 2011. A copy number variation morbidity map of developmental delay. Nat. Genet. 43, 838–846. Gersen, S.L., Keagle, M.B. (Eds.), 2013. The Principles of Clinical Cytogenetics, 3rd ed. Springer Science+Business Media, New York. Haines, J.L., Korf, B.R., Morton, C.C., et al. (Eds.), 2012. Current Protocols in Human Genetics. John Wiley & Sons, Inc, Hoboken, NJ. Kearney, H.M., South, S.T., Wolff, D.J., et al., 2011. Working Group of the American College of Medical Genetics. American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. Genet. Med. 13 (7), 676–679. Manning, M., Hudgins, L., 2010. Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet. Med. 12 (11), 742–745. Zarrei, M., MacDonald, J.R., Merico, D., et al., 2015. A copy number variation map of the human genome. Nat. Rev. Genet. 16 (3), 172–183.



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E-ONLY FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 34-1 Standardized diagram or ideogram of human chromosomes at the 400-band stage. Fig. 34-2 Partial karyotypes of structural chromosome rearrangements. Fig. 34-3 Fluorescence in situ hybridization (FISH) of a standard metaphase spread using a set of three overlapping cosmids at D17S379. Fig. 34-4 MLPA deletion analysis of SMN1 representing a heterozygous carrier of spinal muscular atrophy.

34 Fig. 34-5 Data from a SNP-based chromosome microarray shows a 14-Mb deletion of human chromosome 1p31. Fig. 34-6 The structure of a typical human gene. Fig. 34-7 Common symbols used in pedigrees. Fig. 34-8 Examples of autosomal-dominant (AD), autosomal recessive (AR), and X-linked (XL) pedigrees. Table 34-3 Next-generation sequencing analysis workflow Table 34-4 Summary of advantages of different nextgeneration sequencing target approaches

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Chromosomes and Chromosomal Abnormalities Maria Descartes, Bruce R. Korf, and Fady M. Mikhail

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. The development and maintenance of the human body is directed by an estimated 20,000 genes, consisting of some 3 billion base pairs (bp) of DNA. These genes encode the struc­ ture of proteins and noncoding RNAs, which together are responsible for the orderly unfolding of human development, beginning with the fertilized egg (zygote), and for the main­ tenance of body structure and function. The entire pool of genetic information must be replicated with each cell division and a complete set of information apportioned to the two daughter cells. In addition, the full complement of genes must be transmitted from generation to generation through the germ cells. Genes do not exist as isolated entities within the cell nucleus but rather are arranged on structural units called chro­ mosomes. Each chromosome contains hundreds or thousands of genes arranged in a linear order. This order is reproducible from cell to cell within an individual organism, and from individual to individual in the population. The normal human chromosome complement consists of 46 chromosomes, including 22 pairs of nonsex chromosomes (autosomes) and either two X chromosomes in females or an X and a Y in males. Each of these chromosomes has a characteristic structure and includes a specific set of genes arranged in a specific order. The chromosomes are units that ensure the orderly distribution of a complete set of genetic information during cell division. Chromosome number and structure are tightly regulated, and deviations from the norm usually are associated with clinical problems. Multiple genes are simultaneously dis­ rupted as a consequence of chromosomal abnormalities; accordingly, the phenotypic consequences usually are com­ plex. Because of the complexity of the nervous system and its dependence on multiple genes, neurologic problems accom­ pany most of the chromosomal disorders. This chapter focuses on the approach to chromosomal disorders in pediatric neurology. The various methods of chro­ mosomal analyses are considered first, followed by a descrip­ tion of the various types of chromosomal abnormalities. This discussion is followed by an overview of the clinical approach to chromosomal abnormalities and then a brief clinical description of chromosomal syndromes relevant to the prac­ tice of pediatric neurology. The chapter closes with a look at the future of cytogenetic analysis.

METHODS OF CHROMOSOME ANALYSIS Chromosome Preparation Chromosome structure is most easily appreciated during mitosis, when the chromatin fiber is condensed and coiled into a characteristic structure. Spontaneously dividing cells are rarely available, except in tumors or chorionic villus tissue used in prenatal diagnosis. Rather, cells are grown in shortterm culture. For routine analysis, peripheral blood lympho­ cytes most commonly are used, although skin fibroblasts also may be cultured and analyzed. Phytohemagglutinin-stimulated peripheral blood usually is grown in culture for 3 days. Block­ ing the mitotic spindle with a drug such as colchicine leads to

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accumulation of dividing cells, which then are induced to swell by treatment with hypotonic saline, fixed, and spread on to a microscope slide (Nussbaum, McInnes, and Willard, 2015a).

Chromosome Banding Until the 1970s chromosomes were identified on the basis of their size and the position of the centromeres. This allowed chromosomes to be classified into groups labeled A to G (A: chromosomes 1-3, B: chromosomes 4-5, C: chromosomes 6-12 and X, D: chromosomes 13-15, E: chromosomes 16–18, F: chromosomes 19–20, G: chromosomes 21–22 and Y), but not unambiguously identified. The introduction of banding techniques finally allowed each chromosome to be identified and permitted the identification of chromosome regions, bands, and subbands. Most laboratories use Giemsa stain banding (G-banding), which involves treatment of the meta­ phase chromosomes with a protease (i.e., trypsin), followed by Giemsa staining for routine analysis. The advent of chro­ mosome banding stimulated a second wave of discovery of structural chromosomal abnormalities during the 1970s. Chromosomes are displayed as a karyotype, which is prepared by arranging homologous chromosomes in an orderly fashion, starting from chromosome 1 and ending with chromosome 22 and including the sex chromosomes. The resolution of this technique, however, is limited to 3 to 5 million bp (Mb) of DNA, which may include dozens of genes (Nussbaum et al., 2015a).

Molecular Cytogenetics The gap between light microscope resolution of chromosome structure and the gene was bridged by the introduction of several molecular cytogenetic techniques. Fluorescence in situ hybridization (FISH) involves hybridizing a fluorescently labeled single-stranded DNA probe to denatured chromo­ somal DNA on a microscope slide preparation of metaphase chromosomes and/or interphase nuclei prepared from the patient’s sample. After overnight hybridization, the slide is washed and counterstained with a nucleic acid dye (e.g., DAPI, or 4′,6-diamidino-2-phenylindole), allowing the region where hybridization has occurred to be visualized using a fluores­ cence microscope. FISH is now widely used for clinical diag­ nostic purposes. There are different types of FISH probes, including locus-specific probes, centromeric probes, and whole-chromosome paint probes (Nussbaum et al., 2015a). FISH using locus-specific probes has been extremely useful in the detection of microdeletion syndromes resulting from deletions of multiple contiguous genes (Figure 35-2). These are subtle submicroscopic deletions that are below the resolu­ tion of the routine G-banded chromosome analysis. Use of FISH usually requires that the patient either exhibits features consistent with a well-defined syndrome with known chromo­ somal etiology or demonstrates an abnormal karyotype. This is because single FISH probes reveal rearrangements only of the segments being interrogated and do not provide



Chromosomes and Chromosomal Abnormalities

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Figure 35-2.  Fluorescence in situ hybridization (FISH) analysis using the DiGeorge/velocardiofacial syndrome probe. Note the deleted Tuple1 (22q11.2) red probe on one chromosome 22 (arrow). The ARSA (22q13.3) green probe is included as an internal control.

information about the rest of the genome. Another limitation of FISH is the number of probes that can be applied in a simultaneous assay. The latest addition to molecular cytogenetic techniques is chromosomal microarray (CMA) technology, including array comparative genomic hybridization (array CGH) and singlenucleotide polymorphism (SNP) arrays (Nussbaum et al., 2015a). Array CGH involves hybridizing a test sample of inter­ est and a control reference sample, each differentially labeled with different colored fluorescent dyes, to an array slide con­ taining thousands of DNA probes. Following hybridization and washing to remove unbound DNA, the array is scanned and analyzed using computer software to measure the relative ratios of fluorescence of the two dyes and detect gains/losses of genomic regions represented on the array (Figure 35-3). Highdensity SNP arrays can also be used to detect genomic copynumber gains/losses. In these experiments, the patient’s DNA is fluorescently labeled with a fluorescent dye and hybrid­ ized to a high-density SNP array. Following hybridization and washing, the array is scanned and analyzed using computer software. The deviation from the expected fluorescent intensi­ ties of the two alleles of an SNP are compared with previously analyzed control samples spanning several adjacent SNPs to detect genomic copy-number gains/losses. High-resolution CMAs can detect genomic copy-number gains/losses bigger that 50 kb across the euchromatic portion of human genome. In the past few years, high-resolution whole-genome-coverage CMA platforms have been increasingly used in clinical molec­ ular cytogenetic labs (Miller et al., 2010). These provide a rela­ tively quick method of scanning the entire genome for gains/ losses with significantly higher resolution and greater clinical abnormality yield than was previously possible. This has led to the identification of novel genomic disorders in patients with autism spectrum disorders (ASDs), developmental delay (DD), intellectual disability (ID), and/or multiple congenital anomalies (MCAs).

CHROMOSOMAL ABNORMALITIES Most chromosomal abnormalities exert their phenotypic effects by increasing or decreasing the quantity of genetic

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Figure 35-3.  Array comparative genomic hybridization (array CGH) analysis using a whole-genome-coverage oligo-array. A chromosome 15 plot is shown with a one-copy loss (heterozygous deletion) in the Prader–Willi/Angelman region at 15q11.2q13.1.

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material. Chromosomal abnormalities can be divided into numerical and structural abnormalities (Nussbaum et al., 2015a).

Numerical Abnormalities The most straightforward of chromosomal abnormalities are alterations of chromosome number. Deviation from the normal diploid complement of 46 chromosomes is referred to as aneuploidy; an extra chromosome results in trisomy, whereas a missing chromosome results in monosomy. Although all the possible chromosomal trisomies have been observed in spontaneous abortions, trisomies 13, 18, and 21 are the only autosomal trisomies to be observed in a nonmosaic state in liveborn infants. All autosomal monosomies are lethal. The only viable monosomy involves the X chromosome (45,X, resulting in Turner syndrome). Aneuploidy results from an error in cell division referred to as nondisjunction, in which two copies of a chromosome go to the same daughter cell during meiosis or mitosis. Nondis­ junction occurs most often in the first meiotic division in the maternal germline. Mitotic nondisjunction results in the pres­ ence of an aneuploid and a normal cell line, a condition referred to as mosaicism. The causes of nondisjunction are unknown. The only well-documented risk factor is advanced maternal age. The term polyploidy refers to presence of a complete extra set of chromosomes; triploidy represents three sets with 69 chromosomes, whereas tetraploidy represents four sets with 92 chromosomes. Rarely, a triploid fetus will be liveborn, but in general polyploidy is lethal. In a few instances, however, mosaicism for a diploid and a triploid cell line producing congenital anomalies has been compatible with long-term survival.

Structural Abnormalities Structural chromosomal rearrangements result from chromo­ some breakage, with subsequent reunion in a different con­ figuration. They can be balanced or unbalanced. In balanced rearrangements the chromosome complement is complete, with no loss or gain of genetic material. Consequently, bal­ anced rearrangements are generally harmless, with the excep­ tion of rare cases in which one of the breakpoints disrupts an important functional gene. Carriers of balanced rearrange­ ments are often at risk of having children with an unbalanced chromosome complement. When a chromosome rearrange­ ment is unbalanced, the chromosome complement contains an incorrect amount of genetic material, usually with serious clinical effects.

Deletions and Duplications A deletion involves loss of part of a chromosome and results in monosomy for that segment of the chromosome, whereas duplication represents the doubling of part of a chromosome, resulting in trisomy for that segment. The result is either decrease (in a deletion) or increase (in a duplication) in gene dosage. In general, duplications appear to be less harmful than deletions. Very large deletions usually are incompatible with survival to term. Deletions or duplications larger than approx­ imately 5 Mb in size can be visualized under the microscope using G-banded chromosome analysis. Clinical syndromes resulting from submicroscopic deletions or duplications (i.e., microdeletions/microduplications) with a size less than 5 Mb have been identified with the help of molecular cytogenetic techniques, including FISH and CMA (Stankiewicz and Lupski, 2010; Vissers and Stankiewicz, 2012).

Translocations Translocations involve the exchange of genetic material between chromosomes. In a balanced reciprocal translocation the exchange is equal, with no loss or gain of genetic material, although it is possible for a gene to be disrupted at one of the breakpoints. More often, the carrier of a balanced transloca­ tion is free of clinical signs or symptoms but is at risk for having offspring with unbalanced chromosomes. The risk for production of unbalanced gametes from a balanced transloca­ tion carrier depends on the chromosomes involved, the spe­ cific breakpoints of the translocation, and the sex of the carrier. Empirical data are available for some specific translocations. Risks include miscarriage and birth of a liveborn child with congenital anomalies, resulting from chromosome imbalance. The phenotype usually is a complex mixture of the results of loss or gain of at least two chromosome segments and there­ fore can be difficult to predict. One specific type of translocation that is relatively common is Robertsonian translocation. This results from a fusion of two acrocentric chromosomes (chromosomes 13, 14, 15, 21, or 22) at the centromere. Carriers of a Robertsonian transloca­ tion have 45 chromosomes and are clinically unaffected. The most common clinically significant outcome is trisomy 21, in which a carrier for a Robertsonian translocation involving chromosome 21 produces a gamete with both the transloca­ tion chromosome and a normal 21, resulting in trisomy 21 after fertilization.

Inversions Inversions occur when there are two breaks in a chromosome and the intervening material flips 180 degrees. Inversions that span the centromere are referred to as pericentric, whereas those that do not are called paracentric. Inversions generally do not result in added or lost genetic material and therefore usually are viewed as neutral changes. Disruption of a gene at one of the breakpoints, however, could change the function of that gene. Also, alteration of gene order at the borders of the inversion could affect the function of blocks of genes that are coordinately regulated (position effect). If a crossover occurs in the inverted segment of a pericentric inversion during meiosis, two recombinant chromosomes result, one with duplication of one end and deletion of the other end, and the other having the opposite arrangement. Such a crossover event in a paracentric inversion results in dicentric or acentric chro­ mosomes that tend to be unstable.

Insertions An insertion occurs when a segment of one chromosome becomes inserted into another chromosome. Because these changes require three chromosomal breakpoints, they are relatively rare. Abnormal segregation in a balanced insertion carrier can produce offspring with either duplication or dele­ tion of the inserted segment, in addition to balanced carriers and normal offspring.

Marker and Ring Chromosomes A marker chromosome is a rearranged chromosome whose genetic origin is unknown based on its G-banded chromo­ some morphology. Usually, these chromosomes are present in addition to the normal chromosome complement and are thus called supernumerary marker chromosomes (SMCs). The birth prevalence of SMCs is in the range of 2 to 7 per 10,000, and 30% to 50% originate from chromosome 15. Ring chromosomes are formed when a chromosome under­ goes two breaks and the broken ends reunite in a ring



structure. Rings encounter difficulties in mitosis and are unsta­ ble, resulting in some cells that lose the ring and are therefore monosomic for the chromosome and others that have mul­ tiple copies of the ring.

Isochromosomes An isochromosome is a chromosome in which one arm is missing and the other duplicated in a mirror-image fashion. The most probable mechanism for the formation of an iso­ chromosome is the misdivision through the centromere in meiosis II, wherein the centromere divides transversely rather than longitudinally. The most commonly encountered iso­ chromosome is that which consists of two long arms of the X chromosome. This accounts for approximately 15% of all cases of Turner syndrome.

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triploid karyotype. Liveborn infants with triploidy exhibit multiple congenital anomalies and rarely survive the newborn period. Those that do usually are mosaics for a diploid and a triploid cell line. The triploid phenotype is distinct and easily recognized. Polyhydramnios or preeclampsia may complicate the preg­ nancy. The placenta may be large, and hydatidiform changes may be seen. Birth weight usually is low. Syndactyly involv­ ing the third and fourth digits is characteristic. Craniofacial features include low-set and malformed ears, hypertelorism, and micrognathia. Cardiac, renal, and central nervous system malformations are common. Long-term survivors often are mosaics and may have less obvious phenotypic features. Body asymmetry and pigmentary dysplasia may be clues to chro­ mosomal mosaicism in general, including, in some cases, triploidy.

Cytogenetic Nomenclature

Aneuploidy

By convention, each chromosome arm is divided into regions, and each region is subdivided into bands and subbands, num­ bered from the centromere outward. Cytogeneticists describe findings of chromosomal analysis using a standardized system of nomenclature (International System for Human Cytoge­ netic Nomenclature) (Nussbaum et al., 2015a). The normal male karyotype is designated 46,XY, and the normal female karyotype is 46,XX. Any chromosomal abnormality is described after the sex chromosome constitution.

Only a minority of aneuploid embryos survive to term; the rest miscarry, usually in the first trimester. Only the most common trisomy and monosomy syndromes compatible with live birth are considered in the following discussion (Nuss­ baum et al., 2015b).

Incidence of Chromosomal Abnormalities Estimates of the incidence of chromosomal abnormalities vary with the mode of ascertainment and the technology used for chromosome analysis. In general, the incidence falls rapidly from conception to birth. The highest rates have been observed among products of conception from first-trimester spontane­ ous abortions. Approximately 50% of these spontaneous mis­ carriages have a chromosomal abnormality. By birth, the rate of chromosomal abnormalities declines to approximately 0.5% to 1% in liveborn infants, although the rate is much higher (5%–10%) in stillborn infants.

CLINICAL INDICATIONS FOR   CYTOGENETIC ANALYSIS Chromosome analysis has been incorporated in the routine battery of tests available to the clinician (Nussbaum et al., 2015a). Some of the more common clinical indications for chromosome analysis include: 1. Problems of early growth and development, including failure to thrive, DD, ID, dysmorphic facies, multiple congenital malformations, short stature, and ambiguous genitalia 2. Fertility problems 3. Family history of known or suspected chromosome abnormality 4. Unexplained stillbirth or neonatal death 5. Prenatal genetic diagnosis 6. Malignant tumor diagnosis and management

SPECIFIC CYTOGENETIC SYNDROMES Polyploidy Tetraploidy is an infrequent chromosomal abnormality, but triploidy occurs fairly often. Most triploid embryos miscarry in the first trimester. In approximately 20% of first-trimester spontaneous abortions, the conceptus is found to have a

Trisomy 13 (Patau Syndrome) Trisomy 13 occurs in approximately 1 in 7000 live births. A majority of affected persons have 47 chromosomes, with an extra copy of chromosome 13. Approximately 5% to 10% have trisomy because of translocation between 13 and another acrocentric chromosome, usually chromosome 14 (Robertso­ nian translocation). Mosaicism occurs in a small proportion of cases and may ameliorate the phenotype. Duplication of part of chromosome 13 resulting from unbalanced transloca­ tion can result in abnormal phenotypic features, although not necessarily similar to those seen in full trisomy 13. Advanced maternal age has been shown to be a factor in the occurrence of this aneuploidy syndrome. Trisomy 13 is associated with congenital anomalies involv­ ing most major organ systems. Holoprosencephaly is the hall­ mark central nervous system anomaly, occurring in about 80% of cases. Other ocular anomalies include microphthalmia, iris colobomata, cataracts, and retinal dysplasia. Premaxillary agenesis and cleft lip or palate also may be present. Ulcer-like defects in scalp skin (cutis aplasia) occur commonly. Limb anomalies include postaxial polydactyly in two-thirds of patients and rocker-bottom foot. Congenital heart defects, especially ventricular septal defect (VSD), are common, as are renal anomalies, including cystic dysplasia.

Trisomy 18 (Edwards’ Syndrome) Trisomy 18 affects approximately 1 in 4000 live births. It is virtually always associated with a 47-chromosome karyotype, although a small proportion of affected newborns have a mosaic karyotype. Segregation of a parental balanced translo­ cation may result in trisomy for part of the short or long arm of chromosome 18. Advanced maternal age has been shown to be a factor in the occurrence of this aneuploidy syndrome. Infants with trisomy 18 have low birth weight and micro­ cephaly. Other common features include a prominent occiput, low-set “simple” ears, and a small mouth. Hands usually are tightly clenched in a characteristic configuration, with the fourth and fifth fingers overlapping the first and second.

Trisomy 21 (Down Syndrome) Trisomy 21 is the most common and widely recognized of the autosomal trisomy syndromes. It occurs in approximately 1 in

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800 live births, with a striking increase in frequency with advanced maternal age. Full trisomy 21 occurs in about 95% of cases. Translocation, usually between chromosome 21 and another acrocentric chromosome, most often chromosome 14, is identified in approximately 4%. A parent who carries such a translocation may be at risk for recurrence of Down syndrome. The remaining 1% of affected persons have a mosaic karyotype. Down syndrome consists of a set of characteristic physical features and developmental impairment. Craniofacial features include upslanted palpebral fissures, epicanthal folds, flat facial profile, and small, low-set ears with narrow ear canals. White speckles (Brushfield spots) may be seen on the iris. A common finding is redundant folds of nuchal skin, which is one of the markers used for prenatal diagnosis by ultrasound examination. Fingers are short, with incurving of the fifth finger (clinodactyly) and, often, a single transverse palmar crease. A wide space between the first and second toes is a frequent finding. The hallmark neurologic feature of Down syndrome is hypotonia. No gross central nervous system mal­ formation is consistently seen, although lack of normal growth of the brain is typical. Impaired neurologic development is a universal feature, but the degree of impairment varies widely. Children with Down syndrome benefit from early interven­ tion, physical therapy, and being reared in a family setting. Linguistic ability may be impaired out of proportion to cogni­ tive impairment. Seizures, including infantile spasms, may be seen with increased frequency. An increased frequency of dementia, associated with pathologic changes of Alzheimer’s disease, has been described in patients with Down syndrome. Congenital anomalies commonly associated with Down syn­ drome include heart and gastrointestinal defects.

Turner Syndrome Turner syndrome is associated with a 45,X karyotype, with a single X chromosome. Mosaicism is not uncommon, however, with a separate cell line containing either a normal 46,XX or XY karyotype, or 46 chromosomes including a structurally rearranged X or Y. Turner syndrome occurs in about 1 in 4000 female live births worldwide but it is much more common in stillbirths and miscarriages. Unlike other aneuploidy syn­ dromes, the frequency of Turner syndrome does not increase with advancing maternal age. Patients with Turner syndrome typically have a female phe­ notype, although those with a cell line including a Y chromo­ some may have some degree of virilization, often with ambiguous genitalia. At birth, infants may manifest pedal edema or diffuse edema. In older children and adults with Turner syndrome, short stature and webbing of the neck are commonly seen. The thorax is broad, with increased distance between the nipples. Congenital anomalies include abnor­ malities of the lymphatic system; cardiac defects, especially coarctation of the aorta and bicuspid aortic valve; and renal anomalies. Although ID is rare, delays in both gross and fine motor development are common in females with Turner syndrome. Some patients display cognitive problems, but difficulties with visuospatial perception are most common. Hearing impair­ ment occurs frequently, and children should be monitored for deficits or progression of impairment.

Klinefelter Syndrome Klinefelter syndrome occurs in about 1 in 1000 males and is associated with a 47,XXY karyotype. The incidence increases as a function of maternal age in half of the cases. Rare patients may have multiple X chromosomes (e.g., 48,XXXY or 49,XXXXY). Usually the presence of multiple X chromosomes

in such persons is associated with more severe cognitive impairment. The diagnosis of Klinefelter syndrome usually is not sus­ pected at birth. Affected males tend to be tall, with long limbs. They display hypogonadism, and virilization may be incom­ plete at puberty; gynecomastia develops in some patients. Azoospermia and infertility are characteristic. Breast cancer is 20 times more common in Klinefelter syndrome than in the normal male population. As in Turner syndrome, ID is not a typical feature of Klinefelter syndrome. Learning disabilities, language delay, and behavior problems are reported.

Other Sex Chromosome Aneuploidies Two other major sex chromosome aneuploidies are 47,XXX and 47,XYY. The XXX aneuploidy is associated with a female phenotype and tall stature; usually other major physical stig­ mata are absent. XYY is associated with a male phenotype and tall stature but no other physical features. Learning disabilities and neuromotor impairment occur commonly in 47,XXX females. The behavioral phenotype of XYY syndrome has been a source of some controversy because of reports associating the karyotype with criminal behavior. The frequency of learn­ ing disabilities and behavioral problems is increased among affected males, although widely ranging cognitive outcomes have been reported.

Structural Abnormalities Structural abnormalities of chromosomes cause phenotypic effects resulting from loss and/or gain of genetic material. In some cases, these occur sporadically as a result of de novo chromosome rearrangements, whereas in others, they may be inherited as a consequence of segregation of a familial bal­ anced chromosomal rearrangement. Some deletion or dupli­ cation syndromes are fairly well characterized in terms of phenotypic effects and may be recognized clinically. For many years, genomic disorders resulting from micro­ deletions and microduplications that are clinically recogniz­ able by their typical constellation of clinical features were tested for by FISH using DNA probes specific to these genomic regions. The advances in CMA technologies over the past decade have allowed their widespread use not only in a research setting but also as a clinically diagnostic modality in a wide variety of human diseases. CMA analysis has been very useful in the study of copy-number variants (CNVs), which can be broadly classified as either benign polymorphic CNVs or pathogenic disease-causing CNVs. Between these two ends of the spectrum, many CNVs have uncertain clinical signifi­ cance, and some of these could potentially be risk factors for human disease. Clinically relevant CNVs can be either recurrent, with a common size and breakpoint clustering in the flanking seg­ mental duplications, or nonrecurrent, with different sizes and variable breakpoints for each CNV (Stankiewicz and Lupski , 2010). These nonrecurrent CNVs typically share a common genomic region of overlap that encompasses the gene(s) asso­ ciated with the observed phenotype. These nonrecurrent rear­ rangements occur at a relatively lower frequency at the individual locus level, but collectively they are as common as recurrent CNVs. Clinically relevant CNVs can encompass mul­ tiple contiguous genes, including dosage sensitive genes, with each contributing to the phenotype independently. Others encompass a single gene or just few genes. Two types of microdeletions and microduplications have been distinguished: the syndromic forms in which the phe­ notypic features are relatively consistent, and those in which the same CNV can be associated with a diverse set of



diag­noses (Girirajan and Eichler, 2010; Cooper et al., 2011; Coe, Girirajan, and Eichler, 2012a, 2012b). The syndromic forms of CNVs were originally described as relatively large microdeletions or microduplications that are highly penetrant, almost always de novo in origin, and usually identified in individuals with ID or MCAs. These are clinically recognizable syndromes that were described well before their genetic causes were known. On the contrary, the more recently described nonsyndromic recurrent CNVs have been reported to have incomplete penetrance and variable expressivity. These have been associated with, but not limited to, DD, ID, autism, sei­ zures, schizophrenia, cardiac and renal anomalies, and other congenital anomalies. Recently it was observed that more than one CNV (the “two-hit” model) can explain the phenotypic variability associated with the nonsyndromic recurrent CNVs (Girirajan and Eichler, 2010; Coe et al., 2012a). Therefore it was proposed that one hit (first CNV) is sufficient to reach a threshold just enough to cause some form of neuropsychiatric disease, whereas a second hit (e.g. second CNV) pushes that individual toward a more severe phenotype with DD and ID. It is worth mentioning that these two hits involve differ­ ent regions/genes in the human genome as opposed to the two-hit model reported in cancer, which involves both alleles of a tumor-suppressor gene. Variable-expressivity CNVs are much more likely to be inherited from less severely affected parents, which suggests that they are by themselves insuffi­ cient to determine the disease outcome. Although the two-hit model was initially applied to large CNVs, it has been pro­ posed that the second hit could also be a smaller CNV or a SNP involving a related gene or a risk allele inherited from a parent. Approximately 70 microdeletion/microduplication syn­ dromes have been reported to date, as shown in the DECIPHER database (https://decipher.sanger.ac.uk/disorders #syndromes/overview). In the following section, some of the syndromic microdeletions and microduplications that are clinically relevant to the practice of pediatric neurology are discussed.

22q11.2 Deletion Syndrome The 22q11.2 deletion syndrome includes the phenotypes previously called DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS, Shprintzen’s syndrome), conotruncal anomaly face syndrome, many cases of autosomal-dominant Opitz G/BBB syndrome, and Cayler’s cardiofacial syndrome (asymmetric crying facies) (Nussbaum et al., 2015b). The con­ dition is clinically heterogeneous. Congenital heart defects are present in most affected individuals (74%), particularly conotruncal malformation. Additional findings include palatal abnormalities and velopharyngeal incompetence (VPI), learn­ ing disabilities, immune deficiencies, hypocalcemia, and char­ acteristic facies. Also reported are hearing loss, seizures without hypocalcemia, speech delays, and behavioral difficulties. The 22q11.2 deletion affects an estimated 1 : 2000 to 1 : 4000 live births. Most cases are de novo, but inherited deletions have been reported in 6% to 28% of patients with the syndrome. The inheritance is autosomal dominant.

Prader–Willi and Angelman Syndromes The recognition of the phenomenon of genomic imprinting has led to the discovery of a new class of genetic disorders associated with aberrations of imprinted genes (Nussbaum et al., 2015b; Kalish, Jiang, and Bartolomei, 2014). The proto­ type disorders are Prader–Willi and Angelman’s syndromes (Nussbaum et al., 2015b). The features of these syndromes are described in Table 35-3. Prader–Willi syndrome (PWS) affects 1 : 5000 to 1 : 10,000 individuals. Approximately 70% to 75%

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of the individuals with PWS have a deletion of the paternally contributed 15q11.2q13.1 region, whereas in Angelman’s syn­ drome (AS), 70% of affected individuals have a deletion of the maternally contributed 15q11.2q13.1 region. Approximately 1 : 40,000 children are affected with AS. Most patients with PWS who do not have the 15q11.2q13.1 deletions have uni­ parental disomy for chromosome 15, with two maternal copies and no paternal copies. Either mechanism—deletion or uniparental disomy—leads to deficiency of a gene or genes on chromosome 15 that are expressed in the paternal but not the maternal homolog. Deletion of a group of small nucleolar RNA (snoRNA) genes, known as the SNORD116 cluster, is thought to play a major role in causing the signs and symp­ toms of PWS. Paternal uniparental disomy accounts for a low percentage of cases of AS. Mutations in the UBE3A gene (a ubiquitin ligase gene involved in early brain development), located at 15q11.2, have been found in some patients with AS. This gene is imprinted in the brain and is the gene responsible for the AS phenotype. A small proportion of patients with PWS or AS may have a small deletion or other mutation that leads to aberrant imprinting of the region.

William–Beuren Syndrome William–Beuren syndrome (WBS) is a microdeletion syn­ drome of chromosome 7 at band q11.23 and occurs in 1 : 10,000 live births. Cardiovascular disease is present in 80% of affected individuals, mostly in the form of supraval­ vular aortic stenosis (SVAS), peripheral pulmonary stenosis, elastin arteriopathy, and hypertension. The 7q11.23 micro­ deletion encompasses the elastin gene (ELN). Characteristic facial features include periorbital fullness, long philtrum, wide mouth, full lips, full cheeks, and small, wide-spaced teeth. Affected individuals have mild to moderate ID, spe­ cific cognitive profile/learning disabilities, and unique or distinctive behavior/personality characteristics. Growth and endocrine abnormalities (hypercalcemia, hypothyroidism, hypercalciuria) and feeding difficulties in infancy are also common.

1p36 Deletion Syndrome The 1p36 deletion syndrome results from a variable-sized deletion in the terminal end of the short arm of chromosome 1. It is considered to be the most common subtelomeric microdeletion syndrome, with an estimated incidence of 1 in 5000 to 1 in 10,000. It accounts for 0.5% to 1.2% of idiopathic ID. Clinical findings include a characteristic craniofacial appearance: microbrachycephaly, large and late-closing ante­ rior fontanel, straight eyebrows, deep-set eyes, epicanthic folds, broad nasal bridge, midface hypoplasia, abnormally formed low-set ears, and limb and skeletal defects. DD and ID with absent/poor expressive language are constant features. Affected individuals often face serious physical disabilities that include congenital heart defects (70%), cardiomyopathy (25%), brain abnormalities (88%), seizures (44%), and elec­ troencephalogram (EEG) abnormalities (100%). Ocular mal­ formations or vision problems and hearing loss are observed in approximately 50% of affected individuals.

Wolf–Hirschhorn Syndrome Wolf–Hirschhorn syndrome (WHS) results from a variablesized deletion in the terminal end of the short arm of chro­ mosome 4. It is characterized by distinctive facial appearance, growth delay, psychomotor retardation, and seizures, and is confirmed by detection of a deletion of the Wolf–Hirschhorn critical region (WHCR) (chromosome 4p16.3). The syndrome has clinical and cytogenetic variability. Characteristic facial

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TABLE 35-3  Comparison of Features of Prader–Willi and Angelman’s Syndromes

Diagnostic criteria

Prader–Willi Syndrome*

Angelman’s Syndrome†

Major clinical criteria Neonatal hypotonia Feeding problems in infancy Rapid weight gain between 1 and 6 years of age Characteristic facies Hypogonadism Developmental delay Hyperphagia

Consistent features (100%) Developmental delay Speech impairment Movement disorder (ataxia of gait, tremulous movement of limbs) Behavioral features: frequent laughter or smiling, hand flapping

Minor criteria Decreased fetal movement Characteristic behaviors Sleep disturbances Short stature Small hands Narrow hands Esotropia/myopia Thick, viscous saliva Speech articulation defects Skin picking

Frequent features (80%) Acquired microcephaly Seizures (usually in patients younger than 3 years) Abnormal EEG (high-amplitude 2- to 3-Hz spike-wave discharge) Associated features (20%–80%) Flat occiput, occipital groove Protruding tongue Prognathism Wide mouth and widely spaced teeth Drooling, chewing, mouthing movements Strabismus Hypopigmentation Brisk lower limb deep tendon reflexes Sleep disturbance

Supportive findings High pain threshold Decreased vomiting Cytogenetics

70%–75% paternal 15q11.2q13.1 deletion

70% maternal 15q11.2q13.1 deletion

Uniparental disomy

20%–25% maternal disomy

2% paternal disomy

Imprinting defect

1%–3%

2%–5%

Gene mutation

Unknown

5%–10% UBE3A gene mutation

EEG, electroencephalogram. *Data from Holm VA, Cassidy SB, Butler MG, et al. Pediatrics 1993;91(8424017):398–402. † Data from Williams CA, Angelman H, Clayton-Smith J, et al. Am J Med Genet 1995;56(2):237–8. (Mutation analysis data from Buiting K, Gross S, Lich C, et al. Am J Hum Genet 2003;72(12545427):571–7.; Jiang Y, Lev-Lehman E, Bressler J, et al. Am J Hum Genet 1999;65(10364509):1–6.)

features include the “Greek warrior helmet” appearance of the nose (the broad bridge of the nose continuing to the forehead), high forehead with prominent glabella, ocular hypertelorism, and microcephaly. ID ranges from mild to severe. Other birth defects have been reported in individuals with WHS. One-third of the patients have structural central nervous system defects, and seizures also can occur. In 75% of patients with WHS, the deletion is de novo; in about 13% of patients, the deletion results from the unbalanced segregation of a parental balanced translocation. It is now recognized that WHS and Pitt–Rogers–Danks syndrome (PRDS) represent the clinical spectrum associated with a single syndrome.

Cri du Chat Syndrome Cri du chat syndrome is a genetic syndrome resulting from a variable-sized deletion in the terminal end of the short arm of chromosome 5. The incidence ranges from 1 : 15,000 to 1 : 50,000. A high-pitched, cat-like cry is among the main clini­ cal features in the newborn period; hence the name of the syndrome. Other frequently described features are microceph­ aly, broad nasal bridge, epicanthic folds, micrognathia, impaired growth, and severe psychomotor and ID. The syn­ drome has significant clinical and cytogenetic variability. Clin­ ical analysis of affected individuals and detailed molecular cytogenetic analysis suggest the existence of two critical regions, one on 5p15.2 for facial dysmorphism, microcephaly, and ID, and another on 5p15.3 for the typical cry. In affected individuals, 80% of cases are the result of a de novo deletion, and 10% are the result of the unbalanced segregation of a parental balanced translocation.

Chromosome 9q Subtelomeric Deletion The chromosome 9q subtelomeric deletion represents one of the most common subtelomeric deletions (6%). The syn­ drome can be caused either by a 9q34.3 microdeletion or by mutations in the EHMT1 gene, which is involved in histone methylation. Affected individuals invariably have severe hypotonia, with speech and gross motor delay. Facial features include micro-/brachycephaly, hypertelorism, syn­ ophrys, arched eyebrows, midface hypoplasia, short nose with upturned nares, protruding tongue, everted lower lip, and downturned corners of the mouth. Congenital heart defects have been reported in approximately 50% of affected indi­ viduals. Epilepsy and behavior and sleep disturbances have also been reported in some (10%–20%).

Jacobsen Syndrome Jacobsen syndrome is a contiguous-gene deletion syndrome caused by deletion of the distal portion of the long arm of chromosome 11 (11q23.3qter). Typical features include DD, ID, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. Some of the facial dysmorphism described includes skull deformities, hypertelorism, epicanthic folds, ptosis, broad nasal bridge, and small ears. Malformation of heart, kidney, gastrointestinal tract, central nervous system, and skeleton is common. The deletion is de novo in 85% of cases, and in the remaining patients it results from the unbalanced segregation of a paren­ tal balanced chromosome rearrangement.



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Charcot–Marie–Tooth Neuropathy Type 1A and Hereditary Neuropathy With Liability to Pressure Palsies

microdeletion encompassing the STS gene (Xp22.31). In 5% of cases, the deletion is extensive enough to involve adjacent genes, resulting in learning disabilities, autism, and epilepsy in some of the affected boys.

Charcot–Marie–Tooth neuropathy type 1A (CMT1A) repre­ sents 70% to 80% of all CMT1 and results from an approxi­ mately 1.5-Mb duplication at 17p12, which encompasses the PMP22 gene (peripheral myelin protein 22). Reciprocal dele­ tion of the same region results in the milder phenotype of hereditary neuropathy with liability to pressure palsies (HNPP). The duplication is inherited in around two-thirds of individuals and is de novo in the remaining third.

Loss of Function of the MECP2 Gene/Duplication of the MECP2 Region (Xq28)

Smith–Magenis Syndrome and Potocki–Lupski Syndrome Approximately 90% of individuals with Smith–Magenis syn­ drome (SMS) have a deletion on chromosome 17 at band p11.2 that encompasses the RAI1 gene. The remaining 5% to 10% of cases carry a mutation in the RAI1 gene. Physical fea­ tures include short stature, obesity, craniofacial dysmorphism, and small hands and feet. Behavior disturbances, especially sleep problems and self-injurious behavior, are frequently reported. All affected individuals have mild to severe learning disabilities. The phenotypic features may be subtle in infancy and early childhood. The reciprocal duplication of this 17p11.2 region has been reported (Potocki–Lupski syndrome). The most frequent fea­ tures of this syndrome are hypotonia in infancy, DD, language and cognitive impairment, autistic features, poor feeding and failure to thrive in infancy, oral-pharyngeal dysphagia, obstruc­ tive and central sleep apnea, structural cardiovascular abnor­ malities, EEG abnormalities, and hypermetropia. Most have short stature and mild to normal facies. Variability in the phe­ notype is observed. It is expected that persons with large dupli­ cations that encompass the more distal CMT1A region will have a more severe phenotype, including peripheral neuropathy.

Loss-of-function mutations involving the MECP2 gene at Xq28 result in Rett syndrome, a severe neurodevelopmental disorder that almost always occurs in females. Males with nonRett mutations in MECP2 demonstrate a wide variety of phe­ notypes, including X-linked ID with spasticity and other variable features. Males with Rett mutations in MECP2 have neonatal severe encephalopathy that is usually lethal. Duplica­ tions at Xq28 that span the MECP2 gene in males are associ­ ated with severe X-linked ID and progressive spasticity. These duplications usually also span the L1CAM gene. Finally, some of the nonsyndromic microdeletions and micro­ duplications that present with neurodevelopmental problems are as follows: Distal 1q21.1 microdeletion and microduplication 2p15p16.1 microdeletion Terminal deletions of the long arm of chromosome 2 (2q37 microdeletion) 3q29 microdeletion 7q11.23 microduplication Maternal duplication of the 15q11.2q13.1 region 15q13.3 microdeletion 15q24 microdeletion 16p11.2 microdeletion and microduplication 16p11.2p12.2 microdeletion 16p13.11 microdeletion and microduplication 17q21.31 microdeletion Distal 22q11.2 microdeletions 22q13 microdeletions (Phelan–McDermid syndrome)

Miller–Dieker Syndrome

THE FUTURE OF CLINICAL CYTOGENETICS

Miller–Dieker syndrome represents a microdeletion syndrome spanning the PAFAH1B1 gene (also known as LIS1) at 17p13.3, which results in severe lissencephaly with characteristic facial changes, other more variable malformations, and severe neu­ rologic and developmental abnormalities. The facial features consist of high and prominent forehead, bitemporal hollow­ ing, short nose with upturned nares, protuberant upper lip with downturned vermillion border, and small jaw. The recip­ rocal duplication results in DD, hypotonia, and facial dysmor­ phism. In contrast to patients with the deletion, those with the duplication have neither gross brain malformations nor lissencephaly.

Clinical cytogenetics began with the cytologic analysis of chro­ mosomes in the 1950s but has steadily moved toward an increasingly molecular approach. This began with the advent of FISH and has accelerated since the introduction of CMA. CMA is moving us toward a whole-genome approach, with no need to know in advance where to look. This is raising questions about whether CMA should be used before a com­ prehensive dysmorphology evaluation because many of the deletions or duplications detected are not associated with well-delineated syndromes. A caution in use of this approach, however, is that some gene-dosage changes are not known to be associated with an abnormal phenotype and are likely to be benign variants of no clinical significance. Therefore correct interpretation of dosage changes still requires a high level of sophistication and care in counseling the patient/family. The resolution of genomic analysis will continue to increase. Clini­ cal whole-exome or whole-genome DNA sequencing is cur­ rently being used to uncover clinically relevant gene mutations with a much higher power than previously possible. Both CMA and whole-exome or whole-genome sequencing will undoubtedly reveal an increasing number of genomic changes that underlie neurologic disorders, leading to an increase in the power and precision of genetic diagnosis.

Neurofibromatosis Type 1 Approximately 5% of patients with neurofibromatosis type 1 (NF1) have deletions of the entire NF1 gene and contiguous genes at 17q11.2, resulting in the NF1 microdeletion syn­ drome. NF1 with large deletions is more likely to have dys­ morphic features, cardiac anomalies, connective tissue dysplasia, and ID. Patients with reciprocal microduplications have been reported.

X-Linked Ichthyosis Resulting From Steroid Sulphatase Enzyme Deficiency Males with X-linked ichthyosis resulting from steroid sulpha­ tase enzyme deficiency have generalized scaling that usually starts shortly after birth. In 90% of cases, it is caused by a

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details.

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SELECTED REFERENCES Coe, B.P., Girirajan, S., Eichler, E.E., 2012a. A genetic model for neurodevelopmental disease. Curr. Opin. Neurobiol. 22 (5), 829–836. Coe, B.P., Girirajan, S., Eichler, E.E., 2012b. The genetic variability and commonality of neurodevelopmental disease. Am. J. Med. Genet. C Semin. Med. Genet. 160C (2), 118–129. Cooper, G.M., Coe, B.P., Girirajan, S., et al., 2011. A copy number variation morbidity map of developmental delay. Nat. Genet. 43 (9), 838–846. Girirajan, S., Eichler, E.E., 2010. Phenotypic variability and genetic susceptibility to genomic disorders. Hum. Mol. Genet. 19 (R2), R176–R187. Kalish, J.M., Jiang, C., Bartolomei, M.S., 2014. Epigenetics and imprint­ ing in human disease. Int. J. Dev. Biol. 58 (2–4), 291–298. Miller, D.T., Adam, M.P., Aradhya, S., et al., 2010. Consensus state­ ment: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anom­ alies. Am. J. Hum. Genet. 86 (5), 749–764. Nussbaum, R., McInnes, R., Willard, H. (Eds.), 2015a. Thompson & Thompson Genetics in Medicine, eighth ed. Elsevier. (Chapter 5: Principles of Clinical Cytogenetics and Genome Analysis). Nussbaum, R., McInnes, R., Willard, H. (Eds.), 2015b. Thompson & Thompson Genetics in Medicine, eighth ed. Elsevier. (Chapter 6: The Chromosomal and Genomic Basis of Disease: Disorders of the Autosomes and Sex Chromosomes). Stankiewicz, P., Lupski, J.R., 2010. Structural variation in the human genome and its role in disease. Annu. Rev. Med. 61, 437–455. Vissers, L.E., Stankiewicz, P., 2012. Microdeletion and microduplica­ tion syndromes. Methods Mol. Biol. 838, 29–75.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 35-1 Normal male human karyotype (46,XY). Fig. 35-4 A newborn with trisomy 13. Fig. 34-5 A patient with trisomy 18 at 7 years of age. Fig. 35-6 Patients with trisomy 21 (Down syndrome). Fig. 35-7 A patient with mosaic trisomy 8. Fig. 35-8 A girl with Turner’s syndrome. Fig. 35-9 A boy with Klinefelter’s syndrome at age 13 years. Fig. 35-10 A boy with Prader–Willi syndrome. Fig. 35-11 A boy with Angelman’s syndrome at 6 years of age. Box 35-1 Common Clues to the Need for Chromosomal Analysis Box 35-2 Common Indications for Prenatal Cytogenetic Diagnosis Table 35-1 Abbreviations Used to Describe Chromosomes and Their Abnormalities, and Representative Examples Table 35-2 Microdeletion/Microduplication Syndromes Listed in the DECIPHER Database

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Approach to the Patient with a Metabolic Disorder Linda De Meirleir and Lance H. Rodan

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Inborn errors of metabolism (IEMs) are genetic disorders that disrupt biochemical processes in the body by altering enzyme activity, cellular transport, or mitochondrial bioenergetics. Over 600 IEMs have been described to date, and this number is increasing with the more widespread use of whole exome sequencing. Although IEMs are individually rare, their collective incidence is approximately 1 in 1000. The clinical manifestations of IEMS are protean because almost every organ and tissue can be affected. The nervous system is often affected with selective vulnerability given its high bioenergetic demand and its reliance on a delicate balance of complex biochemical processes for normal functioning. It is particularly important for the pediatric neurologist to be familiar with the diagnosis of IEMs because most are associated with neurologic symptoms, and many have effective, disease-specific treatments.

INHERITANCE The inheritance pattern of most IEMs is autosomal recessive because residual enzyme activity is usually sufficient to preclude the development of disease; however, X-linked and autosomal dominant inheritance are possible (Table 36-1). X-linked recessive disorders can present variably in carrier females based on the pattern of X-inactivation. X-linked dominant disorders are often lethal in males. Disorders of mitochondrial DNA (mtDNA) are maternally inherited and show phenotypic variability based on the percentage and tissue distribution of mutant mtDNA (termed “heteroplasmy”). A detailed three-generation pedigree should be obtained in every patient presenting for evaluation for an IEM. Particular attention should be paid to any history of sudden infant death syndrome (SIDS), siblings with neurologic disorders, including epilepsy and “cerebral palsy,” and parental consanguinity.

LABORATORY EVALUATION Most inborn errors of metabolism can be diagnosed through specialized biochemical testing. This includes measurement of metabolites in body fluids and specific enzyme assays. Molecular testing is clinically available for most disorders, either as single gene tests or next generation targeted gene panels based on disease category. A molecular diagnosis may be useful for predicting prognosis and treatment response (e.g., cofactor responsiveness) and can be used for prenatal testing to reduce recurrence risk. Newborn screening protocols have been instituted in a number of countries that evaluate for some of the treatable IEMS, potentially including organic acidemias, fatty acid oxidation and carnitine disorders, some amino acidopathies, galactosemia, and biotinidase deficiency. The specific disorders included and methodologies vary considerably from country to country and even between states in the United States. Readers are encouraged to contact their local newborn screening laboratory to determine which disorders are included in their screening program. It should be emphasized that this testing represents screening and not diagnostic testing, and

both false positive and false negative results are possible. Normal newborn screening does not preclude the possibility of an inborn error of metabolism. Likewise, abnormal newborn screening must be followed by confirmatory diagnostic evaluation by a clinician with expertise in biochemical genetics.

CLASSIFICATION When evaluating a patient for an inborn error of metabolism, it is necessary to use a systematic and organized approach to maximize the potential for diagnosis. Different approaches to the diagnosis of IEMs have been described. One approach groups IEMs into categories based on the affected metabolic pathway (e.g., urea cycle) or organelle (e.g., lysosome) because most disorders in each grouping share some clinical and biochemical features (see Table 36-2). Another approach, particularly suited for the pediatric neurologist, is a symptoms-based approach focused on neurologic phenotype. This chapter provides a symptoms-based approach that incorporates age of onset and predominant neurologic signs. Before approaching these aforementioned symptom categories, it is useful for the reader to adopt a broad framework for classifying IEMs based on pathophysiology and general symptomatology. This broad classification divides IEMs into small molecule disorders, large molecule disorders, disorders of cerebral energy metabolism, and miscellaneous IEMs. This is a modified version of the original classification proposed by Saudebray and associates that is adapted for the pediatric neurologist (Saudubray et al., 2012). This classification will be referred to throughout this chapter. Small molecule disorders are IEMs affecting intermediary metabolism, including the metabolism of amino acids, organic acids, fatty acids, ketones, and ammonia. These disorders result in intoxication from accumulation of substrate and are often associated with basic and readily detectable biochemical abnormalities such as acidosis, hyperammonemia, or hypoglycemia. These disorders generally present acutely with encephalopathy and may also be accompanied by ataxia, headache, nausea, and respiratory abnormalities. The disease course of these IEMs is often episodic with periods of deterioration provoked by illness, fasting, or other bioenergetics stressors. Most of these disorders are amenable to specific treatments based on dietary modification and/or cofactor supplementation. Large molecule disorders are IEMs that affect synthesis or catabolism of complex molecules and include disorders of the lysosome and peroxisome, disorders of glycosylation, and disorders of complex lipid metabolism. Large molecule disorders typically follow a chronic course that may be static or gradually progressive. Many of these disorders are associated with congenital malformations or dysmorphic physical features. A number of lysosomal disorders can be treated effectively with enzyme replacement therapy. Disorders of cerebral energy metabolism include defects impairing mitochondrial bioenergetics, pyruvate metabolism, creatine metabolism, coenzyme Q10 biosynthesis, and the transport of glucose into the CNS. In general, disorders of

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TABLE 36-1  Iems With X-Linked and Autosomal Dominant Inheritance Inheritance X-LINKED RECESSIVE DISORDERS Ornithine transcarbamylase deficiency Phosphoribosylphosphate synthetase deficiency Lesch Nyhan syndrome Lowe syndrome Fabry disease Hunter syndrome X-linked adrenoleukodystrophy Menkes syndrome Monoamine oxidase A deficiency X-linked creatine transporter deficiency X-LINKED DOMINANT DISORDERS X-linked chondrodysplasia punctata CHILD syndrome Beta propeller-associated neurodegeneration (X-linked dominant) AUTOSOMAL DOMINANT DISORDERS Cystinuria Glucose transporter 1 deficiency SLC6A1-related myoclonic astatic epilepsy Autosomal dominant GTP cyclohydrolase deficiency POLG1-related progressive external ophthalmoplegia HEM skeletal dysplasia Porphobilinogen deaminase deficiency

Classification of IEM Urea cycle disorder Disorder of purine disorder Disorder of purine disorder Disorder of phospholipid metabolism Lysosomal disorder Lysosomal disorder Peroxisomal disorder Disorder of copper transport Disorder of neurotransmitter metabolism Disorder of energy metabolism

Disorder of cholesterol biosynthesis Disorder of cholesterol biosynthesis Neurodegeneration with brain iron accumulation

Disorder of amino acid metabolism Disorder of energy metabolism Disorder of neurotransmitter metabolism Disorder of neurotransmitter metabolism Disorder of energy metabolism Disorder of cholesterol biosynthesis Disorder of heme biosynthesis

energy metabolism follow a chronically progressive course, often punctuated by episodic exacerbations. Developmental delay and seizures are a common manifestation, and many disorders in this group can also be associated with movement disorders. Several of these disorders have effective treatments: pyruvate dehydrogenase deficiency and glucose transporter 1 deficiency are treated with the ketogenic diet; creatine deficiency syndromes may respond to creatine supplementation; and disorders of coenzyme Q10 biosynthesis are treated with CoQ10 replacement. Finally, there are a number of IEMs that are not easily classified into these categories, including disorders in the metabolism of carbohydrates, purines and pyrimidines, vitamins, minerals/heavy metals, and biogenic amine neurotransmitters (Table 36-3).

PART 1: CLINICAL PRESENTATION OF IEMS   IN THE NEONATE OR INFANT LESS THAN   2 YEARS OF AGE As a general rule, the age of presentation and severity of an IEM is proportional to the degree of enzyme deficiency. Although this section describes IEMs that typically present in infancy, the reader should be cognizant that milder forms of many of these disorders may present for the first time in older children and adults.

Acute Encephalopathy Many inborn errors of metabolism present in early life with acute or subacute encephalopathy, particularly small molecule disorders and disorders of cerebral energy metabolism (Chapters 37 and 42). Many of these disorders present after a well period in the context of metabolic stressors such as prolonged fasting, illness, and some medications. Most small molecule disorders do not present in fetal life because the placenta is capable of removing many toxic metabolites. IEMS presenting with acute encephalopathy may be accompanied by abnormalities in tone, seizures, ataxia, emesis, and respiratory abnormalities. Basic biochemical abnormalities are common and may suggest a specific disease category. Urine ketones are always abnormal in the neonate due to increased physiologic ketone utilization and suggest an IEM until proven otherwise. Ketoacidosis with hyperammonemia suggests an organic acidemia, of which propionic and methylmalonic acidemias are prototypical. Inappropriate ketosis is also a feature of maple syrup urine disease and disorders of ketone degradation (e.g., ketothiolase deficiency). Hyperammonemia without metabolic acidosis suggests dysfunction of the urea cycle. There may be accompanying respiratory alkalosis (Chapter 38). Hypoglycemia with insufficient ketosis is the hallmark of the fatty acid oxidation and carnitine disorders, disorders of ketone synthesis (e.g., HMG-CoA lyase deficiency), and hyperinsulinism. Recurrent ketotic hypoglycemia accompanied by hepatomegaly suggests a glycogen storage disorder or disorder of gluconeogenesis. Disorders of gluconeogenesis are also associated with fasting-induced blood lactate elevation (Chapter 39). Persistent elevations of blood lactate in the neonate or infant that is not critically ill, septic, or hypoperfused should raise consideration for a mitochondrial disorder or disorder of pyruvate metabolism (Chapter 42). A normal blood lactate to pyruvate ratio (less than 20 to 25), a marker of cytoplasmic redox status, is seen in pyruvate dehydrogenase deficiency and some forms of pyruvate carboxylase deficiency. Pyruvate carboxylase deficiency may also be associated with hyperammonemia and hypoglycemia. A number of IEMs can present with acute liver failure in the neonate or infant associated with hepatic encephalopathy, including galactosemia, tyrosinemia type 1, hereditary fructose intolerance, and mitochondrial disorders. Concurrent proximal renal tubulopathy may be present in any of these disorders and is a useful diagnostic clue. In addition, a Reyelike syndrome, including fulminant liver failure, metabolic acidosis, and cerebral edema, has been reported in fatty acid oxidation and carnitine disorders, organic acidemias, urea cycle disorders, ketogenesis disorders, gluconeogenesis defects, hereditary fructose intolerance, and mitochondrial disorders. This may be provoked by certain medications, including valproic acid and ASA. In the absence of basic biochemical abnormalities, neuroimaging findings may suggest a specific IEM in the neonate or infant presenting with acute or subacute encephalopathy. Symmetric signal change in the basal ganglia, often associated with diffusion restriction, can be seen in organic acidemias, mitochondrial disorders, and biotin-thiamine responsive basal ganglia disease. These findings can mimic a hypoxic-ischemic injury. Acute white matter injury with diffusion restriction can be seen in maple syrup urine disease, glycine encephalopathy (nonketotic hyperglycinemia), and sulfite oxidase deficiency/ molybdenum cofactor deficiency, although the specific patterns are different. Stroke or stroke-like lesions that cross classic vascular territories can be seen in mitochondrial disorders, congenital disorders of glycosylation, and Menkes syndrome (Van der Knaap and Valk, 2005).



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TABLE 36-2  Classification of IEMs by Pathway and Organelle Category

Symptoms

Biochemical Investigations

Urea cycle disorders

Hyperammonemic encephalopathy

Ammonia, plasma amino acids, urine organic acids (orotic acid)

Fatty acid oxidation & carnitine disorders

Hypoketotic hypoglycemia, episodic rhabdomyolysis, cardiomyopathy, hepatopathy, Reye-like syndrome

Plasma acylcarnitines, free/total carnitine

Organic acidemias

Ketoacidosis, hyperammonemia, metabolic stroke, developmental delay

Urine organic acids, plasma acylcarnitines

Aminoacidopathies

Epilepsy, developmental delay, acute CNS events (toxic, ischemic)

Plasma amino acids, additional metabolic studies based on suspected diagnosis

Peroxisomal disorders

Retinopathy, sensorineural hearing loss, brain malformation, dysmorphisms, leukoencephalopathy

Plasma VLCFAs, phytanic acid, pristanic acid, pipecolic acid, RBC plasmalogens, bile acid intermediates in blood and urine

Lysosomal disorders

Hurler phenotype (coarse facial features, dysostosis multiplex, hepatosplenomegaly, corneal opacitiy), leukoencephalopathy, progressive myoclonus epilepsy, cherry red spot, organomegaly, gaze palsy

Enzymology, urine MPS screen, urine oligosaccharides

Disorders of cholesterol biosynthesis

Multiple congenital anomalies, static developmental delay

Measurement of plasma cholesterol precursors

Congenital disorders of glycosylation

Congenital anomalies, hypotonia, abnormal fat pads, abnormal coagulation profile

Plasma transferrin analysis, urine oligosaccharides and free glycans

Biogenic amine disorders

Movement disorder, diurnal fluctuation, dysautonomia, oculogyric crisis

CSF neurotransmitters, CSF/urine pterins, plasma phenylalanine

Mitochondrial disorders

Highly pleiotropic presentations, including CNS, PNS, multiple organs, failure to thrive, retinopathy, hearing loss, ophthalmoparesis, stroke-like events, epilepsy

Elevated lactate in blood or CSF, elevated plasma alanine

MR spectroscopy can occasionally provide additional information beyond structural imaging. Maple syrup urine disease may be associated with a branch-chain ketoacid peak at 0.9 ppm. Mitochondrial disorders, disorders of pyruvate metabolism, and organic acidemias may be associated with lactate elevations in regions of structurally normal brain. The clinician must keep in mind that if regions of brain affected by stroke, infection, or injury are sampled, lactate may be secondarily elevated. Hyperammonemia may be associated with an elevated glutamine peak. A few small molecule disorders are associated with abnormal urine odor, including the maple syrup odor of urine and ear wax in maple syrup urine disease, the musty odor of urine and sweat in phenylketonuria, and the sweaty feet odor of urine in isovaleric acidemia and glutaric acidemia type 2. Specific diagnosis requires evaluation of: urine organic acids and plasma acylcarnitines for organic acid disorders; plasma acylcarnitine profile and free/total carnitine for fatty acid oxidation and carnitine disorders; and plasma amino acids for amino acidopathies and urea cycle disorders. A number of urea cycle disorders are also associated with elevations of urine orotic acid. Homocysteinurias require the measurement of total serum homocysteine for biochemical diagnosis, which is not included in standard plasma amino acid analyses. Biochemical abnormalities in some of these disorders may be normal when the child is well, warranting reevaluation at times of illness.

Epilepsy Epilepsy in the neonate or infant should raise suspicion for an inborn error of metabolism in a number of circumstances, including medically refractory epilepsy, myo-

clonic seizures/myoclonus, concurrent nonneurologic manifestations (see Table 36-4), microcephaly, and epileptic encephalopathies, including early myoclonic encephalopathy (Chapter 76). Seizures beginning in the first weeks of life that do not respond to standard anticonvulsant treatment should always prompt early evaluation for treatable metabolic epilepsies, including vitamin and cofactor responsive epilepsies and small molecule disorders (see Table 36-5). Pyridoxine and pyridoxal-5-phosphate responsive epilepsies may be associated with irritability, grimacing, and abnormal eye movements, a useful clinical clue at the bedside. The neonate with medically refractory epilepsy should be trialed on pyridoxine, pyridoxal-5-phosphate, folinic acid, and biotin pending metabolic test results. Myoclonus with profound hypotonia, respiratory failure, and persistent hiccups beginning hours to days after birth suggests glycine encephalopathy. This diagnosis is further supported by burst suppression on EEG, and neuroimaging demonstrating agenesis of corpus callosum and diffusion restriction of the actively myelinating structures. MR spectroscopy may demonstrate a glycine peak at 3.55 ppm. CSF and often plasma glycine are elevated with a CSF to plasma ratio greater than 0.08 in the classic form. Microcephaly is a useful clinical clue when evaluating the neonate or infant with severe epilepsy for an IEM. Congenital microcephaly is a feature of amino acid synthesis disorders, including serine, asparagine, and glutamine synthetase deficiencies. Postnatal microcephaly is common in severe methylene-tetrahydrofolate reductase (MTHFR) deficiency, glucose transporter 1 deficiency, sulfite oxidase deficiency, molybdenum cofactor deficiency, and Menkes syndrome. In some circumstances, the electroclinical epilepsy syndrome can suggest specific inborn errors of metabolism.

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As previously mentioned, early myoclonic encephalopathy should prompt evaluation for glycine encephalopathy but has also been described in sulfite oxidase deficiency/molybdenum cofactor deficiency, organic acidemias, pyridoxine/pyridoxal5-phosphate dependent epilepsies, Zellweger syndrome, and adenylosuccinate lyase deficiency. Atypical absence epilepsy has been described in glucose transporter 1 deficiency and serine synthesis disorders. Myoclonic-astatic epilepsy has been reported with glucose transporter 1 deficiency and defects in the presynaptic GABA transporter SLC6A1. Malignant migratory focal epilepsy of infancy has been reported in association with defects in the phospholipase C-beta 1 enzyme. Specific EEG patterns have been described in some IEMs, including a theta frequency waveform resembling mu waves in the central head regions termed “comb waves” in the neonate with maple syrup urine disease and rhythmic high amplitude delta waves with superimposed spikes and polyspikes (RHADS) in the posterior head region in the mitochondrial disorder Alpers syndrome. Progressive attenuation of the EEG has been reported in the infantile form of neuronal ceroid lipofuscinosis, and a photoparoxysmal response at slow flash frequencies is characteristic of the late infantile form. Any relation of seizures to meals should be determined; fasting induced (normoglycemic) seizures can be seen in glucose transporter 1 deficiency. Postprandial exacerbation of seizures can be seen in disorders of pyruvate metabolism and hyperammonemic disorders. An atypical response to specific anticonvulsants should also be noted. Phenobarbital may exacerbate seizures in glucose transporter 1 deficiency, and valproic acid can worsen seizures in glycine encephalopathy and urea cycle disorders. Valproic acid can also induce liver failure in POLG1 associated mitochondrial disorders.

Abnormal Development Associated With Congenital Anomalies and/or Dysmorphic Physical Features The presence of congenital anomalies or dysmorphic physical features in the neonate or infant with abnormal development should alert the clinician to a possible underlying genetic disorder. In addition to chromosomal disorders and monogenic nonmetabolic genetic syndromes, the pediatric neurologist should maintain a high index of suspicion for inborn errors of metabolism—particularly large molecule disorders— because a number of these disorders have specific treatments (Chapter 41). Static developmental delay associated with congenital microcephaly, craniofacial dysmorphism (ptosis, short and upturned nose, cleft palate), 2 to 3 toe syndactyly, genito­ urinary and cardiac malformations, and midline brain anomalies, including dysgenesis of corpus callosum and holoprosencephaly are features of Smith-Lemli-Opitz Syndrome (SLOS), a disorder of cholesterol biogenesis. Serum cholesterol levels are often low, but specific measurement of the cholesterol precursor 7-dehydrocholesterol is necessary for biochemical diagnosis. Additional disorders of cholesterol biosynthesis are also associated with developmental delay and may have associated ichthyosis and skeletal abnormalities (Jira, 2013). Developmental delay and regression associated with craniofacial dysmorphism (high forehead, epicanthal folds, hypoplastic supraorbital ridges), large anterior fontanelle, redundant neck skin, cystic kidneys and liver, proximal limb shortening, and brain malformations, including polymicrogyria, are features of the peroxisomal biogenesis disorders, of which Zellweger syndrome is prototypical. Affected children

typically have significant central hypotonia that can mimic a neuromuscular disorder. Epilepsy is also common. There may be accompanying retinopathy and sensorineural hearing loss. In addition to structural brain anomalies, there is progressive white matter injury in the CNS. The biochemical evaluation for a peroxisomal biogenesis disorder includes measurement of plasma very long chain fatty acids for elevated fractions of C26:C22 and C24:C22 fatty acids. In addition, there may be decreased levels of RBC plasmalogens, elevated plasma pipecolic acid, abnormal bile acid intermediates in urine and blood, and elevated plasma phytanic and pristanic acid (NB: phytanic acid is derived entirely from the diet and is not a reliable marker in the neonate) (Chapter 43) (Klouwer et al., 2015). Moderate to severe developmental delay associated with nonspecific facial dysmorphism, abnormal fat pads, and cerebellar hypoplasia is characteristic of the congenital disorders of glycosylation, particularly the most common type 1a. Affected children are hypotonic, which is typically central in etiology although there may be superimposed neuropathy. There are often associated clotting abnormalities. This group of disorders can be screened for by evaluating the pattern of glycosylated transferrin and measuring urinary oligosaccharides and free glycans (Chapter 40) (Freeze et al., 2012). Multiple congenital anomalies, including anorectal malformations and shortening of distal phalanges, can be seen in disorders of glycophosphatidylinositol (GPI) anchor biosynthesis, often in association with abnormal alkaline phosphatase levels (high or low) and epilepsy. Seizures may be responsive to supplementation with pyridoxine. This group of disorders can be screened for by evaluating GPI-linked epitopes on granulocytes using flow cystometry. Progressive developmental regression associated with coarsening of the facial features, skeletal anomalies, corneal opacity or cataracts, hernias, and hepatosplenomegaly are features of many lysosomal storage disorders, including the mucopolysaccharidoses, oligosaccharidoses, and mucolipidoses (Chapter 41). Neuroimaging may demonstrate prominent perivascular spaces with surrounding white matter gliosis; over time, this pattern may become more confluent resembling a leukodystrophy. A skeletal survey may show characteristic features of dysostosis multiplex, including j-shaped sella turcica, beaking of vertebral bodies, and abnormally shaped acetabulum and phalanges. Screening for a lysosomal storage disorder begins with measurement of urine mucopolysacharides to evaluate for mucopolysaccharidoses and urine oligosaccharides to evaluate for oligosaccharidoses. Salla disease/infantile sialic acid storage disease is evaluated by measuring urinary free sialic acid. If a specific disorder is suspected, enzyme activity can be measured blood or fibroblasts (Pastores and Maegawa, 2013). Developmental regression beginning at several months of age associated with lax-appearing skin, fair complexion, sparse and wiry hair, and progressive microcephaly should suggest Menkes syndrome. There may be associated vascular tortuosity and bladder diverticulae. Epilepsy and autonomic dysfunction are common. There may be subdural collections mimicking nonaccidental injury. Serum copper and ceruloplasmin are low, as is urinary excretion of copper (NB: serum copper and ceruloplasmin are often low in the first month of life in healthy children). There is an elevated HVA to VMA ratio in urine due to secondary dysfunction of the copper dependent enzyme dopamine beta hydroxylase (Chapter 46) (Bandmann et al., 2015). Less often, small molecule disorders and disorders of energy metabolism are associated with malformations and dysmorphic features. Untreated maternal phenylketonuria is associated with congenital microcephaly and heart defects in



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the neonate. The congenital form of glutaric acidemia type II is associated with polymicrogyria, renal cysts, anterior abdominal wall defects, and rocker bottom feet. Multicystic dysplastic kidney and neuronal migration abnormalities can also be seen in the congenital form of carnitine palmitoyltransferase 2 (CPT2) deficiency, a disorder of carnitine metabolism. As previously mentioned, glycine encephalopathy is associated with dysgenesis of the corpus callosum. Glutamine synthetase deficiency is associated with complex brain malformations, enteropathy, and necrolytic skin lesions. The most severe presentation of serine synthesis disorders, termed “Neu Laxova syndrome,” is associated with multiple congenital anomalies and early lethality. Pyruvate dehydrogenase deficiency is associated with dysgenesis of corpus callosum and large periventricular cysts; individuals may also have facial features reminiscent of fetal alcohol syndrome. Finally, mitochondrial disorders may be associated with brain malformations.

mitochondrial disorders, which may present with asymmetric stroke-like involvement (e.g., MELAS syndrome). In addition, disorders of neurotransmitter metabolism may present with focal dystonia. Specific behavioral abnormalities may provide a useful clue to the underlying diagnosis. Autistic behavior can be seen in disorders of creatine metabolism, untreated PKU, cerebral folate deficiency, succinic semialdehyde dehydrogenase deficiency, and purine/pyrimidine disorders, including adenylosuccinate lyase deficiency. Autistic features associated with aggressive and hyperactive behavior are seen in Sanfilippo syndrome (MPSIII), a mucopolysacharidosis that is associated with more subtle extraneurologic features. Children with Sanfilippo syndrome may also demonstrate a lack of fear (Kluver-Bucy syndrome). Prominent self-mutilation is a feature of Lesch-Nyhan syndrome, a disorder of purine metabolism.

Abnormal Development in the Absence of Congenital Anomalies or Dysmorphic   Physical Features

Nonspecific failure to thrive is a feature of many small molecule disorders and disorders of energy metabolism. A formal ophthalmology evaluation is an important component in the diagnostic evaluation of the infant with neuroregression. Many of the neuronopathic lysosomal disorders have telltale ophthalmologic stigmata including cherry red macular spot, corneal opacities, and supranuclear gaze palsy. Mitochondrial disorders may be associated with retinopathy, ptosis, ophthalmoparesis, and, rarely, cataracts. Peroxisomal disorders may also be associated with retinopathy and cataracts. The skin and hair may be affected in IEMs presenting with developmental regression. Menkes disease was mentioned in the previous section. Sparse and fragile hair, the result of trichorrhexis nodosa, is seen in the urea cycle disorder arginosuccinate synthetase deficiency. Skin rash and alopecia are features of biotinidase deficiency and holocarboxylase synthetase deficiency. Eczema is a feature of untreated phenylketonuria. Developmental regression with hepatosplenomegaly in a nondysmorphic infant should raise the possibility of a neuronopathic lysosomal storage disorder, particularly NiemannPick and Gaucher disease.

IEMs account for up to 1% to 5% of children with static developmental delay, making IEMs an uncommon cause relative to chromosome disorders and fragile X syndrome. It is even more uncommon for IEMs to cause static developmental delay without additional neurologic or extraneurologic signs or symptoms. Untreated phenylketonuria is an example of an IEM that can rarely present with essentially isolated developmental delay. In contrast, IEMs are a relatively common cause of developmental regression in childhood and must always be evaluated for in these circumstances. IEMs presenting with progressive developmental regression include disorders of energy metabolism, the chronic presentation of small molecule disorders, some large molecule disorders in the lysosomal and peroxisomal categories, and additional disorders in the miscellaneous category.

Associated Neurologic Symptoms Epilepsy is a common accompanying feature in IEMs and was covered in the previous section (Chapter 76). The motor pathways are also frequently affected in IEMs and manifest with abnormalities of tone, ataxia, and/or extrapyramidal symptoms. Spasticity is a relatively nonspecific sign but can be prominent in metabolic leukodystrophies such as Krabbe disease, Canavan disease, and metachromatic leukodystrophy. Spastic diplegia mimicking cerebral palsy is also a notable feature of arginase deficiency and hyperammonemia, hyperornithemia, and homocitrulluria (HHH) syndrome. Prominent extrapyramidal symptoms, including dystonia, chorea, and parkinsonism, may be seen in the primary disorders of biogenic amine (neurotransmitter) metabolism and transport. Additional useful clinical clues include diurnal fluctuation, oculogyric crises, and dysautonomia. Extrapyramidal symptoms may also be seen in the purine and pyrimidine disorders, mitochondrial disorders, disorders of creatine metabolism, cerebral folate deficiency, glucose transporter 1 deficiency, and in organic acidemias after metabolic basal ganglia injury (Chapter 93). An exaggerated startle may be seen in GM2 gangliosidosis, hyperekplexia disorders, sulfite oxidase deficiency, and asparagine synthetase deficiency. The motor findings in IEMs are almost always bilaterally symmetric because metabolic CNS insults affect specific tracts and pathways symmetrically. An exception to this rule is

Associated Nonneurologic Symptoms (Table 36-4)

Neuroimaging When evaluating an infant for a neurodegenerative metabolic disorder, neuroimaging is often useful to narrow the differential diagnosis. If possible, the clinician should attempt to distinguish between primary white matter disorders (leukodystrophies) and gray matter disorders. Progressive demyelination is seen in Krabbe leukodystrophy, metachromatic leukodystrophy, multiple sulfatase deficiency, peroxisomal disorders, cerebral organic acidurias (Canavan disease, L2 hydroxyglutaric aciduria), and mitochondrial disorders, particularly involving complex 1 of the respiratory chain. Hypomyelination, or permanently deficient myelination, is a feature of Salla disease/infantile sialic acid storage disease, fucosidosis, and cerebral folate deficiency (Chapter 99) (Schiffmann and van der Knaap, 2009). Early cerebral cortical atrophy may be seen in GM1 and GM2 gangliosidosis, neuronal ceroid lipofuscinoses, mitochondrial disorders, and disorders of amino acid biosynthesis, including serine and asparagine synthetase deficiencies. The clinician should be aware that early cerebral atrophy may be associated with secondary dysmyelination. Significant cere­ bellar atrophy in an infant can be seen in mitochondrial disorders, disorders of coenzyme Q10 biosynthesis, neuronal ceroid lipofuscinoses, congenital disorders of glycosylation,

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adenylosuccinate lyase deficiency, and infantile neuroaxonal dystrophy; associated T2 hyperintensity of the cerebellar cortex consistent with gliosis is a feature of infantile neuroaxonal dystrophy, congenital disorders of glycosylation, and mitochondrial disorders. Abnormalities of the deep gray nuclei may be a useful clue to the underlying diagnosis. Many lysosomal disorders are associated with T2 hypointensity of the thalamus (dark thalamus sign). Symmetric basal ganglia T2 hyperintensity may suggest a mitochondrial disorder, disorder of pyruvate metabolism, biotin-thiamine responsive basal ganglia disease, or an organic acidemia. MR spectroscopy demonstrates an increased NAA peak in Canavan disease. A decreased or absent creatine peak suggests one of the creatine deficiency syndromes, including X-linked creatine transporter deficiency, guanidinoacetate methyltransferase deficiency, and arginine-glycine amidinotransferase deficiency.

Neuromuscular Weakness In the course of evaluating the neonate or infant with peripheral hypotonia and weakness, a number of inborn errors of metabolism should be considered (Chapter 150). As always, appropriate localization within the neuraxis is a prerequisite step. The infantile form of Pompe disease presents in the first months of life with progressive skeletal myopathy with hyperCKemia, hypertrophic cardiomyopathy, and feeding and respiratory difficulties. Macroglossia is a useful clinical clue. ECG demonstrates very short PR intervals with giant QRS complexes. Biochemical diagnosis is made through enzyme assay of alpha glucosidase. Treatment is available with enzyme replacement therapy. Barth syndrome, an X-linked recessive disorder of phospholipid metabolism, is associated with infantile-onset skeletal myopathy, dilated cardiomyopathy that may be associated with endocardial fibroelastosis or left ventricular noncompaction, failure to thrive, and neutropenia. Urine levels of 3-methylglutaconic acid are elevated. Skeletal myopathy is a common presentation of mitochondrial disorders. Involvement of the CNS, cardiomyopathy, hepatic or renal dysfunction, retinopathy, or sensorineural hearing loss are common accompanying features. Laboratory studies may demonstrate elevations of serum lactate and alanine. Muscle biopsy rarely shows ragged red fibers in infants. Electron microscopy may demonstrate dysmorphic mitochondria. Studies of mitochondrial complex enzyme activity, typically normalized to levels of citrate synthase activity, may be decreased. These abnormalities are not specific, and it is important for the clinician to be cognizant of the possibility that these abnormalities represent secondary mitochondrial dysfunction due to a different underlying disease process. Skeletal myopathy with elevated CPK may be seen in disorders of long chain fatty acid oxidation and carnitine metabolism; however, these abnormalities are often intermittent and provoked by fasting or intercurrent illness. In the neonate or infant, skeletal muscle involvement is often overshadowed by recurrent hypoglycemia, cardiomyopathy, and hepatopathy. Fatty acid oxidation and carnitine disorders causing rhabdomyolysis will be further described in a subsequent section. Neuropathy developing in the first 2 years of life has been described in mitochondrial disorders, congenital disorders of glycosylation, neonatal adrenoleukodystrophy, disorders of cobalamin metabolism, infantile neuroaxonal dystrophy, Arts syndrome, serine deficiency syndromes, and riboflavin

transporter disorders. A demyelinating neuropathy often ac­­ companies Krabbe and metachromatic leukodystrophies. Lysosomal storage disorders may present with compressive mononeuropathies. Abnormal neuromuscular transmission has been described in DPAGT1 (dolichyl-phosphate Nacetylglucosamine phosphotransferase) deficiency, a congenital disorder of glycosylation.

CLINICAL PRESENTATION OF IEMS IN CHILDHOOD (GREATER THAN 2 YEARS   OF AGE) AND ADOLESCENCE Ataxia Whereas cerebellar pathway dysfunction can occur in infancy, frank ataxia is more noticeable in the older child who is ambulatory and relies on a high degree of dexterity for activities of daily living. IEMs presenting with ataxia as a predominant feature can be divided into three groups: disorders associated with insidiously progressive ataxia; disorders associated with episodic ataxia; and ataxic disorders associ­ ated with myoclonus and epilepsy (progressive myoclonus epilepsies). IEMs manifesting in childhood or adolescence with chronically progressive ataxia as the presenting feature include ataxia with vitamin E deficiency, abetalipoproteinemia, Refsum dis­ ease, cerebrotendinous xanthomatosis, the subacute and chronic forms of GM2 gangliosidosis, Niemann-Pick disease type C, mitochondrial disorders, PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract) syndrome, and disorders of coenzyme Q10 biosynthesis (Lyon et al., 2006). Many of these disorders are also associated with peripheral neuropathy and ophthalmologic signs. Episodic ataxia has been reported in a number of small molecule disorders and disorders of energy metabolism, including maple syrup urine disease (intermittent form), urea cycle disorders, Hartnup disease, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, biotinidase deficiency, and mitochondrial disorders. Episodes are often provoked by bioenergetic stressors such as infectious illness or by increased protein intake in MSUD and urea cycle disorders. These disorders must be distinguished from episodic ataxia resulting from genetic channelopathies. The combination of progressive ataxia, myoclonus, epilepsy, and cognitive regression are features of the progressive myoclonus epilepsies. This category includes a number of lysosomal disorders such as the neuronal ceroid lipofuscinoses (NCLs), sialidosis, and a subtype of Gaucher disease type 3; mitochondrial disorders, including myoclonic epilepsy with ragged red fibers (MERRF) syndrome; and Lafora disease. Many of these disorders are associated with vision disturbance, either from retinal disease (NCLs, sialidosis, mitochondrial disease) or occipital seizures in Lafora disease. Progressive myoclonus epilepsy can also be caused by a number of nonmetabolic genetic defects.

Dystonia Dystonia beginning in childhood or adolescence as a presenting symptom is a feature of a number of IEMs (Chapter 93). Glutaric acidemia type 1 can present with acute metabolic striatal stroke in the first 5 years of life in a previously developmentally normal child, resulting in severe generalized dystonia. Acute basal ganglia injury associated with extrapyramidal signs can also be seen in mitochondrial Leigh syndrome and biotin-thiamine responsive basal ganglia disease. The latter



disorder has an excellent response to the combination of thiamine and high dose biotin. Exercise-induced paroxysmal dystonia is a feature of glucose transporter 1 deficiency. Intermittent dystonia can also be seen in pyruvate dehydrogenase deficiency. Focal dystonia with diurnal variation is a feature of Segawa disease due to dysfunction in one of two enzymes involved in dopamine biosynthesis, GTP cyclohydrolase, or tyrosine hydroxylase. This dystonia has an excellent and sustained response to low dose L-dopa. Gradually progressive generalized dystonia is a prominent feature of late onset GM1 gangliosidosis. MR brain imaging in this disorder may demonstrate T2 hypointensity of globi pallidi. There may be subtle extraneurologic features, including skeletal anomalies and short stature. There are a growing number of IEMs associated with progressive brain mineralization and extrapyramidal signs. The classic brain mineralizing disorder is Wilson disease, in which copper accumulates in the liver and brain. Pediatric Wilson disease is usually associated with hepatic disease, but pure neurologic presentations are possible. Dystonia may be accompanied by prominent bulbar dysfunction, parkinsonism, ataxia, psychiatric symptoms, and cognitive regression. Ophthalmologic evaluation demonstrates pathognomonic Kayser-Fleischer rings, copper deposits in Descemet’s membrane of the cornea, in 90% of patients with CNS disease. Neuroimaging is characteristic and demonstrates T1 hyperintensity of globus pallidus, T2 hyperintensity thalami and striatum, white matter hyperintensities, and a characteristic pattern of involvement in the midbrain and pons. Serum ceruloplasmin and total copper are decreased, and 24-hour urine copper is increased. Another category of neurodegenerative disorders with brain mineralization is the disorders of brain iron accumulation (NBIA). The prototypical disorder in this category is pantothenate kinase associated neurodegeneration that in its classic form presents in the first decade with chronically progressive generalized dystonia, pyramidal signs, and retinal degeneration. Neuroimaging demonstrates mineralization of globus pallidus, most evident on susceptibility weighted sequences, with a central region of T2 hyperintensity creating the appearance of an “eye of the tiger.” Additional disorders in this category presenting in childhood include: mito­chondrial membrane protein-associated neurodegeneration (MPAN); PLAG2-related neurodegeneration (PLAN); Beta-propeller protein-associated neurodegeneration (BPAN); fatty acid hydroxylase-associated neurodegeneration; Kufor-Rakeb syndrome; Woodhouse-Sakati syndrome; and COASY proteinassociated neurodegeneration. Each of these disorders is linically distinct and has a specific neuroimaging pattern. Diagnosis is made through molecular studies; multigene panels are available. In recent years, the first genetic disorder of brain manganese deposition was described due to mutations in the SLC30A10 gene. This disorder presents in childhood with progressive dystonia associated with polycythemia and liver disease. Neuroimaging demonstrates T1 hyperintensity of the globus pallidus. Blood manganese is markedly elevated. This disorder may be amenable to treatment with chelation therapy and iron supplementation.

Recurrent Rhabdomyolysis Recurrent rhabdomyolysis should prompt evaluation for a metabolic myopathy or channelopathy (Chapters 49 and 150). IEMs associated with rhabdomyolysis include disorders of long chain fatty acid oxidation and carnitine metabolism

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(e.g., CPT2 deficiency), muscle glycogenoses, lipin-1 deficiency, mitochondrial disorders, and myoadenylate deaminase deficiency. Some of these disorders can be associated with a progressive chronic myopathy between episodes of rhabdomyolysis. The precipitants for rhabdomyolysis are important in establishing the differential diagnosis. Muscle breakdown in the long chain fatty acid oxidation and carnitine disorders may be precipitated by prolonged moderate intensity exercise, illness, or prolonged fasting (typically longer than 12 hours). Symptoms provoked by exercise typically begin hours after the exercise. Associated symptoms include liver dysfunction, cardiomyopathy, cardiac arrhythmia, and hypoketotic hypoglycemia. Carnitine palmitoyltransferase 2 deficiency is the most common of these lipid disorders to present in childhood or adolescence with isolated exercise-induced rhabdomyolysis (Berardo et al., 2010). Muscle glycogenoses presenting with recurrent rhabdo­ myolysis include myophosphorylase deficiency (McArdle disease), phosphofructokinase deficiency, adolase A deficiency, lactate dehydrogenase deficiency, phosphoglycerate kinase deficiency, and phosphoglycerate mutase deficiency. Muscle fatigue, weakness, and rhabdomyolysis in these disorders are typically provoked by anaerobic activity, in particular isometric muscle contraction. Symptoms often begin during exercise with muscle stiffness and painful cramps. In myophosphorylase deficiency, muscle symptoms may improve after 10 minutes of aerobic activity (“second wind” phenomenon) due to increased utilization of blood-borne glucose and free fatty acids. Phosphofructokinase deficiency, phosphoglycerate kinase deficiency, and aldolase A deficiency are associated with hemolytic anemia, which may be well compensated. Myophosphorylase deficiency is the most common of the muscle glycogenoses and typically presents in the first decade of life. Lipin-1 deficiency, a disorder of phospholipid metabolism, presents in childhood with severe episodes of rhabdomyolysis provoked by febrile infectious illness. Myoadenylate deaminase deficiency is a disorder of the purine-nucleotide cycle, an important pathway in muscle for replenishing the citric acid cycle during exercise. Some individuals present with recurrent exercise induced rhabdomyolysis, whereas others remain asymptomatic, which has raised the question of whether this enzyme deficiency alone is sufficient to cause disease.

Vascular Stroke Classic homocystinuria due to cystathionine beta-synthase deficiency can present in childhood or adolescence with arterial ischemic or venous infarction. Associated features include developmental delay, marfanoid habitus, high myopia, lens dislocation, and osteopenia. Complexion is often pale, and there may be malar flushing or livedo reticularis. Diagnosis is confirmed by the finding of elevated serum total homocysteine. Fabry disease is an X-linked, semidominant lysosomal disorder with multisystem involvement. Males may present with arterial ischemic stroke in adolescence or early adulthood from large vessel vasculopathy; the posterior circulation is preferentially affected. Over time, affected individuals develop progressive white matter disease from small vessel angiopathy. A classic neuroimaging finding is a T1-weighted bright pulvinar of the thalamus. Associated features in childhood include gastrointestinal symptoms, painful acroparasthesia, hypohidrosis, and skin lesions termed “angiokeratomas.” Cardiomyopathy and renal disease may develop in adulthood. Diagnosis

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in males is accomplished by measuring alpha-galactosidase enzyme activity in nucleated cells; females require molecular testing because enzyme results overlap with the normal range.

Cognitive and Motor Regression Gradually progressive loss of cognitive faculties as the predominant symptom in the older child or adolescent can be seen in a number of IEMs, including X-linked adrenoleukodystrophy, neuronopathic lysosomal disorders, mitochondrial disorders, and disorders of brain mineralization. All of these disorders are ultimately associated with additional neurologic findings, potentially including ataxia, spasticity, dystonia, and epilepsy with disease progression (Chapter 52). The childhood cerebral form of X-linked adrenoleukodystrophy typically presents between 4 to 8 years of age with cognitive decline, behavior change, and auditory verbal agnosia. With disease progression, children develop vision loss, spasticity, ataxia and occasionally epilepsy. MR imaging typically demonstrates characteristic white matter abnormalities of periventricular white matter with a posterior predominance associated with a rim of contrast enhancement. Imaging abnormalities typically precede the onset of symptoms. Most boys have associated adrenal insufficiency at the onset of neuroregression. The diagnosis is established by demonstrating elevated levels of plasma very long chain fatty acids (Chapter 99). The subacute form of GM2 gangliosidosis classically presents between 2 to 10 years with progressive cognitive impairment, spasticity, ataxia, seizures, retinopathy and optic atrophy. A cherry red macular spot is usually absent. The chronic form of GM2 gangliosidosis presents in the first decade with cognitive and motor regression, psychosis, motor neuron disease, and cerebellar atrophy. The diagnosis is made by finding reduced enzyme activity of hexosaminidase A in nucleated cells. Niemann-Pick Type C classically presents in middle to late childhood with cognitive regression, ataxia, and vertical supranuclear gaze palsy. Children may also develop dystonia and epilepsy. There may be hepatosplenomegaly. A history of gelastic cataplexy is another useful diagnostic clue. Biochemical diagnosis can be made with filipin staining and cholesterol esterification studies of cultured skin fibroblasts. Plasma oxysterols can be used as a screening test.

Psychiatric Symptoms A number of IEMs can present in childhood or adolescence with psychiatric symptoms as the predominant manifestation. In these circumstances, more common etiologies should first be considered, including drug ingestion, primary psychiatric disease, and inflammatory brain disorders. Cobalamin C deficiency, a disorder in the metabolism of vitamin B12, can rarely present after a normal early childhood with subacute psychiatric symptoms, often associated with signs of subacute combined degeneration of the spinal cord. Decompensation can be provoked by exposure to nitrous oxide, an inhibitor of the enzyme methionine synthase. The diagnosis is confirmed by elevated serum total homocysteine and plasma or urine methylmalonic acid in the presence of normal plasma vitamin B12 levels. Milder forms of the urea cycle disorders often associated with some residual enzyme activity can present with episodic psychiatric symptoms. These episodes may be variably associated with alteration of consciousness, headache, emesis, and ataxia. Episodes may be provoked by illness, high protein intake, and some medications such as valproic acid.

Acute intermittent porphyria, a disorder of heme biosynthesis, rarely presents in the pediatric age group with the exception of the very rare, autosomal recessive 5-aminolevulinate (ALA) dehydratase deficiency. The classic presentation of acute intermittent porphyria includes acute episodes of psychosis, peripheral neuropathy, autonomic dysfunction, abdominal pain, and hyponatremia from SIADH. Episodes may be provoked by medications and hormonal factors, including menses. Diagnosis is confirmed by elevated levels of urine ALA, coproporphyrin, and RBC zinc protoporphyrin. Secondary inhibition of ALA dehydratase can also be seen in tyrosinemia type 1 due to accumulating succinylacetone. As mentioned in the previous sections, Niemann-Pick Type C, the chronic form of GM2 gangliosidosis, and Wilson disease can occasionally present initially with isolated psychiatric symptoms. With progression of disease, cognitive regression and additional focal neurologic signs become apparent.

CONCLUSIONS Although individually rare, inborn errors of metabolism collectively are not uncommon in the practice of child neurology. Given its high energetic demand, the nervous system is especially vulnerable and is often the sole presenting system of these disorders that may have protean manifestations. Laboratory diagnosis can be made by testing of metabolites, enzymatic function, or single gene or next generation gene sequencing panels. The IEMs can be conceptualized as disorders of small molecules, large molecules, and bioenergetics. Age of onset and severity tend to be related to degree of enzyme insufficiency. Many of the disorders, especially of small molecule and cerebral energy metabolism, present in early life with acute or subacute encephalopathy. Seizures in the first weeks of life that do not respond to standard anticonvulsant treatment should prompt early evaluation for treatable metabolic epilepsies including vitamin and cofactor responsive epilepsies and small molecule disorders. The presence of dysmorphism may suggest a metabolic disorder, especially large molecule disorder, which may have a specific treatment as well. IEMs are an uncommon cause of static developmental delay, compared with chromosome disorders and Fragile X, but a relatively common cause of developmental regression. IEMs in the older child and adolescent may present with ataxia, dystonia, rhabdomyolysis, stroke, cognitive or motor regression, or psychiatric symptoms. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bandmann, O., Weiss, K.H., Kaler, S.G., 2015. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 14 (1), 103–113. Berardo, A., DiMauro, S., Hirano, M., 2010. A diagnostic algorithm for metabolic myopathies. Curr. Neurol. Neurosci. Rep. 10 (2), 118–126. Freeze, H.H., Eklund, E.A., Ng, B.G., et al., 2012. Neurology of inherited glycosylation disorders. Lancet Neurol. 11 (5), 453– 466. Jira, P., 2013. Cholesterol metabolism deficiency. Handb. Clin. Neurol. 113, 1845–1850. Klouwer, F.C., Berendse, K., Ferdinandusse, S., et al., 2015. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J. Rare Dis. 10, 151. Lyon, G., Kolodny, E.H., Pastores, G.M. (Eds.), 2006. Neurology of Hereditary Metabolic Disease of Children, third ed. McGraw Hill, U.S.United States, pp. 417–420.

Pastores, G.M., Maegawa, G.H.B., 2013. Neuropathic lysosomal storage disorders. Neurol. Clin. 31 (4), 1051–1071. Saudubray, J.M., van den Berghe, G., Walter, J.H. (Eds.), 2012. Inborn Metabolic Diseases: Diagnosis and Treatment, vol. 28, fifth ed. Springer Medizin Verlag, Heidelberg, p. 656. Schiffmann, R., van der Knaap, M., 2009. Invited article: an MRI based approach to the diagnosis of white matter disorders. Neurology 72, 750. Van der Knaap, M.S., Valk, J. (Eds.), 2005. Magnetic Resonance of Myelination and Myelin Disorders, third ed. Springer-Verlag Berlin, Heidelberg, Germany.

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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Table 36-3 IEMs in the miscellaneous category. Table 36-4 Nonneurologic features of IEMs. Table 36-5 Metabolic evaluation of the neonate or infant with suspected metabolic epilepsy.

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Aminoacidemias and Organic Acidemias Renata C. Gallagher, Gregory M. Enns, Tina M. Cowan, Bryce Mendelsohn, and Seymour Packman

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Approximately 4% of individuals born in the United States have a genetic or partly genetic disorder. Inborn errors of metabolism contribute significantly to this total. Although each disease is individually rare, the aggregate incidence of metabolic disease is relatively high and may be greater than 1 in 1000 newborns. Newborn screening programs using tandem mass spectrometry, which can detect approximately 20 inborn errors of metabolism, typically have reported an incidence of 1 in 2000 to 1 in 4000. Because there are hundreds of known metabolic conditions, the aggregate estimate seems reasonable. Metabolic diseases infrequently produce symptoms immediately at birth, and they can manifest with slowly progressive encephalopathies. In this setting, histologic or biochemical abnormalities may be present in the fetal central nervous system (CNS) by 4 to 5 months’ gestation. Inborn errors of metabolism also can manifest with rapid clinical deterioration in the newborn period or after an interval period of good health. Presenting clinical features are often nonspecific, and they may be misdiagnosed as infection, cardiovascular compromise or other causes of hypoxemia, trauma, primary brain anomalies, or the effects of a toxin. Recognition of patterns of clinical presentation and rapid implementation of laboratory investigations are essential for the initiation of appropriate therapy without delay. If appropriate therapy is not initiated in a timely manner, there is a high risk of morbidity or mortality, regardless of the cause of the acute illness. This chapter provides an overview of the diagnosis and treatment of two categories of inborn errors: aminoacidopathies and organic acidemias. The general approaches described are broadly applicable to other heritable metabolic disorders, such as disorders of fatty acid oxidation, urea cycle disorders, and lactic acidosis syndromes. Descriptions of selected disorders of amino acid and organic acid metabolism are provided to illustrate and emphasize the approaches to diagnosis, treatment, and genetic counseling in this area of genetic medicine. In this print version of the chapter, we discuss phenylketonuria, followed by representative aminoacidopathies and organic acidemias likely to be encountered by the pediatric neurologist in an acute or critical clinical setting. For a comprehensive and detailed discussion of additional organic acidemias and aminoacidopathies and important general concepts in the diagnosis, treatment, and genetic counseling involved in heritable metabolic disorders, readers are referred to the online version of this chapter.

SIGNS AND SYMPTOMS: GENERAL CONCEPTS See the online version of the chapter.

PHYSICAL FINDINGS: GENERAL CONCEPTS See the online version of the chapter.

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LABORATORY APPROACHES TO DIAGNOSIS: GENERAL CONCEPTS See the online version of the chapter.

TREATMENT: GENERAL CONCEPTS See the online version of the chapter.

INHERITANCE AND GENETIC COUNSELING: GENERAL CONCEPTS See the online version of the chapter.

AMINOACIDEMIAS Phenylketonuria Phenylketonuria (PKU) is an autosomal-recessive disorder caused by deficient activity of phenylalanine hydroxylase (PAH), a hepatic enzyme that converts phenylalanine to tyrosine (Figure 37-1). The biochemical block results in the accumulation of phenylalanine, which is then converted to phenylpyruvic acid and phenyllactic acid, phenylketones that are excreted in the urine. A range of reduced PAH-specific activity correlates broadly with the severity of the phenotype. Tetrahydrobiopterin is a necessary cofactor in the PAH reaction, and elevated phenylalanine levels rarely may be caused by inherited disorders of tetrahydrobiopterin synthesis (see Figure 37-1). Mandatory population newborn screening for PKU, in combination with postnatal presymptomatic therapy, was begun in the 1960s. Phenylalanine is neurotoxic, and untreated or poorly treated patients with classic phenylketonuria typically have profound intellectual disability. Patients exposed to chronically elevated phenylalanine levels ultimately develop microcephaly, seizures (e.g., tonic-clonic, myoclonic, infantile spasms), tremors, athetosis, and spasticity, and they may be misdiagnosed as having cerebral palsy. Psychiatric and behavior problems, including autistic behavior and attention-deficit hyperactivity disorder, are common. Brain magnetic resonance imaging (MRI) may detect dysmyelination, especially T2 enhancement in the periventricular white matter, a finding that is potentially reversible with the initiation of dietary therapy. Elevated maternal blood phenylalanine levels can cross the placenta and cause fetal birth defects, including microcephaly, dysmorphic features, and congenital heart defects. Dietary control (phenylalanine levels < 360 µM) should ideally be achieved before 3 months before conception, and mothers with PKU should be monitored carefully by an experienced center throughout pregnancy. The presymptomatic institution of and continued adherence to specific dietary therapy prevents intellectual disability. However, children and adults with PKU may experience



Aminoacidemias and Organic Acidemias Phenylalanine

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Tyrosine

Phenylalanine hydroxylase

(1) 4–Hydroxytetrahydrobiopterin Carbinolamine dehydratase 7,8–Dihydrobiopterin (BH2) (2)

6–Pyruvoyltetrahydropterin 6–Pyruvoyltetrahydropterin (5) synthase

Tetrahydrobiopterin (BH4) (6) Sepiapterin reductase

Dihydroneopterin GTP cyclohydrolase

(4)

Dihydropteridine reductase

GTP

(3) NAD

NADH

Figure 37-1.  Regulation of phenylalanine hydroxylase activity. Phenylalanine is converted to tyrosine (1) by the holoenzyme phenylalanine hydroxylase (PAH). PAH requires tetrahydrobiopterin (BH4) as an active cofactor and is recycled by the sequential actions of carbinolamine dehydratase (2) and dihydropteridine reductase (3). BH4 is synthesized in vivo through a complex series of steps that involve guanosine triphosphate (GTP) cyclohydrolase (4), 6-pyruvoyltetrahydropterin synthase (5), and sepiapterin reductase (6). Genetic defects at any of these steps may be associated with hyperphenylalaninemia. (From Wilcox WR, Cederbaum SD. Amino acid metabolism. In: Rimoin D, Connor J, Pyeritz R, Korf B, eds. Principles and practice of medical genetics, 4th ed. Philadelphia: Churchill Livingstone, 2002:2406.)

cognitive symptoms, such as problems in executive functioning, and disturbance in emotional (e.g., depression, anxiety, phobias) and behavioral (e.g., hyperactivity) functioning despite early and continuous treatment. Selective restriction of phenylalanine intake by using phenylalanine-free medical formulas and foods (and tyrosine supplementation), which provides enough additional protein and nutrients to support normal growth, remains the mainstay of PKU therapy. Most clinics in the United States strive to maintain plasma phenylalanine levels between 120 and 360 µM in children younger than 12 years and between 120 and 600 µM in individuals older than 12 years, although there is some evidence to suggest that lowering upper phenylalanine targets even further improves neurocognitive function. An expert, coordinated team approach is clearly the most effective way of managing phenylketonuria; stricter management improves developmental outcome. In conjunction with dietary therapy, oral administration of tetrahydrobiopterin, the naturally occurring cofactor for the PAH reaction, may be used to control plasma phenylalanine levels. Response to tetrahydrobiopterin is especially robust in mild hyperphenylalaninemia but has also been documented in patients with classic or variant PKU. A trial of tetrahydrobiopterin may be offered to PKU patients of any severity to determine clinical response. Administration of dietary supplementation of large neutral amino acids (LNAAs) is a complementary approach to therapy. LNAAs compete with phenylalanine for transport across the blood–brain barrier by the L-type amino acid carrier and consequently decrease the level of phenylalanine in the central nervous system (CNS) and may increase brain neurotransmitter and essential amino acid concentrations. A novel therapeutic approach currently in clinical trials uses the nonmammalian enzyme phenylalanine ammonia lyase (PAL). This enzyme converts phenylalanine to

transcinnamic acid, a harmless compound, and it has been found to reduce hyperphenylalaninemia in PKU animal models and patients in clinical trials. Other novel therapies are under close investigation, especially given the findings of suboptimal outcomes in phenylketonuria patients who have been continuously treated from the neonatal period. (Enns et al., 2010)

Biopterin Disorders See the online version of the chapter.

Hepatorenal Tyrosinemia See the online version of the chapter.

Other Categories of Tyrosinemia See the online version of the chapter.

Maple Syrup Urine Disease In 1954, John Menkes and colleagues described four siblings who died in early infancy from a cerebral degenerative disease, with onset occurring when they were 3 to 5 days old. Symptoms included feeding difficulty, irregular respiratory pattern, hypertonia, opisthotonus, and failure to thrive. All had urine with the smell of maple syrup. Soon thereafter, another patient with a similar history was found to have elevated levels of branched-chain amino acids in urine and blood, and the syndrome was initially referred to as maple sugar urine disease. Maple syrup urine disease is caused by mitochondrial branched-chain α-ketoacid dehydrogenase complex deficiency. The enzymatic defect leads to accumulation of branched-chain amino acids and branched-chain α-ketoacids. Five forms of

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maple syrup urine disease (i.e., classic, intermediate, intermittent, thiamine-responsive, and dihydrolipoyl dehydrogenase [E3] deficiency) have been delineated based on clinical presentation, level of enzyme activity, and response to thiamine administration.

Clinical Manifestations Classic Maple Syrup Urine Disease.  In the classic form, the clinical phenotype is one of severe neonatal encephalopathy, unless presymptomatic therapy is initiated because of abnormal newborn screening, prenatal diagnosis, or positive family history. Untreated neonates typically develop symptoms by the end of the first week of life. Feeding difficulties, alternating hypertonia and hypotonia, opisthotonic posturing, abnormal movements (“fencing” or “bicycling”), and seizures commonly occur. The characteristic urine smell develops on day 5 to 7 of life. Unless an underlying inborn error of metabolism is suspected, affected children may be misdiagnosed as having sepsis and progress to coma and death. Ketosis is often found, and hypoglycemia may occur, but severe metabolic acidosis tends not to occur. Plasma amino acid analysis reveals elevated levels of branchedchain amino acids and the diagnostic presence of alloisoleucine in plasma. Urine organic acid analysis demonstrates excretion of branched-chain α-ketoacids. Hyponatremia and cerebral edema are frequent sequelae during acute metabolic decompensation. Other complications include pseudotumor cerebri, pancreatitis, and eye abnormalities. Ocular findings in untreated or late-diagnosed patients include optic atrophy, gray optic papilla, nystagmus, ophthalmoplegia, strabismus, and cortical blindness. Children who survive the initial metabolic crisis typically have significant neurodevelopmental delays and spasticity. Although motor, visual, and learning deficits may occur, rapid identification of affected infants and careful institution of appropriate therapy can result in normal development. Neuroimaging studies (Figure 37-3) are typically abnormal in patients with untreated classic maple syrup urine disease (MSUD) who are in crisis. Computed tomographic (CT) scans appear normal in the first few days of life, but they reveal progression to marked generalized cerebral edema if the patient remains untreated. An unusual pattern of edema may occur, characterized by involvement of the cerebellar deep white matter, posterior brainstem, cerebral peduncles, posterior limb of the internal capsule, and posterior aspect of the centrum semiovale. Edema tends to subside in the second month of life. Patients with classic maple syrup urine disease in metabolic crisis with associated hyponatremia demonstrate a prominently increased T2 signal on brain MRI in the brainstem reticular formation, dentate nucleus, red nucleus, globus pallidus, hypothalamus, septal nuclei, and amygdala. One report observed that brain MRI abnormalities were absent or only slight in sick patients with maple syrup urine disease in the absence of hyponatremia. Cranial ultrasonography of neonates in acute metabolic crisis reveals symmetrically increased echogenicity of the periventricular white matter, basal ganglia, and thalami. Chronic changes, including hypomyelination of the cerebral hemispheres, cerebellum, and basal ganglia and cerebral atrophy, may supervene in poorly controlled patients. CT- and MRI-defined abnormalities and the clinical phenotype may improve after implementation of appropriate dietary therapy. Diffusion-weighted imaging and spectroscopy have also documented abnormalities during the acute phase of disease. Markedly restricted proton diffusion, suggestive of cytotoxic or intramyelinic sheath edema, was demonstrated in the brainstem, basal ganglia, thalami, cerebellar and periventricular white matter, and cerebral cortex in six patients with maple syrup urine disease.

MR spectroscopy demonstrated abnormal elevations of branched-chain amino acids, branched-chain α-ketoacids, and lactate in the four patients. All of these changes were reversed after the institution of appropriate nutritional and antibiotic therapy to treat intercurrent illness. However, in a recent study of a cohort of classic MSUD adolescents and adults under dietary control, persistent signal changes were noted in the cerebral hemispheres, internal capsule, brainstem, and central cerebellum (Klee et al., 2013). The authors ascribed the signal alterations to dysmyelination and considered them consonant with clinical studies showing that learning disabilities and variable social, educational, and professional outcomes are present in teenagers and adults with MSUD. A characteristic comblike electroencephalogram (EEG) pattern may be demonstrated for some patients with classic MSUD between the second and third weeks of life. This unusual rhythm pattern resolves with the institution of dietary therapy. Intermediate Maple Syrup Urine Disease.  Children who have the intermediate form of MSUD do not present in the neonatal period, despite having persistently elevated plasma levels of branched-chain amino acids. Developmental delay and failure to thrive are common. Severe neurologic impairment is absent; episodes of metabolic decompensation may occur, although severe ketoacidosis episodes are variable. These children have a higher tolerance for dietary protein than those who have the classic form. Rarely, patients with intermediate-type MSUD respond to thiamine administration. Intermittent Maple Syrup Urine Disease.  Patients with intermittent MSUD typically come to medical attention when they are 5 months to 2 years old and after stress induced by infection or high protein intake; some have been detected as late as the fifth decade of life. The intermittent form of MSUD can be particularly difficult to diagnose because affected individuals have normal levels of branched-chain amino acids and no odor between episodes of metabolic decompensation. Episodic decompensation is characterized by ataxia, disorientation, and altered behavior, which may progress to seizures, coma, and even death unless therapy is instituted. Early development and intellect are usually normal. Thiamine-Responsive Maple Syrup Urine Disease.  The clinical course of patients with the thiamine-responsive variant of MSUD is similar to that of the intermediate form of the disease. Plasma levels of branched-chain amino acid and urine excretion of branched-chain α-ketoacids decline days to weeks after thiamine administration (10-1000 mg/day) is started. Patients are also treated with nutritional regimens similar to those used in other forms of MSUD. Developmental delay may be present, but normal intelligence has also been documented. Dihydrolipoyl Dehydrogenase–Deficient Maple Syrup Urine Disease.  The dihydrolipoyl dehydrogenase (E3)– deficient form of MSUD is characterized by ketoacidosis crises in infancy. There is also lactic acidemia because the E3 subunit of the branched-chain α-ketoacid dehydrogenase complex is also required for catalytic function of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. In addition to the typical MSUD metabolites, urine organic acid analysis reveals the presence of lactate, pyruvate, and α-ketoglutarate. The neonatal period is usually uneventful, but progressive neurologic deterioration, characterized by developmental delay, hypotonia or hypertonia, and dystonia, supervenes. Death in early childhood is common. Attempts at therapy had limited success in early reports. However, more recent case reports and studies have identified patients with a wide clinical spectrum, with survival to at least the third decade. In some such patients, and



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A

B

C Figure 37-3.  Maple syrup urine disease. A, Axial view, T2-weighted image shows edema in the internal capsules, lateral thalami, and globus pallidi. B, Axial view, calculated apparent diffusion coefficient image at the same level shows hypointensity, indicated by reduced water diffusion, in the affected areas. C, Proton MR spectroscopy (echo time of 26 msec) shows a large peak at 0.9 ppm, believed to represent resonances of methyl protons from branched-chain amino acids and branched-chain α-ketoacids that accumulate as a result of defective oxidative decarboxylation of leucine, isoleucine, and valine. (Courtesy of Dr. A James Barkovich, University of California, San Francisco, CA.)

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depending on the mutations, there is a positive clinical response to riboflavin, perhaps based on a chaperone-like effect of enzyme stabilization.

Laboratory Tests MSUD can be detected easily and accurately by tandem mass spectrometry analysis of the newborn blood spot. Plasma amino acid analysis demonstrates elevations of leucine, isoleucine, and valine (5- to 10-fold greater than normal) and the pathognomonic finding of elevated alloisoleucine. Levels of branched-chain amino acids are greatly elevated in urine and cerebrospinal fluid (CSF). The branched-chain α-ketoacids 2-oxoisocaproic acid, 2-oxo-3-methylvaleric acid, and 2oxoisovaleric acid, derived from the branched-chain amino acids leucine, isoleucine, and valine, respectively, are found to be elevated on urine organic acid analysis during metabolic crises. Branched-chain amino acids levels and excretion of branched-chain α-ketoacids may be normal between episodes of decompensation in the intermittent form of disease. The branched-chain α-ketoacid dehydrogenase complex consists of three catalytic components—a thiamine pyrophosphate-dependent carboxylase (E1) with an α2β2 structure, a transacylase (E2), and a dehydrogenase (E3)— and two regulatory enzymes (a kinase and a phosphatase). Deficient activity of this complex leads to the accumulation of leucine, isoleucine, and valine and their corresponding α-ketoacids. The decarboxylation activity can be measured in leukocytes, lymphoblasts, or fibroblasts, and it is loosely related to the clinical phenotype: 0% to 2% of normal activity in classic MSUD, 3% to 30% activity in intermediate, 5% to 20% in intermittent, 2% to 40% in thiamine-responsive, and 0% to 25% in E3 deficiency. Because significant overlap exists between measured enzyme activity and clinical phenotype, enzymatic activity cannot be used to predict the clinical course with certainty. In parallel findings on molecular analyses, identified mutations also cannot be correlated with phenotype.

Genetics MSUD is a pan-ethnic, autosomal-recessive condition that can be caused by mutations in any of the components of the mitochondrial branched-chain α-ketoacid dehydrogenase complex. In a study of 63 individuals, E1β subunit mutations were most common (38%), followed by E1α (33%), and E2 (19%) mutations. Branched-chain α-ketoacid dehydrogenase phosphatase or kinase mutations are also thought to cause MSUD. The overall incidence is approximately 1 case per 150,000 people in the general population, but MSUD is more common in Old Order Mennonites in southeastern Pennsylvania (1 in 176 births). A novel founder mutation in the E1β subunit has been reported in the Ashkenazi Jewish population.

that requires prompt intervention. Initial intervention is aimed at correcting dehydration, starting high-dose intravenous thiamine, and providing adequate calories (approximately 120-140 kcal/kg per day) to prevent further protein catabolism and higher rise in plasma leucine levels. To this end, high-dextrose intravenous fluids (to provide approximately 10 mg/kg per minute) and intralipid are often administered. Branched-chain amino acid–free parenteral nutrition or enteral formula, delivered by continuous nasogastric drip, can also be used. The rate of decrease of leucine is slowed in the face of valine and isoleucine levels inadequate to stimulate protein synthesis. Acute valine and isoleucine deficiency can be avoided by careful supplementation of these amino acids. Leucine is reintroduced to the diet after therapeutic levels are achieved. Hemodialysis and continuous venovenous extracorporeal removal therapies result in more rapid fall in plasma levels of branched-chain amino acids, and this modality is now established as an effective standard-of-care therapy for acute metabolic decompensation. Liver transplantation has been increasingly performed on large numbers of patients as an essential component of longterm therapy in classic MSUD, even in nonexigent (i.e., elective) clinical circumstances (Strauss et al., 2006). It has become apparent that as patients reach adolescence and adulthood, they show variable intellectual deficits, attention deficits, deficits in executive function, psychological symptoms (e.g., anxiety, depression), and poor social adjustment, even with a history of apparently excellent dietary control and an absence of a history of acute metabolic crises (Strauss et al., 2006). Following transplant, leucine levels either remaining normal or are in a treatment range on an unrestricted protein diet. Long-term clinical evaluations are proceeding, but neuropsychological and patient and family reporting appear to support improvement or stabilization of neurologic status. Three patients who underwent successful transplantation were able to resume normal diets and were no longer at risk for metabolic decompensation. In an important variation of the transplant protocol, domino hepatic transplantation for MSUD has been successfully performed. A novel treatment approach under investigation takes advantage of the observation that when used in the treatment of urea cycle disorders, Na phenylbutyrate causes a lowering of branched-chain amino acid levels (Burrage, Nagamani, Campeau, and Lee , 2014). Na phenylbutyrate was found to increase the activity of the branched-chain ketoacid dehydrogenase by preventing phosphorylation—and, thereby, inactivation—of the E1α subunit. The increased residual enzyme activity of the branched-chain ketoacid dehydrogenase would be expected to lower branched-chain amino acid levels. Studies are under way using Na phenylbutyrate in cohorts of MSUD patients (Burrage et al., 2014).

Treatment

Glycine Encephalopathy

Chronic care of the child with MSUD includes regular visits to an integrated metabolic clinic for medical and nutritional assessment. Adequate calories (100-120 kcal/kg per day) and protein (2-3 g/kg per day) are needed for growth. Chronic valine or isoleucine deficiency may cause an exfoliative dermatitis, and supplementation of these amino acids is often needed. Thiamine supplementation is administered to patients with thiamine-responsive forms of MSUD. Because patients on restricted diets are at risk for micronutrient and essential fatty acid deficiencies, patients should be periodically monitored for such deficits and supplementation given as needed. Acute metabolic decompensation (e.g., fasting or illness severe enough to cause catabolism) is a medical emergency

Glycine encephalopathy is an autosomal-recessive disorder caused by defective function of the glycine cleavage enzyme system, leading to accumulation of glycine in all body tissues, including the CNS (Figure 37-4). The glycine cleavage enzyme system has four components: glycine decarboxylase, also known as the P protein (it uses pyridoxal-phosphate as a cofactor); aminomethyltransferase, also known as T protein (it is a tetrahydrofolate dependent protein); the glycine cleavage system H protein (a hydrogen carrier protein); and the L protein or lipoamide dehydrogenase (the cofactor is lipoate). Infants with classic disease present in the first week of life with apnea, lethargy, severe hypotonia, and feeding difficulties. Respiratory failure, hiccups, and intractable seizures develop, and many infants die unless assisted ventilatory support is



Aminoacidemias and Organic Acidemias P

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Figure 37-4.  The glycine cleavage system. Circles designate proteins with the active group shown. In the presence of P and H proteins, glycine is decarboxylated, and the remaining aminoethyl group binds to the reduced lipoic acid on the H protein. T protein is required to release ammonia and transfer the x carbon of glycine to tetrahydrofolate (THF), forming 5,10-CH2-THF. The L protein is necessary to regenerate the correct form of the H protein. (From Scriver C, Beudet A, Sly W, Valle D, eds. The metabolic and molecular basis of inherited disease, 8th ed. New York: McGraw-Hill, 2001:2066, Fig, 90-2. Reprinted with permission from The McGraw-Hill Companies.)

provided. The EEG commonly has a burst suppression pattern, but hypsarrhythmia has rarely been reported. There are also later-onset forms, including presentation at greater than 4 months of age. A review of 124 patients stratified affected individuals into four categories. Those who could only smile were termed severe. Those who had achieved additional developmental milestones were termed attenuated. Three attenuated forms were delineated, poor, intermediate, and mild; these were defined as a developmental quotient (ratio of developmental age to chronologic age) of less than 20, between 20 and 50, and greater than 50, respectively. Predictors of outcome included age at seizure onset, CSF glycine value, ratio of CSF to plasma glycine, and the presence of severe brain malformations (Swanson et al., 2015). Of presenting neonates, 85% have the severe form of the disease and 15% the attenuated; the proportion for infantile onset is 50% severe and 50% attenuated. In the previously described series of 124 affected individuals, 21% died in the neonatal period, 45% had the severe form, and 34% had an attenuated form (Swanson et al., 2015). Brain imaging results are normal for about one-half of the neonatal-onset cases. Relatively common brain abnormalities include agenesis of the corpus callosum, progressive atrophy, and delayed myelination. Mild and transient forms of glycine encephalopathy have been reported. Mild forms manifest in infancy or early childhood after an uneventful pregnancy and neonatal period. Clinical features include seizures (in most cases) and relatively mild developmental delay. Transient glycine encephalopathy is characterized by the same initial clinical and biochemical findings as the classic form, but it has only rarely been reported. In the transient form, elevated CSF and plasma glycine levels partially or completely normalize, and most patients have normal development. The diagnosis of glycine encephalopathy is established by detecting an elevated CSF glycine concentration, typically 15 to 30 times normal, in association with an increased ratio of CSF to plasma glycine (normal < 0.02). Classic neonatal-onset patients often have ratios higher than 0.2, whereas atypical patients have ratios of approximately 0.09. A ratio higher than

0.08 is usually considered diagnostic of glycine encephalopathy. The plasma and CSF samples should be obtained as closely as possible to one another, and the presence of blood in the CSF invalidates the amino acid results. Other causes of increased CSF glycine levels include valproate therapy, brain trauma, and hypoxic-ischemic encephalopathy. Secondary elevations of plasma glycine, associated with ketosis, are often encountered in organic acidemias (e.g., methylmalonic, propionic, and isovaleric acidemias and β-ketothiolase deficiency; these are the ketotic hyperglycinemias). Because pyridoxine-dependent epilepsy, pyridoxamine 5’-phosphate oxidase deficiency, and cerebral folate deficiency may have presentations similar to that of glycine encephalopathy, concentrations of alpha-aminoadipic semialdehyde, pyridoxal 5’-phosphate, and 5-methyltetrahydrofolate should also be assessed in the CSF. Urine S-sulfocysteine should be sent to test for isolated sulfite oxidase deficiency and molybdenum cofactor deficiency, which may also present with intractable seizures in the newborn period. Confirmation of the diagnosis may be accomplished by assaying the glycine cleavage system in liver tissue, although, in practice, molecular testing of the genes encoding glycine cleavage system subunits is less invasive and more widely available, and the enzyme defect may be secondary, as described in the following discussion. Comprehensive mutation analysis in 68 families with glycine encephalopathy detected GLDC (P protein gene) or AMT (T protein gene) mutations in 68% of neonatal and 60% of infantile types, respectively. No GCSH (H protein gene) mutations were identified. Strikingly, evaluation of patients with abnormal glycine cleavage activity in liver, but without mutations in genes encoding the enzymes of the glycine cleavage system, were identified to have defects in mitochondrial lipoate synthesis]. These defects include those in enzymes involved in lipoate synthesis and transfer and those in iron-sulfur cluster biogenesis because lipoate synthase is a protein that contains ironsulfur clusters. Importantly, individuals with lipoate synthase defects, sometimes also referred to as variant or atypical glycine encephalopathy, have varied biochemical and clinical

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presentations. It is important to be aware of these classes of defects and the biochemical and phenotypic overlap of lipoate synthesis defects, which include iron-sulfur cluster biogenesis defects, with glycine encephalopathy. Treatment of glycine encephalopathy has not improved the overall dismal prognosis in the classic form of disease. Therapy is focused on controlling seizures with antiepileptic drugs, decreasing tissue glycine levels, and administering N-methylD-aspartate (NMDA) receptor antagonists to diminish glycineinduced neuronal excitotoxicity. Valproate is contraindicated because it can inhibit the glycine cleavage enzyme system and can cause hyperglycinemia in patients without glycine encephalopathy. Sodium benzoate is given because of its ability to conjugate to glycine to form hippurate, which can then be excreted in the urine. A glycine-specific mitochondrial enzyme, benzoyl-coenzyme A (CoA):glycine acyltransferase, catalyzes the condensation of benzoate and glycine to form hippurate. Sodium benzoate therapy can reduce plasma levels of glycine to the normal range and may have a mild effect on CSF glycine levels, but it does not affect the very poor prognosis. Because high-dose sodium benzoate therapy can result in carnitine deficiency, plasma carnitine levels should be monitored closely and appropriate supplementation provided. Dextromethorphan, an antagonist of the NMDA receptor, is also commonly used in therapy. Treatment with dextromethorphan may lead to improved seizure control and level of interaction in some patients. Rarely, ketamine has been used, but it may provide benefit in controlling seizures and improving overall level of interaction. A low-protein diet has no proven efficacy and may result in severe protein malnutrition, micronutrient deficiency, and exfoliative dermatitis if not monitored carefully.

Sulfur Amino Acid Metabolism and the Homocystinurias See the online version of the chapter.

Hartnup’s Disease See the online version of the chapter.

Histidinemia See the online version of the chapter.

ORGANIC ACIDEMIAS Propionic Acidemia See the online version of the chapter.

Methylmalonic Acidemias Multiple genetic defects can lead to methylmalonic acidemia, alone or in combination with elevated homocysteine because both compounds are processed by enzymes that require B12. B12 is acquired through dietary sources and must be appropriately transported and modified to participate in methylmalonic acid and homocysteine metabolism. The isolated methylmalonic acidemias and those in combination with elevated homocysteine are caused by deficiencies in the transport or modification of vitamin B12 (cobalamin) or by mutations in enzymes requiring a B12 cofactor, in addition to several other mechanisms, such as a transcription factor defect that causes combined methylmalonic acidemia and homocystinuria (see Figure 37-6A and B). Because there are a variety of causative defects, this group of conditions has significant

clinical heterogeneity and differences in response to therapy. Incidence is estimated at 1 case per 50,000 persons, or greater.

Pathophysiology The canonical inherited isolated methylmalonic acidemias are caused by defects in the enzyme methylmalonyl-CoA mutase, which requires an adenosylcobalamin cofactor, or in the enzymes that modify B12 to adenosylcobalamin. The latter cases are sometimes denoted by the genetic complementation group because the causative genes were identified over time; these are cblA, cblB, and cblD-MMA. Isolated methylmalonic acidemia can also be caused by a defect in methylmalonylCoA epimerase (encoded by the MCEE gene), which converts D-methylmalonyl-CoA to L-methylmalonyl-CoA; in methylmalonate semialdehyde dehydrogenase (ALDH6A1); in a disorder of mitochondrial energy metabolism, succinyl-CoA synthase deficiency (SUCLA2, SUCLG1); and in association with mutations in ACSF3, in which malonic acid may also be elevated (Pupavac et al., 2016). Elevations of both methylmalonic acid and homocysteine are caused by defects in other genes encoding enzymes, transport proteins, and receptors that affect cobalamin trafficking and modification and can also be caused by dietary deficiency of B12 (Pupavac et al., 2016). Methylmalonyl-CoA is derived from propionyl-CoA; both are intermediates in the catabolism of isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, and odd-chain fatty acids. Methylmalonyl-CoA mutase converts L-methylmalonyl-CoA to succinyl-CoA, which then enters the tricarboxylic acid cycle. The major causes of isolated methylmalonic acidemia are mutase deficiency (mut0, mut–), cblA, and cblB. CblD-MMA (formerly described as cblH) is also a cause of isolated methylmalonic acidemia but is more rare. Mutase activity is completely and partially abolished in the mut0 and mut– groups, respectively. CblC, cblD-combined, cblF (LMBRD1), and cblJ (ABCD4) are associated with elevations of both methylmalonic acid and homocysteine, as is cblX, an X-linked defect in HCFC1, a transcription factor that affects expression of the gene defective in cblC disease, MMACHC. Defective adenosylcobalamin synthesis is responsible for cblA, cblB, and cblDMMA. CblC and cblD-combined, cblF, and cblJ cause methylmalonic acidemia and homocystinuria because of their effects on both adenosylcobalamin and methylcobalamin biosynthesis (Figure 37-6A and B). CblE (MTRR), cblG (MTR), and cblD-HC affect methylcobalamin synthesis and therefore homocysteine metabolism alone.

Clinical Manifestations As with propionic acidemia and other disorders, there are early- and late-onset forms, which likely result, in part, from residual protein function. There is significant variability in presentation of the methylmalonic acidemias, depending on the particular underlying defect. Common features of the canonical isolated methylmalonic acidemias are failure to thrive, developmental delay, megaloblastic anemia, and neurologic dysfunction. Mut0, cblA, and cblB patients often present in the first days to weeks of life with poor feeding, dehydration, increasing lethargy, emesis, and hypotonia. Metabolic acidosis and secondary hyperammonemia, as with propionic acidemia, may be catastrophic. Mild mut– or other forms of methylmalonic acidemia may present later in infancy or in childhood with hypoglycemia, acidosis, seizures, and lethargy. A patient with cblC disease can present early in infancy with signs and symptoms of metabolic decompensation, in later childhood, or in adulthood with myopathy, lower-extremity paresthesias, and thrombosis as a result of elevated plasma homocysteine. Other features of cblC



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Cell mem bran e

Extracellular space

Biotin

Protein synthesis CH3 CH

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Propionyl-CoA Odd-chain fatty acids Threonine Methionine Methylcitric acidCholesterol

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A Figure 37-6.  A, Pathways in the metabolism of the branched-chain amino acids, biotin, and vitamin B12 (cobalamin).

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Mitochondrion

(S or R)-MMSA

Valine Isoleucine Methionine Threonine Odd chain fatty acids Cholesterol

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B Figure 37-6, cont’d  B, Updated depiction of cobalamin metabolism. Cbl, cobalamin; cbl, defect in metabolism of cobalamin; HCU, homocystinuria; MMA, methylmalonic acidemia; OHCbl, hydroxocobalamin; TC, transcobalamin. (A, From Rezvani I. Defects in metabolism of amino acids. In: Behrman R, Kliegman R, Jenson H, eds. Nelson textbook of pediatrics, 16th ed. Philadelphia: WB Saunders, 2000:355. B, With permission from Pagon RA, Adam MP, Ardinger HH, et al., (eds), Isolated Methylmalonic Acidemi, GeneReviews®, Copyright © 1993-2016, University of Washington, Seattle. All rights reserved, www.genereviews.org.)

disease include hemolytic-uremic syndrome, cardiomyopathy, subacute combined degeneration of the cord, and psychiatric manifestations such as psychosis. Children with cblC disease can have ocular abnormalities, including optic atrophy, and progressive pigmentary retinopathy with resultant nystagmus, strabismus, and worsening vision (Fischer et al., 2014). They may also exhibit hydrocephalus and microcephaly. Cranial imaging may reveal pathology of the basal ganglia and white matter. The two initial cases reported with cblD presented in later childhood with mental retardation and behavioral problems, although subsequent reports have documented infantile onset with hypotonia and seizures and early childhood presentations with ataxia and gait abnormalities. CblF patients have been reported to have minor facial anomalies and hematologic defects. Transcobalamin II deficiency, a B12 transport deficiency, can manifest as failure to thrive in the first months of life, with neurologic disease, hematologic disease, and mental retardation. A benign form of methylmalonic acidemia has been reported in otherwise healthy children; some of these may be caused by mutations in the genes encoding mutase, those encoding epimerase, or in ACSF3. There are also reports of individuals with mutations in the receptor for

transcobalamin bound to cobalamin (TCblR); this may be a benign condition.

Laboratory Tests Methylmalonic acidemia can clinically resemble other organic acidemias, necessitating analysis of urine organic acids for diagnosis. Elevated C3 (propionyl) acylcarnitine identifies methylmalonic acidemia, propionic acidemia, and B12 deficiency; therefore, urine organic acid analysis is required after an abnormal newborn screen with elevated C3 acylcarnitine. As with propionic acidemia, some cases are not identified through newborn screening, and some infants will develop clinical symptoms before the newborn screen results are available. Therefore if there is a clinical concern, testing for an organic aciduria should be performed. Ketosis and hyperammonemia are common in the acute neonatal presentation of these conditions, and if these are present, urine organic acids and other biochemical tests should be performed. Urine organic acid analysis reveals large amounts of methylmalonic acid, methylcitrate, propionic acid, and 3-hydroxypropionic acid in mutase deficiency and cblA and cblB disease. Serum



Aminoacidemias and Organic Acidemias

amino acids sometimes demonstrate elevation of glycine. When elevated serum or urine methylmalonic acid is identified, it is critical to obtain a total plasma homocysteine as a specific test to assess for defects that cause elevations of both compounds because elevated homocysteine may not be detected through plasma amino acid analysis. Serum B12 levels must be assessed to ensure that elevated methylmalonic acid and homocysteine levels, if present, are not the result of a nutritional deficiency of cobalamin. Total plasma homocysteine levels are elevated in cblC, cblD-combined, cblF, cblJ, and CblX diseases. Total and free carnitine levels tend to be low. The cobalamin transport deficiencies are assessed by measuring serum cobalamin levels and absorption by the Schilling test, in addition to DNA testing (Pupavac et al., 2016). Determination of the form of methylmalonic acidemia was often performed through complementation studies in fibroblasts, but this does not identify all causes (Pupavac et al., 2016). DNA mutation analysis is now the appropriate first test. One next-generation sequencing panel includes 24 genes associated with elevated methylmalonic acid (Pupavac et al., 2016).

3-Methylcrotonyl-CoA Carboxylase Deficiency

Treatment

See the online version of the chapter.

Guidelines for acute and chronic management of methylmalonic acidemia have been developed (Baumgartner et al., 2014). The principles of management are similar to those for propionic acidemia. One critical difference is that some forms of methylmalonic acidemia are responsive to vitamin B12, and hydroxocobalamin (preferred) or cyanocobalamin should be given empirically to a child presenting with hyperammonemia and ketosis. If methylmalonic acidemia is identified, intramuscular or subcutaneous hydroxocobalamin should be continued if the child appears to have a form that is responsive to B12 (cblA, mut–), which can be difficult to assess. During acute metabolic crises, treatment of known methylmalonic acidemia is directed toward stopping catabolism and restricting protein intake. The usual protein intake is stopped for 12 to 24 hours from last intake, and fat and glucose are given orally or intravenously. Chronic and acute therapy include carnitine; intramuscular, subcutaneous, or intravenous hydroxocobalamin; and metronidazole or neomycin to decrease intestinal propionate production in some cases. Betaine and folate are used if homocysteine is elevated. Treatment of hyperammonemia, which can be marked in the initial presentation, is similar to that for propionic acidemia (Baumgartner et al., 2014). Improved growth and enhanced nutritional status are seen in patients with methylmalonic acidemia fed an elemental medical food. Patients should consume a diet low in the macronutrient precursors proximal to the metabolic block and receive adequate calories and total protein to enable growth. Plasma methylmalonic acid levels are followed for metabolic control. Frequent complications in methylmalonic acidemia include tubulointerstitial nephritis, leading to end-stage renal disease, and basal ganglia stroke, often affecting the globus pallidus. Cardiomyopathy is reported but is less common than in propionic acidemia (Baumgartner et al., 2014). Liver transplantation has been performed but is not curative of the disease. It protects against recurrent metabolic crises but not against metabolic stroke, and it does not lead to a complete clinical or biochemical correction because the pathway is active in other tissues. Kidney transplant, often performed for renal failure, may also protect against metabolic decompensation (Baumgartner et al., 2014), although this is still unclear.

Isovaleric Acidemia See the online version of the chapter.

295

See the online version of the chapter.

Biotinidase Deficiency See the online version of the chapter.

Holocarboxylase Synthetase Deficiency See the online version of the chapter.

3-Methylglutaconic Aciduria See the online version of the chapter.

Beta-Ketothiolase Deficiency See the online version of the chapter.

Canavan’s Disease Glutaric Aciduria Type I In 1975, glutaric acidemia and aciduria were described in siblings with a neurodegenerative disorder beginning in infancy and characterized by opisthotonus, dystonia, and athetosis. Glutaric acidemia type I, also known as glutaryl-CoA dehydrogenase deficiency, is an autosomal-recessive condition caused by deficiency of glutaryl-CoA dehydrogenase and has an estimated prevalence of approximately 1 case per 100,000 persons. In the United States glutaric acidemia type I is relatively common in the Old Order Amish. Glutaric acidemia type II is also known as multiple acyl-CoA dehydrogenase deficiency (MADD) and is associated with defects in mitochondrial electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase; it is discussed further in Chapter 37. Glutaric aciduria type III is not associated with clinical symptoms and is the result of a deficiency of the enzyme that converts glutarate to glutaryl-CoA. Glutaryl-CoA dehydrogenase is a key enzyme in the degradation pathway of lysine, hydroxylysine, and tryptophan. Deficiency results in accumulation of glutarate and, to a lesser extent, of 3-hydroxyglutarate and glutaconate in body tissues, blood, CSF, and urine (Hedlund, Longo, and Pasquali, 2006). The classic symptom of glutaric acidemia type I (GAI) is irreversible focal striatal necrosis during an acute illness, most often between the ages of 3 and 18 months. Such an event is termed an encephalopathic crisis. Sequelae of the acute injury to the basal ganglia include irreversible disabling dystonia and, in some cases, dyskinesia, in addition to shortened life expectancy (Kolker et al., 2006). Crucially, newborn screening has changed the natural history of this condition. The combined use of chronic management and emergency management in the treatment of individuals identified presymptomatically greatly reduces neurologic injury (Hedlund et al., 2006; Kolker et al., 2006). Macrocephaly is a feature of GAI and may not be present at birth, but head growth velocity is increased; in some cases progressive macrocephaly has led to the identification of GAI before striatal injury (Kolker et al., 2006). Intraretinal hemorrhages and subdural hematomata caused by the rupture of bridging veins associated with macrocephaly may be present and may be mistaken for nonaccidental injury; this can also lead to the identification of affected individuals before striatal injury. In some cases, striatal injury is not associated with an identified encephalopathic crisis but is insidious, with gradual appearance of symptoms. Systemic manifestations typical of

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many other organic acidemias, such as pronounced metabolic ketoacidosis, hypoglycemia, and hyperammonemia, generally do not occur (Hedlund et al., 2006). There is a window of neurologic susceptibility to striatal damage during the first years of life. A seminal natural history study of 279 individuals in 37 countries demonstrated that 95% of encephalopathic crises occurred before 2 years of age and that additional basal ganglia injury occurred up to roughly 6 years of age but not beyond (Kolker et al., 2006). Crucially, individuals who are identified presymptomatically and treated according to established guidelines may avoid the devastating neurologic injury in the vulnerable period (Kolker et al., 2006). A late-onset leukodystrophy has been described, and the natural history of this manifestation is unknown. A characteristic early brain MRI finding is symmetric widening of the sylvian fissure with poor operculization (“bat wing” appearance) caused by frontotemporal atrophy or hypoplasia (Figure 37-8). Other features include basal ganglia injury, subdural hematomata, ventriculomegaly, and delayed myelination (Hedlund et al., 2006). Diffusion-weighted imaging may be more sensitive in demonstrating brain lesions than CT or MRI. Urine organic acid analysis often documents highly elevated glutaric acid and lesser elevations of 3-hydroxyglutarate and glutaconate, but some children with a classic neurologic phenotype have low or undetectable levels of these metabolites (so-called low excretors). Newborn screening using tandem mass spectrometry has the potential for presymptomatic detection of GAI, although the existence of a low-excretor phenotype can result in missed cases. Roughly one-third of affected individuals have a low excretor phenotype, which is associated with residual enzyme activity of up to 30%. Crucially, these individuals are at no less risk of severe neurologic injury (Kolker et al., 2006). Increased glutarate and 3-hydroxyglutarate levels in the CNS may induce an imbalance in glutamatergic and GABAergic neurotransmission by inhibiting glutamate decarboxylase, the key enzyme in gamma-aminobutyric acid (GABA) synthesis,

A

or through direct damage to striatal GABAergic neurons. 3-Hydroxyglutarate may mimic the excitatory neurotransmitter glutamate and thereby cause excitotoxic cell damage mediated through activation of NMDA receptors. Glutarate was shown to inhibit synaptosomal uptake of glutamic acid and produce striatal lesions when injected directly into the brain of a rat. Other potential contributors to neurotoxicity include cytokine-induced cell damage, mitochondrial dysfunction, increased production of reactive oxygen species, and production of toxic quinolinic acid, an intermediate in tryptophan metabolism in the brain. Other reports have emphasized the relatively weak neurotoxicity of glutarate and 3-hydroxyglutarate in animal models and primary neuronal cell cultures. The pathogenesis of striatal necrosis and brain lesions in GAI remains the subject of intensive investigation. Animal models may help resolve these conflicting results. Presymptomatic treatment of GAI includes restriction of dietary lysine intake, carnitine, and sometimes riboflavin; supplementation; and rapid intervention in times of intercurrent illness (Kolker et al., 2006). This therapy is continued in symptomatic patients, who also require symptom management, which includes anticholinergic drugs such as trihexyphenidyl and botulinum toxin to treat generalized or focal dystonia resulting from striatal injury. Stereotactic pallidotomy has been performed, as has deep brain stimulation.

5-Oxoprolinuria See the online version of the chapter.

Isobutyryl-CoA Dehydrogenase Deficiency See the online version of the chapter.

3-Hydroxyisobutyric Aciduria See the online version of the chapter.

B

Figure 37-8.  Magnetic resonance imaging (MRI) in glutaric acidemia. A, Axial view, T2-weighted image shows markedly enlarged sylvian fissures bilaterally and abnormal hyperintensity of the central tegmental tract. B, Axial view, T2-weighted image at a slightly higher level shows abnormal hyperintensity of the lentiform nuclei bilaterally. (Courtesy of Dr. A James Barkovich, University of California, San Francisco.)



2-Methylbutyryl-CoA Dehydrogenase Deficiency See the online version of the chapter.

Mevalonate Kinase Deficiency See the online version of the chapter. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. REFERENCES Baumgartner, M.R., Horster, F., Dionisi-Vici, C., et al., 2014. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J. Rare Dis. 9, 130. Burrage, L., Nagamani, S., Campeau, P., et al., 2014. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum. Mol. Genet. 25, R1R8. Enns, G.M., Koch, R., Brumm, V., et al., 2010. Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol. Genet. Metab. 101, 99. Fischer, S., Huemer, M., Baumgartner, M., et al., 2014. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J. Inherit. Metab. Dis. 37, 831–840. Hedlund, G.L., Longo, N., Pasquali, M., 2006. Glutaric Acidemia Type 1. Am. J. Med. Genet. C Semin. Med. Genet. 142C (2), 86–94.

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Klee, D., Thimm, E., Wittsack, H.J., et al., 2013. Structuralwhite matter changes in adolescents and yound adults with maple syrup urine disease. J. Inher. Metab. Dis. 36, 945–953. Kolker, S., Garbade, S.F., Greenberg, C.R., et al., 2006. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr. Res. 59, 840–847. Pupavac, M., Tian, X., Chu, J., et al., 2016. Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism. Mol. Genet. Metab. 117, 363–368. Strauss, K., Mazariegos, G., Sindhi, R., et al., 2006. Elective liver transplantation for the treatment of classical maple syrup urine disease. Am. J. Transplant. 6, 557–564. Swanson, M.A., Coughlin, C.R., Scharer, G.H., et al., 2015. Biochemical and Molecular Predictors for Prognosis in Nonketotic Hyperglycinemia. Ann. Neurol. 78, 606–618.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 37-2 The tyrosine metabolic pathway. Fig. 37-5 Abbreviated diagram for the transsulfuration pathway. Fig. 37-7 Patient with Canavan’s disease.

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38 

Inborn Errors of Urea Synthesis Sandesh C.S. Nagamani and Uta Lichter-Konecki

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Inherited disorders of the urea cycle represent a group of inborn errors of metabolism that are associated with hyperammonemic encephalopathy and high mortality and morbidity. They comprise deficiencies of a cofactor-synthesizing enzyme, five catalytic enzymes, and amino acid transporters involved in urea synthesis (Fig. 38-1). These disorders are classified as follows (estimated prevalence rates are given in parentheses) (Brusilow and Horwich, 2001; Tuchman et al., 2008; Ah Mew et al., 2003): • Deficiency of cofactor synthesis • N-acetylglutamate synthase (NAGS) deficiency (prevalence unknown) • Deficiency of catalytic enzymes • carbamoyl-phosphate synthase 1 (CPS1) deficiency (1 per 62,000) • ornithine transcarbamylase (OTC) deficiency (1 per 14,000) • argininosuccinate synthase 1 (ASS1) deficiency (citrullinemia) (1 per 57,000) • argininosuccinate lyase (ASL) deficiency (argininosuccinic aciduria) (1 per 70,000) • arginase 1 (ARG1) deficiency (hyperargininemia) (1 per 353,000) • Deficiency of transporters • citrullinemia type II (mitochondrial aspartate/glutamate carrier [citrin] SLC25A13 deficiency) (1 per 21,000 in Japan; possibly more common in China) • hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (mitochondrial ornithine transporter, ORNT1 or SLC25A15 deficiency) (prevalence unknown)

catalyzing the rate-limiting step of the urea cycle. CPS1 uses ATP, bicarbonate, and glutamine or ammonia to synthesize carbamoyl-phosphate. This reaction is where the first atom of waste nitrogen enters the cycle. OTC, a mitochondrial enzyme, synthesizes citrulline from carbamoyl-phosphate and ornithine. Citrulline is actively transported by the ornithine transporter (ORNT1/SLC25A15) from the mitochondrion to the cytosol, where it is conjugated with aspartate to form argininosuccinic acid by ASS1. Here, the second atom of waste nitrogen is contributed to the cycle by aspartate. ASL cleaves argininosuccinic acid to yield fumarate and arginine. The final step in the urea cycle involves cleavage of arginine by ARG1 to form urea and ornithine. The ornithine is transported back into the mitochondrion by ORNT1/SLC25A15. Although the complete urea cycle is only present in hepatocytes, other tissues also express some urea cycle enzymes. The intermediates of the urea cycle are linked to the citric acid cycle, the nitric oxide cycle, and possibly other pathways. The enzymes ASS1 and ASL are also required for synthesis of arginine, which is important for generation of nitric oxide (NO), creatine, polyamines, and agmatine. Thus deficiency of urea cycle enzymes may also affect nonureagenic functions, which may contribute to some of the distinct features observed in urea cycle disorders.

CLINICAL DESCRIPTION OF UREA   CYCLE DISORDERS N-Acetylglutamate Synthase Deficiency

All of the urea cycle disorders (UCDs) are inherited as autosomal-recessive traits, except for OTC deficiency, which is X-linked. Other than in ARG1 deficiency, infants with a complete deficiency of any other urea cycle enzyme commonly present in the newborn period with hyperammonemic coma. Universal newborn screening and the availability of drugs and hemodialysis for treatment of hyperammonemia have resulted in improved survival; mortality, however, still remains high, and the majority of survivors have intellectual disability. Patients with late-onset disease may present at any age with hyperammonemic crises that carry a risk of mortality (10%) and intellectual disability.

Inherited NAGS deficiency leads to hyperammonemia by causing a secondary deficiency of CPS1 activity. NAGS deficiency is characterized by hyperammonemia in the newborn period or later in life that can be fatal or lead to intellectual and developmental disabilities. Plasma amino acid analysis usually demonstrates an increased level of glutamine and reduced or absent levels of citrulline. Urinary orotic acid levels are normal or low. Because enzyme analysis requires large amounts of liver tissue and may not be entirely reliable, analysis of genomic DNA for mutations in the NAGS gene is the preferred diagnostic method. Previously, treatment for NAGS deficiency was limited to low-protein diet and use of ammonia scavengers (Table 38-1); however, synthetic cofactor therapy with N-carbamyl-L-glutamate is now approved.

THE UREA CYCLE

Carbamoyl-Phosphate Synthase 1 Deficiency

Dietary protein, on average, contains approximately 16% nitrogen. More than 90% of the nitrogen that is not used for anabolic processes is typically metabolized and excreted as urea. Deficiency of one of the enzymes or transporters required for urea synthesis results in accumulation of nitrogen in the form of ammonia, leading to encephalopathy. One cofactor and its synthesizing enzyme, five catalytic enzymes, and two transporters are necessary for optimal urea cycle activity (see Fig. 38-1). The cofactor N-acetylglutamate, which is synthesized by NAGS, activates CPS1, the first enzyme

CPS1 deficiency can manifest with hyperammonemic crises in the newborn period or later in childhood. Biochemically, the principal findings are hyperammonemia, increased glutamine, and reduced or absent citrulline in plasma. Urinary orotic acid levels are normal or low. Patients with neonatal-onset disease generally demonstrate less than 5% of the normal CPS1 activity in liver, whereas those with late-onset disease have higher residual activity. Therapy consists of dialysis and/or intravenous ammonia scavengers during severe hyperammonemic episodes and low-protein diet and oral ammonia scavengers

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TABLE 38-1  Long-Term Alternative-Pathway Treatment of Urea Cycle Disorders (UCDs)* Disorder

L-Citrulline

L-Arginine

NAGS deficiency

—

CPS1 or OTC deficiency

0.15–0.20 g/kg/d or 3.8 g/m2/d

Citrullinemia

Free Base

Sodium Phenylbutyrate

N-Carbamylglutamate

—

—

~0.10 g/kg/d

—

0.45–0.60 g/kg if < 20 kg 9.9–13.0 g/m2/d in larger patients

—

—

0.40–0.50 g/kg/d or 8.8–15.4 g/m2/d

0.45–0.60 g/kg if < 20 kg 9.9–13.0 g/m2/d in larger patients

—

Argininosuccinic acidemia

—

0.40–0.50 g/kg/d or 8.8–15.4 g/m2/d

0.45–0.60 g/kg if < 20 kg 9.9–13.0 g/m2/d in larger patients

—

Argininemia

—

—

0.45–0.60 g/kg/d if < 20 kg 9.9–13.0 g/m2/d in larger patients

*Drugs and dose ranges are those commonly used in patients with UCDs; however, doses can vary and need to be adjusted based on the severity of the disorder and patient response. When using doses at the upper recommended range or above, consideration should be given to increased risk of drug toxicity. CPS1, carbamoyl-phosphate synthase 1; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase.

Cytoplasm

Mitochondrion

AcCoA

Glutamate

CoASH

N-acetylglutamate

ORNT1 Urea Ornithine

ARG1 Arginine

NAGS

Ornithine

CP

OTC Citrulline

CPS1

NH3 HCO3– 2 ATP

Aspartate CITR

ORNT1

Fumarate

Citrulline ASS1 Aspartate Argininosuccinic acid

ASL

Figure 38-1.  The urea cycle. AcCoA, acetyl coenzyme A; ASL, argininosuccinate lyase; ARG1, arginase 1; ASS1, argininosuccinate synthase; CITR, citrin; CoASH, coenzyme A; CPS1, carbamoylphosphate synthase 1; NAGS, N-acetylglutamate synthase; ORNT1, ornithine transporter 1; OTC, ornithine transcarbamylase.

for chronic treatment (see Table 38-1). Patients with the neonatal-onset form who survive the initial crisis generally require liver transplantation to have any quality of life.

Ornithine Transcarbamylase Deficiency OTC deficiency is transmitted as an X-linked recessive disorder and thus is much more severe in males (Lichter-Konecki et al., 2013). The classic presentation of OTC deficiency in hemizygous males is that of a catastrophic illness in the first week of life. In symptomatic female heterozygotes and in males with partial OTC deficiency, symptoms may occur at any time from infancy to adulthood. These patients generally have 5% to 30% of normal OTC activity in the liver. Biochemically, the findings are hyperammonemia, hyperglutaminemia, reduced or absent citrulline in plasma, and increased urinary orotic acid. More than 340 different point mutations and polymorphisms have been found in the OTC gene. Although most families have point mutations, small and large deletions have been identified. When the mutation has been identified, carrier testing and prenatal diagnosis can be offered to the family.

Detection of heterozygous females with OTC deficiency is important for both identifying at-risk family members and prenatal diagnosis. Such detection can be accomplished by either molecular studies or, in cases where no mutation is found, by an allopurinol load. When administered allopurinol (300 mg given orally to adults), in 90% of heterozygotes with OTC deficiency, there is increased excretion of orotic acid. Approximately 15% of OTC-deficient heterozygous females will become symptomatic during their lifetime. Therapy for neonatal-onset OTC deficiency consists of dialysis and intravenous ammonia scavengers, followed by maintenance on a low-protein diet and long-term ammonia scavengers (see Table 38-1). Patients with the neonatal-onset form who survive the initial crisis generally require liver transplantation for prevention of recurrent metabolic crises.

Citrullinemia Citrullinemia is characterized by marked elevation of citrulline in the blood (Quinonez and Thoene, 2004). Two distinct forms have been reported: neonatal- or childhood-onset citrullinemia (type I; with diminished levels of ASS1 in all organs) and citrullinemia type II or citrin deficiency, an adultonset citrullinemia that in some but not all cases is preceded by neonatal cholestasis and liver dysfunction. Biochemically, the principal findings in type I are hyperammonemia, citrullinemia, and citrullinuria. Citrulline levels are elevated 50-fold to 100-fold above normal. Urinary orotic acid levels are also increased. Therapy consists of dialysis during severe hyperammonemic crises, followed by low-protein diet and long-term ammonia-scavenger therapy (see Table 38-1). After the initial crisis, patients are, in general, more stable and easier to manage than patients with more proximal urea cycle defects.

Citrullinemia Type II or Citrin Deficiency Citrin deficiency is caused by mutations in SLC25A13, a gene that encodes citrin, a mitochondrial membrane protein. This carrier enables the exchange of mitochondrial aspartate for cytosolic glutamate across the inner mitochondrial membrane. The lack of aspartate to conjugate with citrulline in this condition leads to a block in urea synthesis. Citrulline levels can be elevated up to 400 µmol/L; plasma ammonia levels are less severely elevated compared with other UCDs. Citrin deficiency can manifest in adulthood with cyclical bizarre behavior (aggression, irritability, and hyperactivity), dysarthria, seizures, motor weakness, and coma. Treatment

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generally relies on ammonia scavengers (arginine and phenylbutyrate); however, liver transplantation is becoming a more common therapy because of the possible liver complications. More recently, a neonatal-onset form of citrin deficiency has been identified; it is associated with intrahepatic cholestasis. Affected infants have multiple metabolic abnormalities, including aminoacidemia, galactosemia, hypoproteinemia, hypoglycemia, and cholestasis. Treatment usually consists of high-protein/low-carbohydrate diet, and the symptoms often disappear within a year. A few children, however, have a severe form of the disorder with liver damage and tyrosinemia that necessitates liver transplantation. Hyperammonemia is not a major component of this disorder.

Argininosuccinic Aciduria Argininosuccinic aciduria derives its name from the marked elevation of argininosuccinic acid in the blood and urine of affected persons. In the severe forms, this disorder can present with hyperammonemic coma in the newborn period, whereas those with mild forms have fewer, if any, episodes of symptomatic hyperammonemia (Nagamani, Erez, and Lee, 2011). A specific abnormality of the hair termed trichorrhexis nodosa develops in affected children. Some patients develop chronic hepatomegaly. Liver function tests can be abnormal and patients may develop cirrhosis. The reasons as to why some patients with this condition develop cirrhosis, and others do not, are not yet understood. Even individuals with no history of hyperammonemia can have intellectual and learning disabilities, and some develop hypertension that is difficult to control. Biochemically, the principal findings are elevated citrulline level, hyperammonemia, argininosuccinic acidemia, and argininosuccinic aciduria. After the initial hyperammonemic crisis and establishment of the diagnosis, treatment consists of a low-protein diet and L-arginine supplementation (see Table 38-1). Ammonia scavengers may be required in those who have metabolic decompensations. Recent evidence also suggests that ASL is required for synthesis of nitric oxide (NO) and that NO deficiency in this disorder may lead to hypertension.

Argininemia Argininemia characterized by significant elevations of arginine is caused by a deficiency of ARG1. Argininemia presents differently from all of the other UCDs (Wong, Cederbaum, and Crombez, 2004). Although rarely hyperammonemia can be observed, this condition usually manifests as a progressive neurologic disorder rather than as an acute encephalopathy. The disease runs a chronic course with development of progressive spasticity (diplegia or quadriplegia). Affected children generally do not succumb to hyperammonemic coma and therefore have a longer life span than those affected by proximal UCDs. Patients may also have acute episodes of ataxia, behavioral disturbances, vomiting, lethargy, and seizures precipitated by intercurrent illnesses. The principal biochemical finding is markedly elevated plasma arginine. Urinary excretion of orotic acid and guanidine compounds also is markedly increased. The diagnosis can be confirmed by measuring ARG1 activity in erythrocytes. The mechanism responsible for the spasticity and cognitive deficits in argininemia is unknown but is unlikely to be the result of the generally moderate hyperammonemia. Arginine, its guanidine metabolites, and altered biogenic amines are candidate neurotoxins. Arginine is the substrate for nitric oxide synthase, so overproduction of NO may play a role in neuropathology. Treatment with ammonia-scavenger therapy and lowering of the arginine level appears to halt the progres-

sion of the spasticity, and botulinum toxin (Botox) and surgical tendon release may improve function.

Hyperornithinemia-HyperammonemiaHomocitrullinuria Syndrome HHH syndrome is rare, and only about 50 individuals have been reported in the literature. Clinical symptoms are similar to those in other UCDs but rarely develop in infancy. Plasma ornithine concentrations are elevated, ranging from 400 to 600 µmol/L. Plasma lysine level typically is low, and urinary excretion of homocitrulline is increased. HHH syndrome is caused by mutations in the ornithine transporter gene, ORNT1, also called SLC25A15. The decreased activity of the transporter leads to decreased ornithine levels in mitochondria and secondary impairment of urea synthesis. The expression of ORNT2, an intronless gene, encoding a protein about 90% identical to ORNT 1, may explain the milder clinical signs and symptoms compared with those in CPS1 and OTC deficiencies. Treatment of HHH syndrome involves protein restriction, ammonia scavengers, and citrulline supplementation.

COMMON CLINICAL PRESENTATIONS OF UREA CYCLE DISORDERS The classic presentation of a complete defect in the urea cycle (other than ARG1 deficiency) is that of a catastrophic illness in the first week of life. Clinical manifestations typically appear between 24 and 72 hours of age, starting as a poor suck, hypotonia, vomiting, lethargy, and hyperventilation, with rapid progression to seizures and coma (Ah Mew et al., 2003). The electroencephalogram (EEG) pattern during hyperammonemic coma is one of low voltage with slow waves and asymmetric δ and θ waves. The tracing may demonstrate a burst-suppression pattern, and the duration of the interburst interval may correlate with the peak of ammonia levels. Neuroimaging studies reveal cerebral edema with small ventricles, flattening of cerebral gyri, and diffuse low density of white matter; evidence of intracranial hemorrhage also may be seen. Partial deficiencies of a urea cycle enzyme have a spectrum of presentations, with hyperammonemic episodes developing in infancy in some, childhood in others, and not until adulthood in still others. Symptoms may be delayed in onset by dietary self-restriction and avoidance of high-protein foods. Signs and symptoms in childhood include anorexia and behavioral abnormalities such as episodes of erratic behavior, acting out of character, irritability, cloudiness to frank changes in mental status and ataxia, nocturnal restlessness, and attention deficit and hyperactivity. In adults, signs and symptoms may mimic those of psychiatric or neurologic disorders and include migraine-like headaches, nausea, dysarthria, ataxia, confusion, hallucinations, and visual impairment (blurred vision, scotomas, vision loss). Neurologic findings in those with severe manifestations may include increased deep tendon reflexes, papilledema, and decorticate/decerebrate posturing. In metabolic decompensation, seizures generally are a late complication; the seizure episode typically is preceded by alteration in consciousness. There are indications that patients with UCDs may also be prone to seizures outside of hyperammonemic episodes; seizures were observed more often in patients with UCDs than in the general population in one clinic. Analysis of data collected longitudinally from patients with UCDs will allow further investigation of this impression. In affected individuals, hyperammonemic episodes can be precipitated by any event that induces catabolism, including



infections, high-protein meals, medication, trauma, surgery, and childbirth. It is not uncommon for the initial hyperammonemic episode in a child with a partial deficiency to occur after weaning, when low-protein breast milk is replaced by formula or cow’s milk. The puerperium in OTC-deficient heterozygotes and valproate therapy in partial CPS1 and ASL deficiencies also have been associated with hyperammonemic crises.

HISTOPATHOLOGIC FEATURES OF UREA   CYCLE DISORDERS Histopathologic examination of the liver in UCDs may be normal but often demonstrates diffuse microvesicular steatosis, marked increased glycogen in periportal cells, and variable portal fibrosis. Cirrhosis has been identified in some patients with argininosuccinic aciduria (ASA), citrullinemia type II, and ARG1 deficiency. Neuropathologic findings in UCDs are similar to those following the hepatic encephalopathy of acute liver failure. They depend on both the duration of hyperammonemic coma and the interval between coma and death. Neonates who die as a result of hyperammonemic coma have prominent cerebral edema and generalized neuronal cell loss on postmortem examination. Histologically, astrocyte swelling was one of the first observations made in an animal model for hepatic encephalopathy, leading to the hypothesis that swollen astrocytes may be the cellular correlate of the brain edema in acute hyperammonemia. In survivors of prolonged coma, changes observed on neuroimaging studies obtained months after the insult include ventriculomegaly with increased sulcal markings, bilateral symmetric low-density white-matter defects, cystic degeneration, injury to the bilateral lentiform nuclei, and diffuse atrophy with sparing of the cerebellum. Neuropathologic findings in those children who subsequently died were consistent with the neuroimaging findings and included ulegyria, cortical atrophy with ventriculomegaly, prominent cortical neuronal loss, gliosis (often with Alzheimer type II astrocytes), and spongiform changes at the gray–white matter interface and in the basal ganglia and thalamus.

MECHANISM OF NEUROPATHOLOGY The mechanism of ammonia-induced neuropathology remains unclear. Ammonia normally is detoxified in astrocytes by glutamate dehydrogenase and glutamine synthase. Accumulation of ammonia and glutamine in the brain has a number of potentially toxic effects.

Downregulation of Astrocytic   Glutamate Transporters The downregulation of astrocytic glutamate transporters and elevations of extracellular glutamate observed in hyperammonemia have led to the hypothesis that the brain damage is caused by overstimulation of neurons by elevated extracellular glutamate levels, a mechanism of brain damage called excitotoxicity.

Elevated Glutamine Levels A negative correlation between the height of brain glutamine levels and brain myoinositol levels has been observed, suggesting depletion of the osmolyte myoinositol by high glutamine levels. High brain glutamine levels may have an osmotic effect and cause brain swelling.

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Altered Water Transport Water transport at blood–brain and brain–cerebrospinal fluid interfaces is facilitated by channel proteins called aquaporins. Aquaporin 4 (AQP4) is the main astrocytic water channel, and altered expression of Aqp4 has been reported in hyperammonemia.

Altered Glucose Metabolism/Disturbed   Energy Metabolism Ammonia stimulates phosphofructokinase, the key enzyme of glycolysis. The ammonium ion (NH4+), under physiologic conditions in vivo, may play a significant role in the regulation of glycolysis in astrocytes. Increased ammonia levels, conversely, inhibit α-ketoglutarate dehydrogenase in the brain. Stimulation of phosphofructokinase and inhibition of αketoglutarate dehydrogenase, the key enzyme of the citric acid cycle, cause increased formation of lactate and compromised brain energy metabolism.

Interference With the Normal Flux of Potassium Ions NH4+ can cross cell membranes through ion channels or membrane transporters, and it can replace K+ on different transporters. Downregulation of the major astrocytic water, gap-junction, and potassium channels during hyperammonemia was described in an animal model for UCDs and led to the conclusion that hyperammonemia may disturb potassium and water homeostasis in the brain.

Oxidative and Nitrosative Stress An increase in free radical production and nitric oxide synthesis causes oxidative/nitrosative (O/N) stress. Ammonia causes free radical production and a decrease in antioxidant enzyme activity. In addition to oxidative stress, there is also nitrosative stress in hyperammonemic encephalopathy, and increased amounts of NO have been found in animal models of hyperammonemia.

DIFFERENTIAL DIAGNOSIS In the newborn period, hyperammonemia is similar in presentation to a number of acquired conditions, including sepsis, intracranial hemorrhage, and cardiorespiratory disorders. The measurement of plasma ammonia levels is critical to distinguish between these conditions and hence should be a part of the routine evaluation for serious illnesses in the newborn period. Apart from UCDs, a number of other inborn errors of metabolism can cause hyperammonemia. These include organic acidemias, nonketotic hyperglycinemia, congenital lactic acidoses, lysinuric protein intolerance, and defects in fatty acid oxidation. An algorithm for distinguishing between these disorders is presented in Fig. 38-2. Plasma amino acid patterns also are often distinct in the specific types of UCDs and help narrow the diagnosis (Fig. 38-2). Specific enzymatic or DNA analyses may be required in some instances for diagnosis; however, such testing should not delay the initiation of treatment. In older children and adults, identification of UCDs resulting from partial deficiencies of enzymes has often been delayed through their misdiagnosis as migraine, cyclical vomiting, viral encephalitis, stroke, Reye’s syndrome, drug toxicity, child abuse, psychosis, postpartum depression, seizure disorder, and cerebral palsy. Studies have found a mean delay of 8

38

302

PART VI  Genetic, Metabolic and Neurocutaneous Disorders Hyperammonemia

Present

Prematurity, respiratory distress prior to 24 hr. of age

Absent and no liver disease

Transient hyperammonemia

Urinary organic acids (with acidosis and/or ketosis)

Inborn errors of metabolism

Abnormal

Urea cycle disorders

Normal

Plasma citrulline Congenital lactic acidosis

Organic acidemia

Fatty acid oxidation defects

Energy metabolism defects

• Propionic acidemia • Methylmalonic acidemia • Isovaleric acidemia

AcyI-CoA dehydrogenase deficiencies

Moderate elevation Argininosuccinic acid in plasma and urine

Marked elevation Citrullinemia type II

Argininosuccinic aciduria

Citrullinemia type I

Normal or reduced

Low, trace, or absent Low or normal Urinary orotic acid Normal or reduced

Elevated

NAGS or CPS1 deficiency

OTC deficiency

Elevated urinary lysine, ornithine, arginine

Plasma arginine

Elevated

Elevated plasma ornithine, urinary homocitrulline Argininemia

LPI

HHH

Figure 38-2.  Algorithm for differential diagnosis of hyperammonemia. Plasma amino acids, serum lactate, and urinary excretion of orotic acid and organic acids are measured. Acyl-CoA, acyl coenzyme A; CPS1, carbamoyl-phosphate synthase 1; HHH, hyperornithinemia- hyperammonemia-homocitrullinuria syndrome; LPI, lysinuric protein intolerance; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase.

to 16 months between the onset of symptoms and diagnosis of late-onset UCDs. Plasma ammonia levels may be elevated during symptomatic episodes and normal when the patient is clinically stable.

Treatment during hyperammonemic crises involves intravenous nitrogen scavengers and hemodialysis. Liver transplantation may be required in individuals who have recurrent metabolic decompensation.

TREATMENT

Dietary Therapy

Long-term therapy for UCDs consists of dietary modifications, supplementation with urea cycle intermediates (e.g., arginine and citrulline), and use of oral nitrogen-scavenging agents.

In all UCDs other than citrullinemia type II, a protein-restricted diet should be combined with alternate-pathway therapy unless liver transplantation has been performed. In general,



using the minimum daily protein requirement for age is recommended. For neonatal-onset disease, half of the protein is given as an essential amino acid supplement (e.g., Cyclinex, Ross Pharmaceuticals), and the remaining half is provided as natural protein. In children receiving sodium phenylbutyrate, monitoring of branched-chain amino acid levels and supplementation of these as needed has been suggested. Additional calories can be provided via nonprotein formulas, such as Prophree or MJ80056. The diet should be supplemented with vitamins, minerals, and trace elements. Routine monitoring of weight, height, hair, skin, nails, and biochemical indices of nutritional status is recommended.

Alternative-Pathway Therapy Long-term therapy generally involves protein restriction combined with alternative-pathway therapy (see Table 38-1). Approaches to stimulating alternative pathways of waste nitrogen excretion vary with the site of the enzymatic block. In the case of ASS1 and citrullinemia type II or ASL deficiencies, arginine can stimulate waste nitrogen excretion through enhanced production and excretion of citrulline and argininosuccinic acid, respectively (Batshaw, MacArthur, and Tuchman, 2001). In CPS1 and OTC deficiencies, and in severe deficiencies of ASS1 and ASL, sodium phenylbutyrate has been used to provide an alternative pathway. It initially is converted to sodium phenylacetate, which is then conjugated with glutamine to form phenylacetylglutamine and excreted by the kidney. Sodium phenylbutyrate, although effective, has an unpalatable taste, is a gastric irritant, and has a high sodium load. To circumvent these shortcomings, glycerol phenylbutyrate, a compound that has three molecules of phenylbutyrate attached to a glycerol backbone, was developed. This medication, which is a colorless and odorless oil, was shown to be as efficacious as sodium phenylbutyrate in prevention of hyperammonemia and was recently approved for use in children greater than 2 years of age. ARG1 deficiency typically has been managed with an arginine-restricted diet supplemented with sodium phenylbutyrate when required. Sodium benzoate, a medication that combines with glycine to form hippuric is also used as an alternate-pathway therapy.

N-Carbamyl-L-Glutamate In NAGS deficiency, administration of N-carbamyl-L-glutamate may be an effective therapy because this structural analog of N-acetylglutamate crosses the mitochondrial membrane and activates CPS1. Several patients with NAGS deficiency have been reported to respond clinically to treatment with N-carbamyl-L-glutamate.

Liver Transplantation Long-term treatment of UCDs depends on the severity of the disease. For neonatal-onset severe CPS1 and OTC deficiencies, current clinical guidelines recommend that liver transplantation be considered as a form of enzyme replacement therapy. This procedure usually is performed at 6 to 12 months of age, with use of alternate-pathway therapy before surgery. More recently, and as a result of favorable outcome with liver transplantation, other neonatal-onset and poorly controlled lateonset UCDs also have been considered for this treatment. The Studies in Pediatric Liver Transplantation (SPLIT) reported on 114 children with UCDs who received a liver transplant between December 1995 and June 2008 (Arnon et al., 2010). The 5-year patient survival rate was 88.7%, and the 5-year graft survival rate was 83.7%. Transplantation corrects most of the metabolic abnormalities in OTC and

Inborn Errors of Urea Synthesis

303

CPS1 deficiencies (although citrulline levels remain low) and prevents future hyperammonemic episodes. In terms of morbidity, concerns have included neurodevelopmental delay, and frequent and prolonged hospitalizations for treatment of infections and regulation of immunosuppressive drugs. Overall, however, the reported quality of life has been much improved, with normalization of diet and a decreased frequency of hospital admissions.

Management of Hyperammonemic Crises In infants with hyperammonemic coma, hemodialysis should be started immediately. In addition, L-arginine HCl (except in hyperargininemia), sodium benzoate, and sodium phenylacetate should be given intravenously. In children with intercurrent hyperammonemia, treatment involves temporary complete elimination of protein and institution of intravenous administration of sodium benzoate, sodium phenylacetate, and potentially L-arginine. (Caution: Arginine HCl may cause metabolic acidosis, and extravasation may lead to tissue necrosis.) Although these medications are not associated with severe adverse events when they are given at therapeutic doses, severe toxicity and death have resulted from dosing errors. Therefore double-checking of drug administration orders and use of dosing per m2 of body surface area in older children and adults are essential. Monitoring of plasma levels of the drug or its metabolites is recommended. In the event that ammonia levels do not respond to conservative management and biochemical abnormalities or clinical signs and symptoms worsen, hemodialysis or highflow continuous veno-venous hemofiltration should be initiated. The relative effectiveness of peritoneal dialysis, exchange transfusion, hemodialysis, and continuous arteriovenous hemofiltration has been the subject of some controversy. Yet nitrogen balance studies clearly demonstrate the advantage of hemodialysis, with continuous arterio-venous hemodiafiltration being second best if hemodialysis is unavailable. Hemodialysis or high-flow continuous veno-venous hemofiltration should be continued until ammonia levels fall to 200 µmol/L; continuous hemofiltration should then be used to stabilize the ammonia level and prevent a rebound.

THERAPIES UNDER INVESTIGATION Hepatocyte Transfer Infusion of donor hepatocytes into a patient’s liver through the portal vein or one of its branches is under investigation as a bridge to liver transplantation in children with severe forms of the disease. This application relies on a proportion of the infused cells to cross the vessel endothelium and to adhere and survive in the liver parenchyma. More studies are required to evaluate the efficacy of this approach. Current research is also exploring biomaterials and induction of liver tissue regeneration as ways to improve engraftment and expansion of the transfused cells. Resection, irradiation, and drug toxicity are being explored as means to induce regeneration.

Gene Therapy An adeno-associated virus (AAV) vector with the OTC cDNA has been created and has been successfully and efficiently delivered to the livers of animal models.

Neuroprotection A pilot study has assessed the feasibility and safety of wholebody therapeutic hypothermia during rescue treatment for

38

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders

neonatal hyperammonemic coma resulting from metabolic diseases. Further studies are required to assess the efficacy of this procedure in UCDs.

Nitric Oxide Supplementation Therapy Although there are animal and human data suggesting that NO supplements may be of benefit in ASL deficiency, this has not been evaluated systematically in humans. An ongoing trial is evaluating the effects of short- and long-term NO supplementation on vascular and cognitive features in this disease. (Clinical trials involving UCDs can be found at www.clinicaltrials.gov.)

OUTCOME Before the development of alternative-pathway therapy, few children with a severe UCD survived infancy. Most died in the newborn period, and the remainder succumbed to intercurrent hyperammonemic episodes or protein malnutrition later in childhood. The mortality and morbidity rates obtained in the 1980s, when the index of suspicion for these disorders was low and a standardized treatment regimen was unavailable, demonstrated 5-year survival rates of approximately 25%; the rate of morbidity (e.g., intellectual disability, seizure disorders) was near universal for infants rescued from hyperammonemic coma. A correlation between intellectual function and duration of hyperammonemic coma rather than the height of the ammonia level was shown. Children in a coma for less than 3 days had a far better outcome than those in a coma for longer periods. With the general availability of plasma ammonia assays at most hospitals, newborn screening, increased index of suspicion for metabolic disorders, standardized alternative-pathway therapy, and prompt institution of dialysis for neonates at tertiary care centers, the outcome has improved, and it is estimated that 70% of those with neonatal-onset disease and 90% of those with later-onset disease survive their initial crisis. With regard to outcome, the Longitudinal Study of the UCD Consortium recently reported that 66% of children with neonatal-onset UCDs ages 4 years and older and 25% of children with late-onset UCDs have intellectual disability and problems with emotional/behavioral regulation, attention, and executive function (Krivitzky et al., 2009).

SUMMARY UCDs are inborn errors of hepatic metabolism that can have significant neurologic consequences. Newborn screening programs, a high-degree of suspicion, and a proactive evaluation strategy that routinely incorporates metabolic tests in evaluation of neonates and young children with encephalopathy are critical for appropriate diagnosis. The availability of special diets, medications, dialysis, and hepatic transplantation has improved survival, but long-term intellectual outcomes are far from optimal.

Acknowledgment Work on which this chapter is based was supported by the following National Institutes of Health (NIH) grants: 5P30HD040677, U54RR019453, M01RR013297. This work was also supported by the Doris Duke Charitable Foundation, Grant #2013095. The project described was supported by Baylor College of Medicine IDDRC Grant Number 1 U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the NIH.

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Ah Mew, N., Lanpher, B.C., Gropman, A., et al., 1993–2015. Urea Cycle Disorders Overview. 2003 Apr 29 [Updated 2015 Apr 9]. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA). Available from: . Arnon, R., et al., 2010. Liver transplantation in children with metabolic diseases: the studies of pediatric liver transplantation experience. Pediatr. Transplant. 14 (6), 796–805. Batshaw, M.L., MacArthur, R.B., Tuchman, M., 2001. Alternative pathway therapy for urea cycle disorders: twenty years later. J. Pediatr. 138 (1 Suppl.), S46–S54, discussion S54–5. Brusilow, S., Horwich, A., 2001. The Urea Cycle Enzymes. In: Valle, D., Beaudet, A.L., Vogelstein, B., et al. (Eds.), The Online Metabolic and Molecular Bases of Inherited Disease, eighth ed. The McGrawHill Companies. New York McGraw-Hill. Krivitzky, L., et al., 2009. Intellectual, adaptive, and behavioral functioning in children with urea cycle disorders. Pediatr. Res. 66 (1), 96–101. Lichter-Konecki, U., Caldovic, L., Morizono, H., et al., 1993–2015. Ornithine Transcarbamylase Deficiency. 2013 Aug 29. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA). Available from: . Nagamani, S.C.S., Erez, A., Lee, B., 1993–2015. Argininosuccinate Lyase Deficiency. 2011 Feb 3 [Updated 2012 Feb 2]. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA). Available from: . Quinonez, S.C., Thoene, J.G., 1993–2015. Citrullinemia Type I. 2004 Jul 7 [Updated 2014 Jan 23]. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA). Available from: . Tuchman, M., et al., 2008. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol. Genet. Metab. 94 (4), 397–402. Wong, D., Cederbaum, S., Crombez, E.A., 1993–2015. Arginase Deficiency. 2004 Oct 21 [Updated 2014 Aug 28]. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews® [Internet]. University of Washington, Seattle, Seattle (WA). Available from: .

39 

Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism Marc C. Patterson

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Carbohydrates are essential elements in the cellular energy economy, and the inability to activate sugars ingested in the diet for use as metabolic fuels (as in the galactosemias), to mobilize glucose from glycogen (as occurs in the glycogen storage diseases), or to oxidize glucose in the glycolytic pathway leads to a variety of phenotypes. The more frequent include symptoms and signs referable to the liver and musculature predominantly and include hepatomegaly, altered volume of skeletal muscle (both increases and decreases), decompensation in the face of stress (manifest as weakness, cramping, and myoglobinuria), and nonspecific manifestations of hypoglycemia. This chapter surveys the primary diseases of carbohydrate metabolism, particularly as they affect the developing nervous system.

ABNORMALITIES OF GALACTOSE METABOLISM Galactosemia Galactosemia describes a family of autosomal-recessive disorders characterized by increased blood levels of galactose. Galactose cannot be used directly for glycolysis, and must be converted to glucose-1-phosphate. Five enzymes are involved in this interconversion in most species: galactose mutarotase, galactokinase, galactose-1-phosphate uridyltransferase, uridine diphosphogalactose-4-epimerase, and phosphoglucomutase (Coelho et al., 2015). Mutations in the GALK, GALT, and GALE genes that encode the second, third, and fourth enzymes, respectively, cause deficiency or absence of these enzymes, with consequent galactosemia (Timson, 2015). These enzymes comprise the Leloir pathway.

Galactose-1-Phosphate Uridyltransferase Deficiency Galactose-1-phosphate uridyltransferase (GALT) deficiency is by far the most common cause of galactosemia. The incidence of galactosemia in Western Europe varies between 1 in 23,000 and 1 in 44,000. Neonatal screening programs have found population incidence rates as high as 1 in 19,700 in Estonia. Pathology.  The precise link between the metabolic abnormality and the neuropathologic condition remains unknown. Galactose-1-phosphate uridyltransferase is present in the brain in low concentrations. Hypoglycemia may contribute significantly to the pathologic findings in many cases. The toxic effect of galactitol accumulation is not fully understood but is clearly relevant to adverse outcomes in the brain and lens. Biochemistry.  The primary abnormality in galactosemia is the deficiency of activity of galactose-1-phosphate urid­ yltransferase (Fig. 39-1) that leads to accumulation of

galactose-1-phosphate in red blood cells, liver, and brain (Coelho et al., 2015). Galactose is metabolized through the following four possible pathways: 1. The reduction of galactose to galactitol 2. Oxidation of galactose to galactono-γ-lactone 3. The reaction of galactose-1-phosphate with uridine triphosphate to form uridine diphosphate galactose and eventually glucose-1-phosphate 4. The reaction of galactose-1-phosphate with uridine diphosphate-glucose to form uridine diphosphate-galactose and glucose-1-phosphate In classic galactosemia, the fourth pathway is obstructed; the other pathways function normally. The GALT locus is at 9p13; various genetic forms of galactosemia result from the presence of inefficient isoenzymes of galactose-1-phosphate uridyltransferase (Table 39-1). Most patients are compound heterozygotes, not true molecular homozygotes. The isoenzymes are separated and identified by electro­ phoresis. Transferase activity is absent in homozygous classic galactosemia (Q188R is the most common mutation in the United States). Activity is normal in the Los Angeles variant (L218L). Newborn screening for galactosemia is now performed in every state in the United States, but the detection rate for Duarte galactosemia varies with methodology. The GALT mutation database (http://www.arup.utah .edu/database/galt/GALT_display.php) contained 336 variants when accessed in 2015, most of which were missense mutations. Clinical Characteristics.  Infants usually are normal at birth, except for a slight decrease in birth weight. Symptoms become apparent when milk feedings begin. Jaundice usually develops between 4 and 10 days of age and persists for a longer period than does physiologic jaundice; it may be severe and the hyperbilirubiunemia may be indirect, requiring exchange transfusion. Progressive hepatic involvement in the first several weeks causes edema, hepatomegaly, and hypoprothrombinemia. Renal dysfunction is accompanied by generalized aminoaciduria, proteinuria, and acidosis. Escherichia coli sepsis is common, and may be the only (and recurrent) feature. Mild hypoglycemia also is common. Cataracts appear between 4 and 8 weeks, reflecting the accumulation of galactose-1phosphate or galactitol. Central nervous system impairment is manifested by lethargy and hypotonia, often associated with cerebral edema, which has been correlated with increased brain galactitol on magnetic resonance (MR) spectroscopy. A subgroup of patients may develop marked ataxia and tremor, which does not correlate with cognitive abilities or dietary restriction.

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders GALACTOSE +ATP

Galactitol Galactokinase deficiency

Galactokinase

Galactose-1-phosphate +UDP-Glucose Galactosemia Galactose-1-phosphate uridyltransferase UDP-Galactose

Clinical Laboratory Tests.  Biochemical tests for galactosemia screen for elevated levels of small molecules and directly assay the enzymes in the Leloir pathway. Bedside urine testing is positive for reducing substances but negative for glucose by the glucose oxidase method. Generalized aminoaciduria, proteinuria, and abnormalities on liver function tests are common. Magnetic resonance imaging (MRI) shows a variety of findings, including mild cerebral atrophy, cerebellar atrophy, ventriculomegaly, delayed maturation of white matter, and multiple small hyperintense lesions in the cerebral white matter on T2-weighted images. Management.  Because galactose is nonessential, exclusion from the diet is relatively easy. Milk and certain fruits and vegetables contain relatively high concentrations of galactose. Studies of the long-term outcome of therapy have been relatively disappointing, particularly in regard to preservation of central nervous system and ovarian function.

+NAD

Epimerase deficiency

in patients who are treated adequately, cognitive disability is common.

UDP-Galactose-4epimerase

Uridine Diphosphogalactose Epimerase Deficiency

UDP-Glucose +Pyrophosphate UDP-Glucose phosphorylase GLUCOSE-1-PHOSPHATE Figure 39-1.  Pathway of galactose metabolism depicting sites of metabolic block that lead to galactosemia. ATP, adenosine triphosphate; NAD, nicotinamide adenine dinucleotide; UDP, uridine diphosphate. TABLE 39-1  Biochemical Criteria for Assigning Phenotypes of Galactosemia* Galactose-1-Phosphate Uridyltransferase Activity†

Mobility†

Phenotype

Zygosity

Normal

Normal

Normal

–

Absent

None

Galactosemia (classic form)

Homozygous

Decreased

Duarte (fast)

Duarte variant

Homozygous

Absent

None

African American variant

Homozygous

Decreased

Normal

Galactosemia (classic form)

Heterozygous

Decreased

Slower

Indiana variant

Heterozygous

Much less

Slower

Rennes variant

Heterozygous

Increased

Faster

Los Angeles variant

Heterozygous

Decreased

Fast

Chicago variant

Heterozygous

Decreased

Normal

Munster variant

Heterozygous

*Characteristics of galactose-1-phosphate uridyltransferase. †Compared with normal.

Galactosemia may prove fatal at any time. Cirrhosis progresses inexorably in patients who do not receive treatment. Gonadal function in women with galactosemia is abnormal and usually manifests as primary ovarian failure. If treatment is not instituted, moderate to severe intellectual and motor retardation ensue in a majority of cases. Even

Uridine diphosphogalactose epimerase (GALE) deficiency has conventionally been separated into peripheral and generalized forms. Children previously recognized with generalized (severe) deficiency of GALE (see Fig. 39-1) had manifestations resembling those in classic galactosemia. Most survivors were dysmorphic and deaf. The GALE locus is at 1p36–p35. The patients are either homozygotes or compound heterozygotes for mutations. Three mutations (S81R, T150M, and P293L) have been reported in children with this intermediate form of GALE deficiency. Patients with GALE deficiency require exogenous galactose for the synthesis of glycolipids and glycoproteins.

Galactokinase Deficiency The birth incidence of galactokinase deficiency varies, ranging from a high of 1 in 52,000 in Bulgaria to 1 in 2200,000 in Switzerland. Deficiency of galactokinase activity causes a clinical condition similar to that in classic galactosemia. Patients have cataracts and accumulation of galactose. The GALK1 gene is located at 17q24. Biochemistry.  Galactokinase deficiency causes the accumulation of galactose, which eventually is metabolized to galactitol (see Fig. 39-1). Enzyme activity is reduced rather than absent in erythrocytes. Galactose-1-phosphate does not accumulate. Clinical Characteristics.  In a review of 55 patients, cataract was present in all cases, except for those detected by newborn screening. Thirty-five percent of the patients had other manifestations; only mental retardation and pseudotumor occurred in more than one patient in this series. The mental retardation was thought to be unrelated to the GALK deficiency. Cataracts, the only consistent manifestation of galactokinase deficiency, form in the first months of life. Management.  Treatment consists of elimination of galactose from the diet, as is the case for classic galactosemia.

ABNORMALITIES OF FRUCTOSE METABOLISM Hereditary Fructose Intolerance Biochemistry Fructose is rapidly absorbed from the gut, facilitated by the glucose transporters GLUT 2 and GLUT5, and is metabolized



Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

in the liver by the fructokinase pathway, through which it is linked to glycolysis, gluconeogenesis, glycogenolysis, and lipid metabolism. Fructose can also be synthesized endogenously from sorbitol, an important point in management. This condition results from a deficiency of hepatic fructose-1-phosphate aldolase B. The enzyme deficiency is inherited as an autosomalrecessive trait and has an estimated prevalence in central Europe of 1 in 26,100. Urinary fructose excretion also is present in a harmless metabolic variant resulting from fructokinase deficiency that should not be confused with hereditary fructose intolerance.

Clinical Characteristics and Differential Diagnosis Patients with hereditary fructose intolerance who ingest fructose experience nausea and vomiting; with continued exposure, weight gain is poor. Hypoglycemia begins immediately and reaches its low point 30 to 90 minutes after ingestion. Subsequent clinical and neuropathologic alterations result primarily from the hypoglycemia. Neurologic impairment is relatively uncommon but may result from hypoglycemia, cardiovascular collapse, or liver failure. Central nervous system complications include seizures with subsequent epilepsy, increased intracranial pressure, mental retardation, quadriplegia, and deafness.

Clinical Laboratory Tests and Diagnosis A hydrogen breath test is often employed to screen for HFI but may produce serious adverse effects. Assay of fructose1-phosphate aldolase B in liver tissue permits definitive diagnosis, but liver biopsy may be avoided by direct genotyping in most patients. Fructosemia causes abnormal glycosylation of transferrin, leading to misdiagnosis of CDG1x on occasion.

Management Fructose elimination from the diet is accomplished by limited selection of vegetables and cereal products. Sorbitol should also be avoided, as it is an endogenous source of fructose. Dietary counseling is essential for successful therapy.

Fructose-1,6-Diphosphatase Deficiency Details are available online.

GLYCOGEN STORAGE DISEASES The biochemistry of the glycogen storage diseases (GSDs) illustrates the diverse effects of genetically determined enzymatic deficiencies along a single metabolic pathway. In spite of a few inconsistencies and a number of unexplained conditions, a logical approach to these diseases is practical. The GSDs are a family of diseases sui generis, with the exception of at least two disorders that can be included under the rubric of lysosomal diseases—Pompe disease and Danon disease. Indeed, the first lysosomal disease defined as such was Pompe disease. General characteristics of this disease family are discussed in Chapter 41. Patients have also been described who accumulate glycogen in autophagic vacuoles but who do not appear to have an enzymatic deficiency. This phenotype, named Danon disease, is known to result from deficiency of lysosomal-associated membrane protein 2. This X-linked dominant disorder has multisystem effects, most consistently involving the heart and skeletal muscle (Endo et al., 2015). There is general agreement on the numeric designations of GSDs I to VI, but the nomenclature beyond that is confusing.

307

For example, GSD types VIII and X were originally considered distinct conditions but are now classified with GSD VI by many authors. Clinical manifestations of GSD often result from glucose deficiency, with ensuing hypoglycemia occurring separately or in association with increased glycogen storage. The location of the enzymatic block in the pathway determines whether the configuration of the glycogen is normal or abnormal. GSDs result in the accumulation in various tissues of increased concentrations of glycogen of normal or abnormal configuration (Table 39-2). These diseases result from a deficiency or absence of specific enzyme activity in the metabolic pathway of glycogen. The glucose molecule is the prime building block in the multistep synthesis of glycogen (Fig. 39-2; see also Table 39-2). Glycogen synthesis occurs in many tissues, predominantly in liver, kidney, and muscle. The details of the metabolic pathway are described online.

Glucose-6-Phosphatase Deficiency (Von Gierke Disease, Glycogen Storage Disease Type I, Hepatorenal Glycogenosis) Pathology Patients with von Gierke disease, now known as glycogen storage disease type I, have hepatomegaly and renomegaly. Light microscopy reveals enormous amounts of glycogen in liver cells and in the cells of the renal convoluted tubules. No increase in the concentration of glycogen is found in skeletal muscle, tongue, or heart.

Biochemistry Two distinct subgroups of glycogen storage disease type I have been identified: those with primary glucose-6-phosphatase deficiency (type Ia) and those phenocopies with additional features of immune impairment (neutropenia and neutrophil adherence defects), now designated as glycogen storage disease type I non-a. Glycogen storage disease type I non-a disorder originally was thought to result from defects in a multicomponent translocase system responsible for transporting glucose-6-phosphatase into microsomes. Cloning of the glucose-6-phosphatase translocase gene (G6PT) demonstrated that the previously proposed subtypes b, c, and d all were associated with mutations in G6PT, producing different kinetic variants. The G6PC gene that codes for glucose-6phosphatase is located at 17q21. All forms share common clinical manifestations that are attributable to abnormal metabolism of glucose-6-phosphate. In type Ia, glucose-6-phosphatase deficiency results in storage of glycogen of normal configuration in the liver and kidneys. The enzyme activity is absent or extremely low.

Clinical Characteristics Hypoglycemia causes much of the morbidity during the first year of life. Seizures are frequent and almost invariably are the presenting complaint of affected children. Hypoglycemia may result in severe, chronic neurologic impairment, including hemiplegia. Hepatomegaly and the failure to thrive syndrome are commonly present. Epilepsy, deafness, and neuroradiologic abnormalities occur far in excess of the rates in the general population or in children with other causes of neonatal hypoglycemia. MRI abnormalities include dilatation of occipital horns and/or hyperintensity of sub­ cortical white matter in the occipital. Subcutaneous fat often is increased, and xanthomas occur over the extensor

39

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders

TABLE 39-2  Glycogen Storage Diseases (GSDs) Name*

Clinical Manifestations

Glycogen Structure

Enzyme Defect

1. Glucose-6-phosphatase deficiency (von Gierke disease, Type I GSD)

Enlarged liver and kidneys; hyperlipidemia; hypoglycemia; ketoacidosis; seizures

Normal

Glucose-6-phosphatase

2. Infantile acid α-glucosidase deficiency (Pompe disease, Type II GSD)

Cardiomegaly; death in infancy; progressive hypotonia and weakness; swallowing and respiratory difficulty

Normal

Acid α-Glucosidase

3. Late infantile acid α-glucosidase deficiency, adult acid α-glucosidase deficiency

Atonic anal sphincter; calf muscle hypertrophy; hip weakness (Gowers’ sign); slow or regressing motor development, contractures of Achilles tendons

(?)Abnormal—short outer chains

Acid α-Glucosidase

4. Debrancher deficiency (Cori disease; Forbes limit dextrinosis, Type III GSD)

Hepatomegaly; hypoglycemia; late-onset weakness; mild growth failure; early, severe weakness with myopathy rare

Abnormal—short outer chains, increased branch points

Amylo-1,6-glucosidase

5. Brancher deficiency (Andersen’s disease, Type IV GSD)

Cirrhosis; growth failure; hepatosplenomegaly; hypotonia; muscle wasting in lower extremities; slow motor development; weakness

Abnormal

Amylo-1,4→1,6transglucosidase

6. Myophosphorylase deficiency (McArdle disease, Type V GSD)

Atrophy in older patients; myoglobinuria; poor stamina; severe muscle cramps with exercise

Normal

Muscle phosphorylase

7. Hepatophosphorylase deficiency (Hers disease, type VI GSD)

Growth retardation; hepatomegaly; hypoglycemia; mild ketosis

Normal

Liver phosphorylase

8. Phosphorylase kinase deficiency; Type IX GSD (also deficiency of activation sequence including loss of activity of 3′,5′-AMP-dependent kinase in muscle and probably liver); Type IX GSD

Marked hepatomegaly, with glycogen storage; no hypoglycemia; no skeletal muscle disease; normal mental development

Normal

Phosphorylase kinase or 3′,5′-AMP-dependent kinase

9. Phosphoglucomutase deficiency (PGM1-CDG; CDG 1t)

Calf hypertrophy; mild generalized weakness; regression in motor development; toe-walking

Normal

Phosphoglucomutase

10. Phosphohexose isomerase deficiency

Late-onset myopathy; muscle cramps; poor stamina

Normal

Phosphohexose isomerase

11. Phosphofructokinase deficiency (Tarui disease; Type VII GSD) Other defects of terminal glycolysis, including deficiency of phosphoglycerate kinase and lactate dehydrogenase

Similar to those in myophosphorylase deficiency

Normal

Muscle Phosphofructokinase Phosphoglycerate kinase; lactate dehydrogenase

12. Glycogen synthetase deficiency; Type 0 GSD

Hypoglycemia; mental retardation; seizures

Normal

Glycogen synthetase

*The accompanying numerals identify these abnormalities in the pathway of glycogen metabolism shown in Figures 39-2 and 39-3.

surfaces of the limbs and buttocks. Affected children frequently have massive enlargement of the liver. Hepatic adenomas develop in between one-half and three-quarters of adults with glycogen storage disease I; about 10% undergo malignant transformation. Type I non-a patients typically have recurrent stomatitis, frequent infections, and chronic inflammatory bowel disease secondary to neutropenia and neutrophil dysfunction.

Clinical Laboratory Tests The diagnosis can be made by assaying the enzyme activity in liver and peripheral white blood cells. Direct assay of hepatic glucose-6-phosphatase activity in liver has been replaced by mutational analysis in most patients. Severe hypoglycemia frequently occurs because of the failure of glucose formation from glucose-6-phosphate. Severe acidosis is usually associated with lactic acidemia and pyruvic acidemia; hyperuricemia is frequent.

Management The goal of therapy is to provide sufficient free glucose to maintain a normal blood glucose concentration. Continuous nocturnal intragastric infusion of glucose has been relatively successful, but is challenging for many children. Subsequently, the use of cornstarch suspensions given during the day obviated the need for nocturnal infusion in some children. Substitution of medium-chain triglycerides for long-chain triglycerides in the diet, along with normal carbohydrate consumption, leads to significant decrease in serum lipid levels, disappearance of eruptive xanthomas, and decrease in liver mass. Surgical treatment for glucose-6-phosphatase deficiency involves creation of a portacaval shunt, which increases the peripheral blood glucose by allowing portal blood to bypass the liver after absorption of glucose from the gut; excellent metabolic control can be achieved over the long term, and the operation does not preclude subsequent liver transplantation.



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Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

-1,4 Glucosidase (unknown pathway)

39 2,3

Glycogen Branching enzyme (amylo 1,4 1,6 transglucosidase)

5

6,7,8

Phosphorylase a* (acts on 1,4 linkages)

Glycogenesis

Glycogen synthetase

Limit dextrin 12

Uridine diphosphate glucose (activated glucose)

UDPG-Phosphorylase

4

Debranching enzyme (amylo-1,6 glucosidase cleaves 1,6 linkages)

7,8

Phosphorylase a* (acts on newly exposed 1,4 linkages after 1,6 linkages broken)

GLUCOSE-1-PHOSPHATE Phosphoglucomutase

Glycolysis (Embden-Meyerhof pathway)

Glucose + ATP

9

Hexokinase

Glucose-6-phosphatase GLUCOSE

Glucose-6-phosphate

Phosphohexose isomerase

Glycogenolysis

Glucosyl chain (1,4 linkages)

10

1

Fructose-6-phosphate Phosphofructokinase Fructose

Fructokinase

11 Fructose-1,6-diphosphate Aldolase

Glyceraldehyde-3-phosphate

Dihydroxyacetone phosphate

**

Lactate Lactic acid dehydrogenase PYRUVATE Figure 39-2.  Pathways of glycogen metabolism depicting sites of metabolic block that lead to glycogen storage disease. See Table 39-2 for description of abnormalities denoted by Arabic numerals enclosed in boxes. *See Figure 39-3 for phosphorylase activation sequence. **Other defects of terminal glycolysis.

Liver transplantation has been reported to produce beneficial results.

Acid α-Glucosidase (GAA, Acid maltase) Deficiency, Infantile Type (Pompe Disease, Idiopathic Generalized Glycogenosis, Glycogen Storage Disease Type II) Pathology Infants with GSD type II have a severe vacuolar myopathy, with accumulation of large amounts of periodic acid–Schiffpositive material within cardiac, skeletal, and smooth muscle

fibers and in liver, renal tubules, lymphocytes, glial cells, anterior horn cells, and brainstem nuclei in infantile cases. Storage in later-onset cases is largely restricted to skeletal muscle.

Biochemistry GSD II is associated with deficient activity of the lysosomal enzyme acid α-glucosidase (α-1,4-glucosidase), located at 17q25.2–q25.3; this is the only enzyme capable of hydrolyzing glycogen to glucose in the acidic environment of the lysosome. Glycogen structure has consistently been normal, and its accumulation is restricted primarily to lysosomes, although lysosomal breakdown and cytoplasmic accumulation with disruption of muscle fibers occur in severe cases. The

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders

accumulation of autophagosomes impairs the effectiveness of enzyme replacement therapy by acting as a sink for infused enzyme. A number of allelic variations have been described and may explain the differences in age at onset. In general, the location and nature of mutations predict the phenotype, but exceptional cases are described in which relatively mild phenotypes occur despite low levels of α-glucosidase expression in cultured fibroblasts.

Clinical Characteristics Development is usually normal for several weeks to several months; then the affected infant presents with feeding difficulties, weakness, or respiratory impairment (Fig. 39-4). Little spontaneous movement occurs, and the cry is short-lived and weak. Swallowing is grossly limited, and the accessory muscles of respiration are weak. Massive cardiomegaly develops, and a serial echocardiography reveals progressive left ventricular posterior wall diastolic thickening. Hepatomegaly is almost universally present. Subcutaneous fat is sparse, and the muscles are small and firm. The tongue often is enlarged. Deep tendon reflexes are lost by the age of 6 months. Affected infants undergo progressive debilitation, and almost all die by 2 years.

Clinical Laboratory Tests Acid α-glucosidase (α-1,4-glucosidase) activity can be measured in blood samples or dried blood spots; mutational analysis is increasingly used as a first line diagnostic approach. A urinary glucose tetrasaccharide, Glc-alpha-1,6 –Glc-alpha1,4Glc –alpha-1,4-Glc (Glc4) has proven to be a sensitive biomarker for Pompe disease. Electromyography (EMG) shows myopathic changes; polyphasic potentials and a reduced interference pattern with low voltage. Unusual high-frequency discharges, best described as myotonic, are very common.

Genetics GAA deficiency is inherited as an autosomal-recessive trait. The gene for human acid α-glucosidase maps to chromosome 17q25.3; it is approximately 20 kb in length and contains 20 exons. More than 300 mutations have been reported in 2015 and are cataloged online at http://cluster15.erasmusmc.nl/ klgn/pompe/mutations.html?lang=en.

Management Dietary supplementation with L-alanine, designed to reduce the elevated protein turnover characteristic of acid α-glucosidase deficiency, has apparently slowed progression of weakness and even reversed cardiomyopathy in some patients with late infantile and juvenile forms. In 2006, ERT received Food and Drug Administration (FDA) approval for treatment of acid α-glucosidase deficiency. Infants who received treatment early in the course of their illness demonstrated improved strength and cardiac function, with survival now extending over several years. It has become apparent that ERT is most effective at reversing cardiomyopathy and extending the life span of infants, but that skeletal muscle disease is relatively resistant to this modality (Hahn et al., 2015).

Late Infantile GAA Deficiency A number of children have been reported who are deficient in acid α-glucosidase activity without the phenotype of Pompe disease. These children are asymptomatic during the first

year of life and live beyond the age of 2 years. Most have slowly progressive weakness but no gross signs of overt deposits of glycogen in skeletal or heart muscle or in visceral organs. Symptoms and signs may mimic those of Duchenne muscular dystrophy (Fig. 39-5). Achilles tendon contractures result in equinus gait. Cardiomegaly is absent, and an intermittent soft, systolic murmur may be heard.

Clinical Laboratory Tests Light and electron microscopy of muscle biopsy material displays moderate glycogen storage; the glycogen-containing areas appear vacuolated (Fig. 39-6). EMG documents polyphasic potentials and a reduced, lowvoltage interference pattern. The bizarre, myotonic potentials described in early infantile acid α-glucosidase deficiency also occur in the late infantile form.

Biochemistry Aside from the accumulation of glycogen and its possible abnormal architecture, the most prominent abnormality described is a deficiency of acid α-glucosidase activity.

Management Attempts to manage patients by dietary means enjoyed modest success after initially disappointing results (see previous mention). At present, ERT appears to offer the best hope for definitive treatment in this group of patients.

Juvenile and Adult GAA Deficiency A slowly progressive myopathy characterizes juvenile and adult GAA deficiency. Limb girdle weakness is the most common presentation, but muscle pain is relatively common. Most patients complain of fatigue. Ventilatory failure may be the presenting complaint in as many as one-third of adults, sometimes with predominantly nocturnal symptoms. Laboratory abnormalities include increased serum enzyme activity of creatine, aspartate aminotransferase, and lactate dehydrogenase. Adult cases cannot be delineated from infantile and late infantile cases on the basis of muscle GAA activity. Adult patients do not have enlargement of the liver, heart, or tongue. EMG changes and histologic and electron microscopic findings in muscle biopsy specimens in adult cases are similar to changes in infantile and late infantile cases. Enzyme replacement therapy tends to slow rather than reverse weakness in late onset cases based on a recent openlabel study (Park et al., 2015).

Amylo-1,6-Glucosidase Deficiency (Debrancher Deficiency, Cori Disease, Forbes Disease, Limit Dextrinosis, Glycogen Storage Disease Type III) Pathology Electron microscopy of skeletal muscle has demonstrated glycogen deposits just inside the sarcolemmal membrane and between the filaments of the I and A bands, as well as between the myofibrils. These abnormalities are not pathognomonic for this glycogenosis, now classified as glycogen storage disease type III. Glycogen storage in liver is indistinguishable from glycogen storage in other hepatic glycogenoses.



Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

311

Biochemistry

Management

The human muscle glycogen debranching enzyme (AGL) is localized to 1p21. It encodes six isoforms that manifest two distinct functions, both as a debranching enzyme and as a transferase. GSD type III has marked genetic heterogeneity. GSD type IIIa is associated with mutations downstream to exon 3, whereas GSD type IIIb is associated with mutations in exon 3. Several designated biochemical categories of type III glycogenosis have been identified. In type IIIa deficiency (both transferase and glucosidase deficiency), debranching enzyme activity is either absent or greatly reduced in liver and muscle. When the enzyme activity is deficient in liver alone, the condition is designated type IIIb. Type IIIc patients have deficient glucosidase but not transferase activity. Myogenic hyperuricemia is common in this condition but is not unique; hyperuricemia also accompanies glycogenosis type V and type VII.

Patients with growth failure and hepatic dysfunction, including hypoglycemia, appear to benefit from the administration of oral cornstarch, but overtreatment with carbohydrates may be harmful. Cardiomyopathy has been shown to improve with either a high protein or ketogenic/high protein diet.

Clinical Characteristics Infantile Type.  Patients with debrancher enzyme deficiency may have muscle or liver involvement, or both. The infantile type usually manifests in the first few months of life and is associated with hypoglycemia, failure to thrive, and hepatomegaly. Affected infants are hypotonic and weak and have poor head control. Glycogen deposition in cardiac muscle is rarely sufficient to create clinical disturbances. Association of debranching disease with profound cardiac muscle and skeletal muscle involvement accompanied by thyroid insufficiency also has been reported. Childhood Type.  GSD type III presents with exercise intolerance and heart failure. Cardiac and skeletal muscle contains increased stores of glycogen. Branching enzyme deficiency was confirmed with further studies. Hyperlipidemia, hypertriglyceridemia, and reduced bone density may all occur. Adult Type.  Debrancher enzyme deficiency also occurs in older children and adults. Adult patients with GSD type III manifesting as chronic progressive myopathy in middle age have been described; they account for a minority of this population. Progression of muscle disease can be monitored with serial ultrasound examinations. Patients with debrancher deficiency should be monitored for cardiac involvement, although this is usually asymptomatic. Progressive cirrhosis may be more common in adult GSD type III than was previously recognized and, occasionally, is complicated by hepatocellular carcinoma. Debrancher deficiency is often associated with hypotonia and hepatomegaly. Later in childhood, patients complain of muscle fatigue without tenderness, cramping, or associated hematuria. Persistent diffuse weakness is present, and wasting of the hand and forearm muscles with loss of body weight ensues. Patients may experience recurrent seizures.

Clinical Laboratory Tests Electromyography and nerve conduction studies show no evidence of peripheral neuropathy, but myopathic discharges are common. Serum creatine kinase activity may increase before and after exercise. Fasting ketotic hypoglycemia is characteristic of GSD, type III; hypertriglyceridemia, hyperlactic acidemia, and hyperuricemia may be observed. Blood lactic acid does not increase on ischemic exercise.

Genetics GSD type III is inherited as an autosomal-recessive trait. The diagnosis is generally confirmed by gene sequencing.

Amylo-1, 4 →1,6 Transglucosidase Deficiency (Brancher Enzyme Deficiency, Glycogen Storage Disease Type IV) GSD type IV (Andersen disease) results from a deficiency of glycogen branching enzyme (GBE), leading to the accumulation of abnormal glycogen resembling amylopectin in affected tissues. The reported phenotypes are marked primarily by liver involvement. GSD type IV has been characterized as the most heterogeneous of the glycogen storage diseases (Magoulas and El-Hattab, 1993).

Pathology Glycogen may accumulate disproportionately in the tongue and diaphragm in comparison with other striated muscles. The characteristic lesion is the polyglucosan body, a periodic acid–Schiff-positive inclusion that also is seen in phosphofructokinase deficiency, Lafora body disease, double athetosis (Bielschowsky bodies), and aging (corpora amylacea).

Biochemistry The first patient described with deficiency of brancher enzyme activity manifested cirrhosis of the liver and glycogen accumulation, but patients with normal and decreased muscle glycogen concentrations also have been described. These biochemical phenotypes correspond to clinical forms with rapidly progressive cirrhosis through nonprogressive liver disease. Brancher enzyme deficiency results in the synthesis of unbranched glycogen composed of elongated chains of glucose molecules joined together in 1,4 linkages. As a result, the glycogen is composed of long outer chains, has few branch points, and resembles the pattern of starch also known as amylopectin.

Clinical Characteristics Manifestations of the disease—failure to thrive, hepatosplenomegaly, and liver failure with cirrhosis—usually appear in the first 6 months of life. Affected infants exhibit delayed motor and social development, hypotonia, weakness, and muscle atrophy, accompanied by absent or decreased deep tendon reflexes. Fetal onset with cervical cystic hygroma, akinesia, polyhydramnios and multiple pterygia is the most severe manifestation of GSD IV. A mild, predominantly myopathic variant has been reported in older children and has a highly variable course. Adults with polyglucosan body disease who manifest late-onset pyramidal quadriparesis, micturition difficulties, peripheral neuropathy, and mild cognitive impairment have been described. Jewish families with adults with polyglucosan body disease were homozygous for a Tyr329Ser mutation in GBE1. Not all such patients have recognized GBE mutations or impaired GBE activity, suggesting both phenotypic and genotypic heterogeneity.

Clinical Laboratory Tests Diagnosis of brancher deficiency by assay of peripheral white blood cells, skin fibroblasts, and amniotic cell activity is feasible, but diagnosis by mutational analysis is usually preferable.

39

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders

Genetics Inheritance is autosomal-recessive. Prenatal testing using cultured amniocytes and chorionic villi is feasible, but has been superseded by molecular analysis when available. The gene encoding brancher enzyme, GBE1, may contain missense, nonsense, intronic donor and acceptor splice-site mutations, small deletion frame shift mutations, small insertion frame shift mutations, or large deletions. Missense mutations are more likely to be associated with milder phenotypes, and truncating mutations or large deletions with severe forms of the disease.

Management Attempts at enzyme replacement were unsuccessful. Liver transplantation has been successful in a number of patients, but mortality in GSD IV patients may be high.

McArdle Disease (Myophosphorylase Deficiency, Glycogen Storage Disease Type V) In 1951, McArdle reported a condition characterized by weakness, fatigue, and severe muscle cramping with pain after exercise. He subsequently noted the lack of normal lactate production in the affected muscles after ischemic work. McArdle disease is classified as glycogen storage disease type V (GSD V).

Pathology Light microscopic studies of muscle reveal moderately increased stores of glycogen beneath the sarcolemmal membrane. Electron microscopy demonstrates disorganization of the I band region and distortion of the myofibrils secondary to glycogen deposition. Quantitative biochemical studies show reduced or absent myophosphorylase activity.

Biochemistry Glycogen breakdown to lactate begins with the initial disruption of the 1,4 linkage between glucosyl units. The enzyme myophosphorylase facilitates this reaction in skeletal muscle. After this linkage is cleaved, glucose-1-phosphate is freed and metabolized to lactate through the Embden-Meyerhof pathway. The myophosphorylase enzyme is regenerated in a complex reaction involving a number of other enzymes, including phosphorylase kinase (see Fig. 39-3). Absence of myophosphorylase activity results in decreased glucose-1-phosphate production; as a result, lactic acid is not formed in exercised muscle, and serum lactic acid concentration is not appropriately elevated (Fig. 39-7).

Clinical Characteristics Affected children have decreased stamina and tire easily. Severe cramping pain after minimal exercise is noted in the involved skeletal muscles. Cardiac symptoms are not usually reported, but cardiac muscle is involved. Myoglobinuria occurs with moderate or strenuous exercise. In adolescence and adulthood, persistent weakness may develop, with moderate loss of muscle bulk. A “second wind” phenomenon has been described. This phenomenon has been attributed to improved energy production when metabolic dependence switches from glycogen stores to blood-borne fuels, including glucose and fatty acids, and is consistently seen in GSD type V but not in GSD type VII, whose phenotype is otherwise indistinguishable. Prolonged or frequent repetitive episodes of myoglobinuria may result in both acute and chronic renal failure.

Onset usually is in childhood; neonatal and adult onset has been reported. A very severe phenotype, lethal in infancy, was reported in a child born to consanguineous parents with mutations in both PYGM and dGK, the gene encoding deoxyguanosine kinase, whose deficiency causes the hepatic form of mitochondrial depletion syndrome.

Clinical Laboratory Tests Exercise results in elevated serum creatine kinase activity and increase in activity of other serum enzymes released from muscle, ostensibly a result of loss of sarcolemmal membrane integrity. The ECG may demonstrate an increased QRS amplitude, a prolonged R-S interval, T wave inversion, and bradycardia. Electromyographic study of contracted muscles after exercise reveals a decreased interference pattern; after ischemic exercise, the contracted muscles may demonstrate no electrical activity. Ischemic exercise testing is described online.

Genetics The gene encoding synthesizing myophosphorylase, PYGM, is located at 11q13. A number of mutations have been described but do not appear to explain the clinical heterogeneity of GSD type V. A initial study of potential genetic modifiers found a strong association between angiotensin-converting enzyme genotype and clinical phenotype, suggesting that angiotensinconverting enzyme is a modifier of PYGM; a further study also found that female gender conferred a more severe phenotype. GSD V is transmitted as an autosomal-recessive trait and may manifest in a heterozygote.

Management A controlled trial of oral sucrose loading showed improved exercise tolerance and stable glucose levels in 12 adults with GSD type V. Although not suitable for continuous use owing to its tendency to induce weight gain, this regimen, combined with aerobic conditioning, appears likely to be useful in improving performance under stressful conditions and may protect against acute rhabdomyolysis. A review of published trials found that there was low-quality evidence of improvement in some disease measures with creatine, sucrose, ramipril, and a carbohydrate rich diet but no unequivocal evidence of clinical benefit (Quinlivan et al., 2014).

Hepatophosphorylase Deficiency (Hers Disease, Glycogen Storage Disease Type VI) Biochemistry GSD type VI was described by Hers in 1959 and is characterized by increased glycogen stores of normal configuration in the liver. Hepatic phosphorylase (hepatophosphorylase) activity is diminished or absent. Because of the possibility of abnormalities in the complex activating mechanism of hepatophosphorylase, systematic study of enzyme activity in suspected hepatophosphorylase deficiency is necessary to exclude phosphorylase kinase deficiency and other metabolic errors in the activating sequence. GSD VI could only be diagnosed by enzymology of liver tissue until the PYGL gene was identified. A series of eight patients with GSD VI from seven families were studied and found to harbor 11 novel mutations, most of which were missense. The patients’ symptoms ranged from hepatomegaly and subclinical hypoglycemia, to severe hepatomegaly with recurrent severe hypoglycemia and postprandial lactic acidosis.



Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

313

EPINEPHRINE, GLUCAGON, AND OTHERS

Adenylate cyclase Inactive form

39

Adenylate cyclase Active form

*ATP Cyclic AMP

8 Protein kinase Inhibited form

Inhibitor ··· cAMP Protein kinase Active form 8

*Phosphorylase kinase Inactive form

ATP

ADP

Phosphorylase kinase-phosphate Active form 8 ATP

ADP

*Phosphorylase b Inactive form Phosphorylase a-phosphate Active form

6,7

* Amplification effect at this step.

Figure 39-3.  Activation sequence of phosphorylase. See Table 39-2 for description of abnormalities denoted by the Arabic numerals enclosed in boxes. ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate. (Modified from Goldberg, N.B., 1974. Vigilance against pathogens. Hosp Pract 9, 127.)

Clinical Characteristics

Genetics

The patients display various degrees of growth retardation, hypoglycemia, ketosis, and hepatomegaly. Specific neurologic findings are absent. Muscle and cardiovascular tissues are not primarily involved.

The gene coding for the enzyme liver glycogen phosphorylase is located on chromosome 14 at 14q21–22. The condition is transmitted as an autosomal-recessive trait. Most mutations are missense; there are no common mutations.

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders

Management Symptoms can be controlled with frequent small carbohydrate meals. No other forms of therapy have been necessary or recommended.

Muscle Phosphofructokinase Deficiency (Tarui Disease, Glycogen Storage Disease Type VII) Biochemistry The enzyme phosphofructokinase transforms fructose-6-phosphate to fructose-1,6-diphosphate. Decreased activity of this enzyme results in increased muscle glycogen stores of normal structure and increased concentration of glucose-6-phosphate and fructose-6-phosphate (Musumeci et al., 2012). Phosphofructokinase exists in five different isoforms with tissue-specific distribution.

Clinical Characteristics Motor development is normal during the first decade, but patients experience decreased exercise tolerance and easy fatigability during childhood. They complain of muscle stiffness and weakness and, occasionally, muscle cramps. Myoglobinuria may follow moderate to strenuous exercise and has precipitated acute renal failure. The clinical pattern is reminiscent of McArdle disease, except for the absence of a “second wind” phenomenon in GSD type VII. Physical examination in patients with GSD type VII is unremarkable, except for variable weakness and loss of skeletal muscle bulk.

Clinical Laboratory Tests After exercise, serum creatine kinase and other serum enzymes released from muscle may be elevated. EMG findings may be normal. Ischemic exercise testing, as described earlier for McArdle disease, results in muscle contracture and decreased lactic acid production. The definitive diagnosis is made by enzymatic assay of muscle tissue.

Genetics The phosphofructokinase gene (PFKM) is encoded at 12q13.3. GSD type VII is prevalent in Ashkenazim; 95% of mutant alleles in this population are accounted for by a splicing mutation in exon 5 (IVS5 + 1 G>A) or a single nucleotide deletion (del C2003).

Hepatic Phosphorylase Kinase Deficiency (Glycogen Storage Disease, type IX) and Activation Abnormalities Some patients with glycogen storage disease have defects in control of the phosphorylase system at the phosphorylase kinase level, rather than a deficiency of the phosphorylase enzyme (see Fig. 39-3). Although they appear to have hepatic phosphorylase deficiency disease, further studies identify the presence of the enzyme when activation cycle materials are added in vitro. Phosphorylase kinase has a hexadecameric structure: (α, β, γ, δ) 4. The δ subunit is calmodulin, which interacts with calcium. The α subunit is encoded by PHKA2 (at Xp22), the β subunit by PHKB, and the γ subunit by PHKG2. Mutations in these three genes have been associated with phosphorylase kinase deficiency and a GSD phenotype. Current nomenclature subdivides phosphorylase kinase deficiency into four types, GSD IX a through d.

Most cases are grouped together as GSD IXa, X-linked liver glycogenosis, or PHKA2- related phosphorylase kinase deficiency. This relatively mild phenotype most often presents with hepatomegaly in childhood, associated with fasting hypoglycemia, growth and motor delays. Hyperketotic hypoglycemia may be associated with nausea and vomiting; transaminases are often elevated. Some patients experience liver fibrosis or cirrhosis. GSD IXb affects liver and muscle and is associated with mutations in PHKB. Liver manifestations usually predominate, and weakness is not apparent in some patients. Hypoglycemia and short stature are also encountered. Phosphorylase kinase deficiency type c (GSD IXc) has a phenotype very similar to types a and b, but generally more severe. The PHKG2 gene is mutated; inheritance is autosomal recessive. Splenomegaly may occur, and the risk of cirrhosis may be greater than in the preceding types. The least common form of phosphorylase kinase deficiency (GSD IXd) is a pure muscle form, associated with mutatins in PHKA1in which the liver is unaffected. The phenotype is characterized by progressive weakness, cramps, and pain after exercise. Most cases present in adults, although earlier onset has been reported. Some patients with the genetic and biochemical defect may be asymptomatic. There are no systematic studies of therapy in type IX glycogen storage disease.

Phosphohexose Isomerase Deficiency (Satoyoshi Disease) Phosphohexose isomerase is also known as glucose phosphate isomerase and phosphoglucose isomerase. This enzyme catalyzes the interconversion of glucose-6-phosphate and fructose6-phosphate in the Embden-Meyerhof pathway. Most reported cases of deficiency of this enzyme have been manifested as hemolytic anemia, but a few kindreds have been reported with skeletal muscle dysfunction. Satoyoshi and associates described a family whose members experienced muscle pain and stiffness with exercise beginning in childhood. The symptoms become more prominent in later life. Muscle contractures do not occur after ischemic exercise. Routine examination is normal. Heavy exercise leads to stiffness and tenderness of the muscles without apparent weakness. Lactic acid does not increase during ischemic exercise and serum creatine kinase is increased, but findings on EMG remain normal. GPI has been assigned to 19cen–q12. It consists of 18 exons and is 40 kb in length. The gene codes for two proteins in addition to hexose phosphate isomerase: neuroleukin, a chemokine, and autocrine motility factor. Antibodies to glucose phosphate isomerase have been shown to sustain a rheumatoid arthritis-like condition in experimental animals and humans. A Japanese report summarized the expanded phenotype of Satoyoshi disease, which includes painful muscle cramps, alopecia, intractable diarrhea, bone and joint deformity, and endocrine disturbances.

Phosphoglucomutase Deficiency   (Thomson Disease) The phosphoglucomutases are a family of enzymes catalyzing the interconversion of glucose-1-phosphate and fructose-1phosphate. The first recognized case presented in early infancy. This was a boy who experienced numerous episodes of supraventricular tachycardia, requiring digitoxin treatment; development then proceeded normally until the age of 2 years, when he began to walk on his toes. Examination revealed mild weakness and poor muscle development. His calf muscles



Diseases Associated with Primary Abnormalities in Carbohydrate Metabolism

were bulky and firm, and shortening of the Achilles tendons was noted. No clinical history of exercise intolerance, muscle pain, or myoglobinuria was elicited. Serum enzyme activities, including creatine kinase, aldolase, glutamic-oxaloacetic transaminase, and glutamic-pyruvic transaminase, were elevated. Examination by EMG showed myopathic changes. In vitro study of biopsy tissue indicated a number of relative enzymatic deficiencies, but phosphoglucomutase deficiency was most pronounced. Glycogen structure appeared normal. Also evident was extensive replacement of muscle tissue by glycogen. A 35-year-old man with exercise-induced cramps, mild limb girdle weakness, episodes of rhabdomyolysis, normal elevation of lactate, and hyperammonemia on a forearmexercise test has also been reported. The investigators suggested that this disorder should be designated glycogenosis type XIV, a suggestion which has not been widely accepted, given the already confusing state of glycogenosis nomenclature. A follow up study of this patient, two others identified by an independent group and sixteen new patients, described the findings in a total of 19 patients (Tegtmeyer et al., 2014). Although the phenotypes were highly variable, all had evidence of liver disease, with elevated transaminases, and, in some cases, steatosis or fibrosis. Most had clinical muscle disease, with weakness and exercise intolerance. Five subjects had experienced rhabdomyolysis. Dysmorphic features included cleft palate and bifid uvula. Cardiomyopathy, short stature, and delayed puberty occurred in fewer than half of the subjects. Laboratory abnormalities included elevated creatine kinase and hypoglycemia. This spectrum of findings is highly suggestive of a congenital disorder of glycosylation (see Chapter 40), and these patients were found to have mixed type I and type II patterns of transferrin glycoforms. Oral galactose treatment improved these laboratory abnormalities in some patients, with resolution of hypogonadotropic hypogonadism in two girls. This disorder is now designated PGM1-CDG (CDG 1t using the older nomenclature).

Other Defects of Glycolysis Causing   Glycogen Storage Three enzyme defects affecting the terminal glycolysis pathway have been reported, involving phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase. Phosphoglycerate kinase deficiency is an X-linked disorder manifesting with varying combinations of hemolytic anemia, seizures, mental retardation, and exercise intolerance with myoglobinuria. Up to 2007, 26 families had been reported. Phosphoglycerate mutase deficiency (PGAMD—glycogen storage disease, type X) has been associated in adults with myalgia, cramps, and myoglobinuria after exercise. Twelve well-verified patients had been described by 2009, nine of whom were African American. A patient with PGAMD who experienced muscle cramps on forearm ischemic exercise testing was protected from cramps by dantrolene, suggesting that cramps in this disease reflect excessive calcium release from the sarcoplasmic reticulum relative to calcium reuptake capacity. Lactate dehydrogenase M subunit deficiency has been reported in three families with exertional myoglobinuria. Additional cases have been identified, and a number of mutations identified in the responsible.

Defects Impairing Glycogen Formation Muscle glycogen storage disease (glycogen storage disease, type 0) results from deficiency of glycogen synthase 1, encoded by the GYS 1 gene. Glycogen synthase 1 catalyzes the addition

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of glucose monomers to the glycogen molecule through alpha-1,4-glycoside linkages. Three families have been reported. Clinical manifestations include exercise intolerance and cardiac disease (leading to seizures and sudden death associated with long QT syndrome in the index case), recurrent syncope, weakness, and muscle pain. Mutations in GYG1, which encodes glycogenin, may also cause muscle glycogen depletion. Glycogenin is required to activate glycogen synthesis; glucose molecules attach to glycogenin to form oligosaccharide chains. The index case was a 27-year-old man who experienced palpitations and dizziness after exercise. He had mild proximal arm, shoulder, and trunk weakness, and an abnormal ECG; an echocardiogram was normal. Skeletal muscle biopsy showed profound depletion of glycogen; endomyocardial biopsy demonstrated hypertrophic cardiomyocytes with enlarged nuclei and central vacuoles. The term glycogen storage disease, type XV was suggested for this entity. Seven adult patients have since been described with a slowly progressive myopathy; in these cases, muscle biopsy demonstrated polyglucosan bodies.

CONCLUSIONS The disorders of carbohydrate metabolism are a large, heterogeneous group, which are most likely to present to the child neurologist with manifestations of a metabolic myopathy. The presence of cardiac, hepatic, or hematologic abnormalities is often helpful in guiding the practitioner to the correct diagnosis. Although molecular testing is increasingly available to accurately diagnose these disorders (Wang et al., 2013), many still require sophisticated biochemical investigation, electrodiagnostic testing and tissue biopsy—guided, as always, by a complete and accurate history and careful physical examination. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Coelho, A.I., Berry, G.T., et al., 2015. Galactose metabolism and health. Curr. Opin. Clin. Nutr. Metab. Care 18 (4), 422–427. Endo, Y., Furuta, A., et al., 2015. Danon disease: a phenotypic expression of LAMP-2 deficiency. Acta Neuropathol. 129 (3), 391–398. Hahn, A., Praetorius, S., et al., 2015. Outcome of patients with classical infantile pompe disease receiving enzyme replacement therapy in Germany. JIMD Reports 20, 65–75. Magoulas, P.L., El-Hattab, A.W., 1993. Glycogen Storage Disease Type IV. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews. University of Washington, Seattle. Available at: . Musumeci, O., Bruno, C., et al., 2012. Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII). Neuromuscul. Disord. 22 (4), 325–330. Park, J.S., Kim, H.G., et al., 2015. Effect of enzyme replacement therapy in late onset Pompe disease: open pilot study of 48 weeks follow-up. Neurol. Sci. 36 (4), 599–605. Quinlivan, R., Martinuzzi, A., et al., 2014. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database Syst. Rev. (11), CD003458. Tegtmeyer, L.C., Rust, S., et al., 2014. Multiple phenotypes in phosphoglucomutase 1 deficiency. N. Engl. J. Med. 370 (6), 533–542. Timson, D.J., 2015. The molecular basis of galactosemia—past, present, and future. Gene doi:10.1016/j.gene.2015.06.077; Jul 2, pii: S0378-1119(15)00801-X. Wang, J., Cui, H., et al., 2013. Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genet. Med. 15 (2), 106–114.

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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 39-4 This 8-month-old infant with infantile acid α-glucosidase deficiency (Pompe disease) is profoundly hypotonic and weak. Fig. 39-5 This 22-month-old child with late infantile acid α-glucosidase deficiency has increased lumbar lordosis,

pseudohypertrophy of the calf muscles, and contractures of the Achilles tendons. Fig. 39-6 Infantile acid α-glucosidase deficiency. Fig. 39-7 This line graph reflects the failure of increase in blood lactic acid concentration during ischemic exercise of the arm in a patient with McArdle disease.

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Disorders of Glycosylation Hudson H. Freeze, Bobby G. Ng, and Marc C. Patterson

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Eukaryotic cells synthesize hundreds of types of sugar chains called glycans, which function within the cell, at the cell surface, and beyond. Within the cell, glycans influence protein folding, stability, turnover, and intracellular trafficking (Varki and Lowe, 2009). At the cell surface, they influence or determine cell-cell binding, receptor-ligand interactions, assembly of signaling complexes, binding to the extracellular matrix, tissue pattern formation, trafficking of lymphocytes, and much more (Varki and Lowe, 2009). The same glycan can function differently on different proteins or in different settings. This three-dimensional complexity makes understanding the roles of glycans challenging, but provides the body with an extraordinarily sensitive fine-tuning mechanism for many physiologic functions. It is not surprising that disrupting normal glycosylation causes moderate to severe pathology in multiple human organ systems. Well over 100 rare inherited disorders of glycan bio­ synthesis have been identified. Most of these are called congenital disorders of glycosylation (CDG) (previously called carbohydrate-deficient glycoprotein syndrome). Others such as muscle-eye-brain disease and Walker-Warburg syndrome were well known, but elucidation of their relation to glycosylation has provided new insights into their pathophysiology and opens new therapeutic possibilities.

DEFINING TYPES OF GLYCOSYLATION Glycan linkage to proteins or lipids defines the biosynthetic pathway. Most CDG defects occur in the N-linked pathway that couples asparagine (Asn) to N-acetylglucosamine (GlcNAc). O-linked glycans occur in many linkages, but mannose (Man) O-Man glycans bound to threonine/serine (Thr/Ser) cause muscle-eye-brain disease and some cases of Walker-Warburg syndrome. A few disorders result from mutations that impair the synthesis of glycosphingolipids, and those deficient in glycophosphatidylinositol (GPI) anchors comprise a rapidly expanding group. Defects in Golgi homeostasis and intracellular trafficking also cause CDG. We focus on glycosylation abnormalities that cause neurologic disorders. Defects in dystroglycan O-Man glycosylation (dystroglycanopathies) are described in Chapter (49).

N-LINKED GLYCOSYLATION Overview Sugar chains are added to newly synthesized proteins in the lumen of the endoplasmic reticulum; most are quickly and extensively remodeled there and, later on, in the Golgi apparatus. All eukaryotic cells make a 14-sugar, lipid-linked oligosaccharide in the endoplasmic reticulum membrane that is composed of Man, GlcNAc, and glucose (Glc). This entire chain is transferred to Asn within an Asn-X-Thr/Ser/Cys consensus sequence (X is any amino acid except proline) concurrently or shortly after newly made proteins emerge from the ribosome into the endoplasmic reticulum lumen. Over 50

genes are required to synthesize and transfer this glycan to proteins. Remodeling begins soon after sugar chain transfer. Up to two-thirds of the original lipid-linked oligosaccharide glycan is discarded, and 6 to 15 other sugar units are then added to create a dazzling array of sugar chains. Why generate this complex process? The initial glycan helps proteins fold and also provides important checkpoints for monitoring proper protein folding in the endoplasmic reticulum. The addition of more sugars in the Golgi usually imparts greater specificity to the sugar chain function.

Biosynthesis Individual monosaccharides can be synthesized from glucose, derived from the diet, or salvaged from degraded glycans. They must be activated to their nucleotide sugar derivatives to construct glycans. The top of Figure 40-1 depicts the pathway for mannose using standard symbols for the sugar (Varki, et al., 2009). Monosaccharide phosphorylation is the first step, and some pathways interconvert phosphorylated forms such as Man-6-P→Man-1-P. Other routes generate uridine diphosphate (UDP)-GlcNAc, UDP-galactose (Gal), and guanosine diphosphate (GDP)-fucose (Fuc) for adding these sugars. For some types of glycosylation, the nucleotide sugar donates the sugar to a lipid carrier dolichol phosphate (P-Dol). These products include Man-P-Dol and Glc-P-Dol. Dolichol itself is made from polyprenols using a specific reductase.

N-Linked Glycan Biosynthesis The lipid precursor is built stepwise, adding sugars in specific linkages and in a specific order (Freeze and Elbein, 2009) as shown in Figure 40-1. It begins with P-Dol + UDP-GlcNAc forming GlcNAc-P-P-Dol on the cytosolic face of the endoplasmic reticulum. Another UDP-GlcNAc donates a second GlcNAc using a different GlcNAc transferase, and this is followed by the addition of five Man units derived from GDPMan. A “flippase” reorients the entire molecule from the cytosolic face into the endoplasmic reticulum lumen in which a series of Man transferases use Man-P-Dol to add four more Man units, to make a three-branched structure. Three glucosyltransferases sequentially add Glc from Glc-P-Dol to one branch to complete the sugar chain. This 14-sugar unit molecule is the optimal substrate for the 8-subunit oligosaccharyl transferase (OST) complex that recognizes the Asn-X-Thr/Ser/ Cys consensus sequence on the protein and adds the sugar chain to Asn. Post transfer, the P-P-Dol is converted back to P-Dol and then to Dol for recycling. Within a few minutes of transfer to protein, the sugar chain is processed (Fig. 40-1) using a set of two glucosidases that remove the Glc units. For some proteins, processing stops here; however, for the majority, a series of α-mannosidases in the endoplasmic and Golgi remove up to six Man units, and UDP-GlcNAc, UDP-Gal and CMP-Sialic acid (Sia) and GDP-Fuc donate their respective sugars to multiple branches

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6P

Fructose 6-P

GTP GMPPA

PMM2

Mannose

1P

Glucose Galactose N-acetylglucosamine Fucose

GDP GMPPB

Sialic acid CTP

Cholesterol Biosynthesis

P P

DHDDS

P P

OH

SRD5A3

DOLK

P P

P P

ALG13

DPAGT1

(15-19)

P P

ALG1

P P

ALG2

P P

P P

P P

ALG2

RFT1

ALG11

ALG11

ALG3 P

NUS1

OH

DOLPP1

CDP

ALG14 DPM1, DPM2 DPM3

P P

P P

P

? Oligosaccharyltransferase Complex

Lumenal ER

P

Cytoplasm

?

MPDU1 P

STT3A, STT3B, DDOST TUSC3, MAGT1 RPN1, RPN2, DAD1, KRTCAP2, DC2

?

MAN1B1

PRKCSH Asn

GANAB

SSR4

MOGS Asn

ALG10

P P

ALG8

P P

ALG6

P P

ALG9

P P

P P

ALG12

ALG5

ALG9

SSR1, SSR2, SSR3

Asn

5

P

Asn

P P

P

P P

Translocon Complex

Ribosome

mRNA 3

Retrograde Transport Complex COG1, COG2, COG4, COG5, COG6, COG7, COG8 COG3

MAN1A1 MAN1A2 MAN1C1 Asn

MGAT1

MGAT2

MAN2A1 Asn

Asn

MAN2A2

UDP

Asn

ST6GAL1

B4GALT1 Asn

Asn

SLC35A3

Asn

CMP

UDP

SLC35A2 UDP

UDP

FUT8

ST6GAL2

Asn

GDP

SLC35A1 CMP

SLC35C1 GDP

Figure 40-1.  N-linked glycan synthesis. The biosynthesis and assembly of the lipid-linked oligosaccharide precursor (LLO), its transfer to protein, and subsequent processing are presented here. The first steps involve the activation and interconversion of monosaccharides such as mannose to form sugar donors, the nucleotide sugars or phosphoryldolichols. Dolichol phosphate serves as the lipid carrier for the sugar chain, which is synthesized in a series of precisely ordered steps that involve addition of N-acetylglucosamine, mannose, and glucose. The completed glycan is transferred to proteins. After transfer to proteins, oligosaccharide processing begins by removing all three glucose units and a mannose unit. Mannose trimming of the protein-bound sugar chains may stop or continue. Addition of a single N-acetylglucosamine or continued mannose trimming next leads to the build-up of sugar chains with two to five branches containing N-acetylglucosamine, galactose, and sialic acid. Fucose may be added to some chains using specific transferases. All of these reactions require delivery of the nucleotide sugar into the Golgi by specific transporters. A series of mutations in seven of the eight COG subunits and a vacuolar H+/ATPase disturb N-glycan processing and other biosynthetic pathways by disrupting Golgi homeostasis. Congenital disorders of glycosylation (CDGs) result from defects in some of these steps, indicated by the gene name in red. ER, endoplasmic reticulum; CMP, cytidine monophosphate; GDP, guanosine diphosphate; UDP, uridine diphosphate.

of the chains. Each nucleotide sugar donor must be translocated from its origin in the cytoplasm or nucleus to the Golgi by a substrate-selective transporter. The transferases and transporters recycle through the dynamic Golgi to maintain their correct relationship to the maturing glycoproteins as they pass through the Golgi. Therefore correct trafficking of the biosynthetic machinery is essential for optimal function.

CONGENITAL DISORDERS OF GLYCOSYLATION Glycosylation is complex, and its disorders defy symptomatic pigeonholing. Congenital disorders of glycosylation (CDG) nomenclature transitioned from a biochemical pathway designation to one based on the mutated gene name. Previously, defects in lipid-linked glycan biosynthesis and transfer to protein defined “group I,” and those affecting biosynthesis and processing of the protein-bound sugar chains constituted “group II.” Each unique gene disorder carried a lower-case letter (e.g., CDG-Ia, CDG-Ib, CDG-IIa). This nomenclature became too complex, and now the mutated gene name adds a “-CDG” suffix. Both monikers will coexist for some time, but the gene designation is preferred (Jaeken, et al., 2008).

Diagnosis Most CDG patients were first recognized by abnormal glycoforms of serum transferrin. Commercially available tests include isoelectric focusing, mass spectrometry, zone electrophoresis, and high performance liquid chromatography; however, electrospray ionization-mass spectrometry (ESIMS) (Babovic-Vuksanovic and O’Brien, 2007) is the most informative because it differentiates absence of entire sugar chains from one or more monosaccharide units. Normal transferrin has two sugar chains, each containing two negatively charged Sia molecules, designated tetrasialotransferrin. Loss of one or two entire chains produces disialotransferrin or asialotransferrin respectively, but this is a misnomer because it is the loss of more than sialic acid. ESI-MS shows losses of 2200 or 4400 mass units, respectively. ESI-MS can also detect loss of single or multiple individual sugars. This distinction helps narrow gene candidates from whole exome or genome sequencing results. ESI-MS is the preferred method (Babovic-Vuksanovic and O’Brien, 2007) and is suitable for routine diagnostics. Transferrin isoform analysis produces few false-positive results. Uncontrolled fructosemia, galactosemia, and recent



heavy alcohol consumption produce a pattern typical of group I disorders. Sometimes, patients with genetically confirmed CDGs develop normal transferrin, and in some patients, previously abnormal patterns normalized in preadolescence. Thus a normal transferrin pattern should not exclude follow-up testing. Healthy neonates sometimes have a slightly abnormal transferrin pattern, which normalizes within a few weeks. Suspicious results in neonates should be repeated. Some genetic centers and commercial laboratories now offer various CDG gene diagnostic panels (Greenwood Genetic Center, Baylor Medical Genetics, Emory Genetic Laboratory), but falling costs and improved bioinformatics make whole exome sequencing the first choice. However, the proven power of transferrin analysis should always accompany a putative genetic result. Prenatal testing is available for confirmed at-risk families.

General Clinical Features Over 1000 CDG patients have been identified, most presenting with multiple organ dysfunctions (Haeuptle and Hennet, 2009). Patients with CDGs have protean presentations that, in some cases, may mimic mitochondrial (oxidative phosphorylation) disorders. An informal survey of CDG-affected families indicated that earlier nonspecific diagnoses frequently included a metabolic defect or cerebral palsy. Most patients first present to pediatric neurology or metabolic clinics. They frequently have combinations of liver, gastrointestinal, and coagulation disturbances. The possibility of a CDG should be investigated in any child presenting with developmental delay, seizures, hearing loss or strabismus, particularly if any of these manifestations is accompanied by abnormal coagulation, liver dysfunction, or a gastrointestinal disorder. Most affected children are hypotonic and demonstrate failure to thrive.

SPECIFIC DISORDERS Table 40-1 summarizes the known glycosylation defects, utilizing the classification scheme published in 2009. This includes the mutated genes and major signs and symptoms. The known defects cover every aspect of the N-linked biosynthetic pathway. Activation or presentation of precursors (PMM2, PMI, DPM1, DPM3 MPDU1 [CDG-Ia, Ib, Ie, If]), glycosyltransferases for lipid-linked oligosaccharide biosynthesis (ALG6, ALG3, ALG12, ALG8, ALG2, DPAGT1, ALG1, ALG9, ALG11, ALG13 [CDG-Ic, Id, Ig, Ih, Ii, Ij, Ik, Il, Ip, Is]), glycosidases that trim the protein-bound sugar chain (MOGS [CDG-IIb], MAN1B1 [MRT15]), Golgi-localized nucleotide sugar transporters (SLC35C1, SLC35A1, SLC35A2 [CDG-IIc, IIf, IIm)), and glycosyltransferases that extend the trimmed chain (MGAT2, B4GALT1 [CDG-IIa and IId]). DOLK (CDGIm) impair dolichol kinase function and impair the final step of the de novo synthesis of dolichol phosphate. SRD5A3 (CDG-Iq) encodes the α-reductase that converts various polyprenols to dolichols. The conserved, eight-subunit, oligomeric Golgi (COG) complex that binds to the cytoplasmic face of the Golgi is needed for intra-Golgi or Golgi to endoplasmic reticulum retrotrafficking of multiple resident glycosyltransferases and nucleotide sugar transporters. Disorganized trafficking impairs multiple glycosylation pathways. Defects have now been identified in COG7, COG1, COG4, COG8, COG5, COG6, and COG2 [CDG-IIe, IIg, IIj, IIh, IIi, IIl, IIn). Appreciation of the importance of Golgi homeostasis in glycosylation led to the discovery of another disorder caused by mutations in a subunit of a vacuolar H+/ATPase that maintains appropriate pH of various organelles within the endocytic and exocytic pathways. The intravesicular pH progressively decreases from

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the endoplasmic reticulum to Golgi, endosomes, and, finally, lysosomes. The remainder of this chapter will focus on prominent CDGs with significant neurologic manifestations. Table 40-1 lists those disorders and their common clinical features.

Defects in Protein N-Glycosylation PMM2-CDG (Ia) PMM2-CDG (CDG-Ia) is the best-known and most frequently recognized form of CDG, first reported by Jaeken and colleagues in 1980 (Jaeken et al., 1980). The defective gene was identified in 1995 as PMM2, which encodes the phosphomannomutase (PMM) that converts Man-6-P→Man-1-P. This defect results in insufficient production of lipid-linked oligosaccharide, leading to empty glycosylation sites. More than 800 patients are known worldwide, and more than 100 mutations have been cataloged (Haeuptle and Hennet, 2009). Hagberg and associates described four stages of the typical (severe) phenotype. The first is the infantile phase, marked by various combinations of dysmorphism, abnormal fat distribution (supragluteal and vulval fat pads, focal lipoatrophy), inverted nipples, cryptorchidism, esotropia, recurrent infections, cardiomyopathy or pericardial effusions, coagulopathies, nephrotic syndrome, hypothyroidism, life-threatening episodes of hepatic failure, and unexplained coma. Up to 20% of infants with PMM2-CDG succumb in this phase. In the second phase (comprising the remainder of the first decade), children experience seizures and strokelike episodes, often precipitated by intercurrent infections. The third phase (in the second decade of life) is marked by slowly progressive cerebellar ataxia and limb wasting and by progressive visual loss secondary to pigmentary retinopathy. Adult survivors have moderate intellectual disability with severe ataxia and hypogonadism, with or without skeletal deformities. Presentations are highly variable. In one girl with PMM2-CDG, findings on computed tomography (CT) of the head were normal at 9 months of age, but subsequent imaging studies demonstrated progressive atrophy. The investigators concluded that the cerebellar hypoplasia reported in infancy in most children with CDG-Ia likely reflects atrophy of antenatal onset rather than hypoplasia. More extensive testing for CDGs has led to the identification of milder PMM2-CDG phenotypes. The patients often have high residual levels of PMM2 activity. Some patients have only borderline cognitive impairment, but strabismus persists in these very mild cases. Few adult CDG-Ia patients are employed. A longitudinal study of eight Spanish patients confirmed the wide range of clinical manifestations, ranging from neonatal hemorrhage, nonimmune hydrops, and death through intellectual disability and motor impairment without acute decompensation in patients in their 20s to one individual with normal development and only gastrointestinal dysfunction in childhood. The carrier frequency of the most common mutant allele (c.422G>A, p.R141H) is about 1 in 70 in the northern European population. The public Exome Aggregation Consortium (ExAC) database, composed of 60,000 exomes, finds a carrier frequency of 1 in 76. It is lethal in the homozygous state. No effective specific therapy for PMM2-CDG exists. Experiments using patient cells suggested that increasing dietary mannose might improve glycosylation in patients, but clinical trials demonstrated no benefit. Subsequent trials on a few patients did not show any clinical improvement. Population studies find the risk of having a second child with PMM2-CDG to be close to 1 in 3 rather than the expected Mendelian ratio of 1 in 4, suggesting that reduced glycosylation

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may have some selective advantage. At-risk couples should be counseled appropriately.

MPI-CDG (Ib) MPI-CDG (Ib) is caused by mutations in MPI, the gene encoding phosphomannose isomerase, which interconverts Man-6-P and Fructose (Frc)-6-P. This reaction produces most of the mannose for glycoprotein synthesis. About 25 patients have been identified since its discovery in 1998 (de Lonlay and Seta, 2009). This phenotype is not associated with any primary neurologic symptoms. Gastrointestinal and hepatic pathology, with hypoglycemia, coagulopathy, and protein-losing enteropathy, is characteristic. MPI-CDG is unique in that simple dietary mannose therapy corrects the abnormalities, except for liver fibrosis. Liver transplantation proved effective in one patient with severe hepatic fibrosis.

ALG6-CDG (Ic) Initial cases of ALG6-CDG (Ic) resembled a less severe version of PMM2-CDG, but more severe cases have appeared. It is characterized by moderate psychomotor retardation, hypotonia, esotropia, seizures, and ataxia. Nevertheless, at least five children have died of CDG-related complications. The defect is in a glycosyltransferase hALG6, which results in production of a truncated lipid-linked oligosaccharide sugar chain that is inefficiently transferred to proteins. Patients sometimes experience life-threatening protein-losing enteropathy during bouts of gastroenteritis. Skeletal dysplasia, including a unique form associated with brachytelephalangy, has been described in a compound heterozygote for ALG6. An adult woman has been identified in whom ALG6 deficiency was associated with intellectual disability, skeletal anomalies, virilization, and deep vein thrombosis. ALG6 deficiency was first identified in 1998 and subsequently in over 90 patients, making it one of the most common forms of CDG.

DPAGT1-CDG (Ij) DPAGT1-CDG (Ij) is caused by a deficiency in UDPGlcNAc:dolichol phosphate N-acetylglucosamine-1 phosphate transferase (GPT) activity encoded by DPAGT1. Two patients had severe hypotonia, intractable seizures, intellectual disability, microcephaly, and exotropia. Using exome sequencing, Ng and associates have identified an additional seven previously unreported cases of DPAGT1-CDG. In four of the seven cases, the patients were characterized by an extremely severe, multicongenital anomaly phenotype that resulted in death for all four. The remaining individuals have severe hypotonia, intractable seizures, intellectual disability, and microcephaly. Subsequent reports have focused on DPAGT1-CDG as a cause of a myasthenic syndrome characterized by fatigable limb girdle weakness with bulbar sparing, response to cholinesterase inhibitors, and the presence of tubular aggregates on muscle biopsy; there is evidence of both presynaptic and postsynaptic neuromuscular transmission defects.

ALG1-CDG (Ik) Eighteen patients with ALG1-CDG (Ik) had been described by 2014. Fifty percent had complications during pregnancy, and several had postnatal complications. Eighty percent were hypotonic, and all had at least one seizure, most being intractable; 8 of the 10 were dysmorphic; 7 of the 10 had visual impairment; and 5 of the 10 were microcephalic. Fifty percent had a fatal outcome. Patients with ALG1-CDG are deficient in GDP-Man:GlcNAc2-P-P-dolichol mannosyltransferase, encoded by the hALG1 gene, which adds the first Man to the lipid-linked oligosaccharide chain.

More recently, Ng and associates identified 39 additional ALG1-CDG cases by various methods, including exome sequencing, targeted gene panels, and traditional Sanger sequencing. It is the largest report of ALG1-CDG cases and triples the number of known cases, making it the third most common CDG in the N-linked pathway. Nearly all the affected had a pronounced neurologic presentation that included developmental delay, hypotonia, seizures/epilepsy, microcephaly, and, for those who could be tested, varying degrees of intellectual disabilities. Other clinical manifestations included facial dysmorphism, coagulopathy, gastrointestinal and skeletal abnormalities. Lethality in the first 5 years occurred in about 45% of the cases.

TUSC3-CDG Twenty-one patients in six kindreds have been described with TUSC3-CDG. Seven of the original cohort all had nonsyndromic, moderate to severe intellectual disability. Two were siblings from a small French family. TUSC3 encodes a subunit of the oligosaccharyltransferase complex (OST). It is not clear why these patients have no other systemic manifestations of hypoglycosylation, but it is theorized that differential tissue expression of another subunit associated with the OST (IAP) might compensate for TUSC3 deficiency in nonneurologic tissues. About one-third of patients have microcephaly and short stature.

SRD5A3-CDG (Iq) Nearly twenty cases of SRD5A3-CDG have been described with virtually all being either homozygous or compound heterozygous for complete loss of function mutations (INDEL, premature stop codons, complete gene deletions). No missense mutations have been identified to date. SRD5A3 encodes for a polyprenol reductase that converts polyprenol to dolichol, and unlike SRD5A1 and SRD5A2, does not appear to play a physiologic role in testosterone production. Affected individuals manifest with neurologic deficiencies and nearly always with some form of ocular problems including nystagmus, cataracts, glaucoma and optic nerve atrophy.

NGLY1-CDG Recently discovered mutations in NGLY1 cause global developmental delay, a movement disorder, hypotonia microcephaly and diminished reflexes, and alacrima by unknown mechanisms (Enns et al., 2014). It shares many symptoms with other typical CDGs. NGLY1 cleaves intact N-glycans from misfolded N-glycosylated proteins that retrotranslocate into the cytoplasm as part of the ERAD pathway, often linked to ER-stress response. It could be considered a highly specific “disorder of de-glycosylation.” The liberated N-glycan chains are further degraded by the proteosome the cytoplasm and lysosomes, and the proteins are degraded in the proteasome. Over 40 patients have been identified in less than 3 years since its discovery, mostly due to the outreach efforts of parents of the index patient.

Defects in Protein O-Glycosylation The most important defects in O-glycosylation are those based in O-mannose pathway, which is covered in Chapter 39. These disorders are listed in Table 40-1.

Defects in Glycosphingolipids (GSL) The GSL biosynthetic pathway is shown in Figure 40-2. Developmental delay, seizures, and blindness are found in



autosomal-recessive Amish infantile epilepsy. A large Amish family was identified with a nonsense mutation in SIAT9 that truncated protein. The presence of abnormal pigmentation that becomes more prominent over time may be a useful diagnostic clue to the presence of this otherwise clinically nonspecific disorder; 20 of 38 affected children were found to have freckled hyperpigmentation on the limbs, with variable hypopigmentation on the limbs and face. SIAT9 is a sialyltransferase needed for synthesis of gangliosides GM3 (Siaα2-3Galβ1-4Glc-ceramide) from lactosylceramide (Galβ14Glc-ceramide). Patients accumulate nonsialylated plasma glycosphingolipids such as GM3 and also lack downstream GM3-dependent molecules. Two children with homozygous nonsense mutations in SIAT9 were found to have evidence of secondary respiratory chain dysfunction and apoptosis in their cultured fibroblasts, attributed to accumulation of globosides Gb3 and Gb4. GalNAc is transferred onto GM3 and GD3 precursors by B4GALNT1 in the biosynthesis of GM2 and GD2 glycosphingolipids and is mutated in hereditary spastic paraplegia subtype 26. Individuals showed developmental delay with varying cognitive impairment and an early onset progressive spasticity due to axonal degeneration. In twelve affected individuals who had IQA in ND1, m.1178G>A in ND4, and m.14484T>C in ND6). NARP affecting an mtDNA structural gene results in neuropathy, ataxia, and retinitis pigmentosa (NARP). It was described in four family members of three successive generations with a variable combination of retinitis pigmentosa, ataxia, developmental delay, dementia, seizures, proximal limb weakness, and sensory neuropathy. This maternally transmitted condition was associated with an mtDNA point mutation involving the gene for subunit 6 of mitochondrial ATPase (MTATP6). The most severely affected family member was a 3-year-old girl. She had had a history of reduced fetal movement, developmental delay, and a pigmentary retinopathy. Additional features included limb hypertonia, hyperreflexia, bilateral Babinski sign, and generalized ataxia. The m.8993T>G mutation in the ATPase 6 gene of mtDNA has been recognized as one important cause of Leigh syndrome. Curiously, a different mutation at the very same nucleotide (m.8993T>C) causes a milder clinical phenotype and a less severe impairment of ATP synthesis in mitochondria isolated from cultured fibroblasts. Mutations in the ATPase 6 gene of mtDNA appear to be associated with various syndromes characterized by the neuroradiologic features of Leigh syndrome or bilateral striatal necrosis. There are now more than 250 pathogenic point mutations affecting synthetic genes but only two distinct and frequent clinical conditions that are maternally inherited and associated with mtDNA point mutations affect tRNA genes. These two conditions are MELAS and MERRF. Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) was first described in 1984 and is the most common mtDNA-related disease. Most patients become symptomatic before age 40 years, and 90% to 100% of patients have normal early development followed by the onset of exercise intolerance, stroke-like episodes, seizures, and dementia. Almost all patients have lactic acidosis and ragged-red fibers in biopsied skeletal muscle. Recurrent migraine-like headaches preceded by nausea and vomiting are common, as is hearing loss, short stature, learning difficulties, hemiparesis, hemianopia, and limb weakness. The cerebrospinal fluid protein concentration is normal in half of the patients and only mildly elevated in the other half. One third of patients have basal ganglia calcifications. Seizures are common and often (or always) precede the strokelike events. Progressive external ophthalmoparesis was noted in approximately 10% of cases. The m.3243A>G mutation in the tRNALeu(UUR) gene (MTTL) of mtDNA is responsible for about 80% of MELAS patients worldwide. Several other mutations in the same gene have been associated with MELAS, as well as increasing numbers of mutations in structural genes of mtDNA. Myoclonic epilepsy and ragged-red fibers (MERRF) was first described in 1980. The major clinical features include cerebellar syndrome, generalized convulsions, myoclonus, dementia, hearing loss, impaired deep sensation, and a positive family history consistent with maternal inheritance. In 1990 Shoffner and colleagues described a point mutation (m.8344A>G) involving the mtDNA gene for tRNALys (MTTK). Two more mutations in the same gene (m.8356T>C and m.8363G>A)

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are less frequent causes of typical MERRF. One mutation in a different gene (m.611G>A in the tRNAPhe) gene (MTTF) has been reported to cause typical MERRF.

THERAPY No panacea for respiratory chain dysfunction and no universal therapy for mitochondrial disorders currently exist. Nevertheless, symptomatic pharmacologic treatments (for example, antiepileptic drugs) and surgical interventions (such as blepharoplasty) are useful in prolonging and improving the lives of patients with these conditions. Exercise therapy has been demonstrated to improve exercise tolerance and quality of life in patients with mitochondrial diseases. Several strategies aimed at curing (or even preventing) mitochondrial diseases have shown promise in vitro or in animals, or have produced encouraging preliminary results in humans (Viscomi et al., 2015).

Mitochondrial Replacement Therapy (MRT) For mtDNA-related diseases, many of which are devastating and undiagnosable prenatally, the ultimate goal is to prevent their occurrence altogether via mitochondrial replacement. In this approach, the nucleus of an oocyte from an mtDNA mutation carrier is transferred to an in vitro-fertilized enucleated oocyte from a normal donor, resulting in the embryo having the nDNA of the biological parents but the mtDNA of a normal mitochondrial donor. In nonhuman primate experiments using oocyte spindle-chromosomal complex transfer, the offspring were healthy and devoid of original maternal mtDNA. The same technique was applied to fertilized and unfertilized but parthenogenically activated human oocytes, and the cells were found to develop into normal blastocysts and containing virtually exclusively donor mtDNA (Paull et al., 2013). Moreover, only donor mtDNA was detected after stem cell lines from blastocysts were differentiated into neurons, cardiomyocytes, and β-cells. Similar results were obtained in the United Kingdom after pronuclear transfer in abnormally fertilized human oocytes developed up to the blastocyst stage. Despite some concerns, the stage appears to be set for approval of this technique for therapeutic application both in the United Kingdom and the United States.

Shifting Heteroplasmy For mtDNA-related disorders, an obvious but challenging goal is to shift heteroplasmy in patients, thereby lowering the mutation load to subthreshold levels. When deprived of glucose and exposed to ketogenic media, cybrids harbouring single mtDNA deletions shifted their heteroplasmy level and recovered mitochondrial function, probably through selective mitochondrial autophagy (mitophagy). A genetic approach to heteroplasmic shifting involves use of restriction endonucleases to eliminate specific pathogenic mutations.

Enhancement of Respiratory Chain Function The most obvious therapeutic approach to mitochondrial disorders is to enhance respiratory chain function, thereby mitigating both energy crisis (ATP deficit) and oxidative stress (toxic build-up of ROS). The compound is used almost universally in patients with mitochondrial disease is CoQ10, given the pivotal role of this molecule in electron transport, its antioxidant properties, and its safety even at high doses. Two synthetic analogs of CoQ10—idebenone and parabenzoquinone—seem more promising. Idebenone, a short-chain benzoquinone, has shown positive results in two studies of patients with LHON. The second compound,

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a parabenzoquinone labeled EPI-743, has so far been tested only in open studies; this compound reversed vision loss in four of five patients with LHON produced clinical improvement in 12 children with various mitochondrial disorders and arrested or reversed disease progression in 13 children with genetically proven Leigh syndrome.

Elimination of Noxious Compounds The second logical therapeutic approach to mitochondrial disease is to eliminate the noxious compounds that accumulate in these disorders. To decrease brain lactate in patients with MELAS, we used dichloroacetate (DCA), which stabilizes pyruvate dehydrogenase in the active form and favors lactate oxidation. Unfortunately, this agent, DCA, had unacceptable neurotoxicity and treatment had to be discontinued. A more promising “detoxifying therapy” may be allogeneic hematopoietic stem-cell transplantation (AHSCT) aimed at restoring sufficient thymidine phosphorylase activity in patients with MNGIE to normalize the circulating toxic levels of thymidine and deoxyuridine. As of 2012, 9 of 24 patients with MNGIE who had undergone AHSCT were alive and had normal blood thymidine phosphorylase activity, virtually undetectable levels of thymidine and deoxyuridine, and mild clinical improvements. A safety study of AHSCT in patients with MNGIE is under way to assess whether transplants can be performed with low morbidity in mildly to moderately affected individuals.

Alteration of Mitochondrial Dynamics Mitochondrial dynamics could be exploited therapeutically in two opposing ways. Mitochondrial fission could be enhanced, thereby favoring mitophagy, a natural “quality control” function that sequesters and eliminates dysfunctional mitochondria, perhaps sensing their abnormally low membrane potential. Alternatively, enhancement of mitochondrial fusion and “networking” would allow complementation of “bad” and “good” mitochondria and normalization of overall mitochondrial function. Although natural mitochondrial proliferation (e.g., RRF) is a futile compensatory mechanism, preliminary studies indicate it may be possible to improve on nature’s strategy by enhancing mitochondrial biogenesis through activation of the transcriptional coactivator PGC-1α, AMPK pathway, or Sirtuin1. The advantage over disease-induced mitochondrial proliferation, which appears to favor mutated mtDNAs, is that

upregulation of mitochondrial biosynthesis increases numbers of all mtDNAs, allowing wild-type genomes to compensate for mutated ones. Encouraging results have been obtained in four mouse models of COX deficiency. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bolender, N., et al., 2008. Multiple pathways for sorting mitochondrial precursor proteins. EMBO J. 9, 42–49. Burté, F., et al., 2015. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat. Rev. Neurol. 11, 11–24. Calvo, S.E., Tucker, E.J., Compton, A.G., et al., 2010. High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat. Genet. 42, 851–858. DiMauro, S., et al., 2013. The clinical maze of mitochondrial neurology. Nat. Rev. Neurol. 9, 429–444. Paull, D., et al., 2013. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature 493, 632–637. Payne, B.A.J., et al., 2013. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390. Pearce, S., Nezich, C.L., Spinazzola, A., 2013. Mitochondrial diseases: translation matters. Mol. Cell. Neurosci. 55, 1–12. Schlame, M., et al., 2002. Deficiency of tetralinoleoyl-cardiolipin in Barth syndrome. Ann. Neurol. 51, 634–637. Schon, E.A., DiMauro, S., Hirano, M., 2012. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878–890. Viscomi, C., Bottani, E., Zeviani, M., 2015. Emerging concepts in the therapy of mitochondrial disease. Biochim. Biophys. Acta 1847, 544–557.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Table 42-1 Comparison of the Human Nuclear and Mitochondrial Genomes Table 42-2 Structural (Mit) Gene Products Encoded by Mitochondrial DNA Box 42-1 Biochemical Genetics Classification of Mitochondrial Diseases

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Peroxisomal Disorders Gerald V. Raymond, Kristin W. Barañano, and S. Ali Fatemi

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Disorders of the peroxisome—organelles found in all eukaryotic cells—are characterized by alterations in their unique metabolic functions in the cell and tissues. The pervasive presence of the peroxisome leads to far-reaching consequences of these genetic disorders. Peroxisomal disorders are divided into two major categories. In the first, the organelle fails to develop normally, leading to disruption of multiple peroxisomal enzymes. The second category consists of those disorders in which the peroxisome structure is normal but functioning of a single peroxisomal enzyme is defective. Box 43-1 lists the known peroxisomal disorders; their combined incidence is estimated at 1 in 25,000 or higher. Because peroxisomal disorders are genetically determined with a majority readily identifiable by biochemical means, including prenatal testing, and nearly all affecting the nervous system, knowledge of these diseases is important. As the pathophysiology of these disorders is better understood, novel therapeutic strategies may be developed, which gives new hope for advances not only in the diagnosis but also in the management and outcome of peroxisomal disorders (Vamecq et al., 2014).

consists of a nine-residue signal located at the amino terminus. It directs the import of a smaller number of proteins using the soluble receptor Pex7p (Wanders, 2014).

METABOLIC FUNCTION OF PEROXISOMES Peroxisomes were named for the presence of hydrogen peroxide and catalase, which decomposes the hydrogen peroxide. It is now known that more than 40 enzymatic functions are found in the peroxisome. Some peroxisomal activities such as oxidation of fatty acids and cholesterol synthesis can occur in other cellular compartments as well. Certain reactions, however, occur exclusively in the peroxisome. These reactions include oxidation of very long-chain fatty acids and pipecolic acid and certain steps in the synthesis of plasmalogens and bile acids. These reactions are abnormal in many peroxisomal disorders. The composition of enzymes within the peroxisome varies among species and within tissues in a species, as well as with maturation, metabolic state, and environmental factors.

STRUCTURE AND FUNCTION OF PEROXISOMES

CLASSIFICATION OF PEROXISOMAL DISORDERS

The peroxisome is bound by a single membrane and contains a fine granular matrix. Histologically, these organelles are identified by the presence of catalase, are present in all human tissues except mature erythrocytes, and demonstrate variation in size and number. They do not contain DNA and appear to be devoid of glycoproteins. The membrane is 6.5 to 7 nm thick and has a trilaminar appearance and a unique protein composition. The peroxisomal membrane contains four ATP binding cassette (ABC) proteins. These proteins have important intracellular roles in transport. As discussed later on, the ABC protein, ABCD1, is defective in X-linked adrenoleukodystrophy, the most prevalent peroxisomal disorder. The process of peroxisomal biogenesis is highly conserved in all eukaryotic organisms, which has permitted the study of yeast to identify the cellular mechanism for the assembly of the organelle and targeting of proteins to the developing vesicle. Peroxisomal proteins are encoded by nuclear genes, synthesized on free polyribosomes, and discharged into the cytosol in the mature form. Work in yeast has identified more than 20 genes labeled PEX whose products, peroxins, are required for the incorporation of peroxisome membrane proteins and matrix protein importation. Peroxins are required for the proper importation and have roles in receptor docking, stability, and translocation across the membrane. Targeting information directing matrix proteins into the peroxisomes is inherent in the mature polypeptide. A majority of proteins destined for the peroxisome use peroxisome targeting sequence 1 (PTS1), which consists of a terminal tripeptide of serine-lysine-leucine (-SKL) that is recognized by the soluble receptor Pex5p. Not all matrix proteins contain the carboxylterminal PTS1 signal. The peroxisomal enzymes, 3-ketoacylcoenzyme A (CoA) thiolase and phytanoyl-CoA hydroxylase, have a different peroxisomal targeting sequence (PTS2). PTS2

Peroxisomal disorders may be divided into two categories: 1. Disorders of peroxisome assembly or biogenesis 2. Single-enzyme defects In the first, the peroxisome fails to form, and abnormalities of multiple peroxisomal functions are present. It is understood that these disorders are defects in protein importation using the PTS1 and PTS2 targeting sequences or membrane incorporation. This group of biogenesis disorders can be further divided by their clinical and biochemical features into the Zellweger spectrum disorders and rhizomelic chondrodysplasia punctata. The second major group consists of a growing number of disorders in which a genetically determined abnormality of a single peroxisomal enzyme is present and peroxisomal structure is intact. All of these disorders are, in actuality, single-gene and, ultimately, single-protein deficiencies, but the downstream consequences of the first group affect more than one peroxisomal pathway, resulting in multiple diagnostic abnormalities. With the emergence of DNA-based diagnosis, the utility of this division may require reassessment. An overview of diagnostic evaluation of peroxisomal disorders is provided in Figure 43-2.

CONDITIONS RESULTING FROM DEFECTIVE PEROXISOME BIOGENESIS Conditions resulting from defective peroxisome biogenesis are listed in Box 43-1; Zellweger syndrome and rhizomelic chondrodysplasia punctata are the respective prototypes. Clinical and biochemical variation between these two types of assembly defects still makes it useful to discuss them separately, although it is important to recognize that these disorders were

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PEROXISOMAL -OXIDATION PATHWAYS L-SPECIFIC

PATHWAY

D-SPECIFIC

Substrates: Straight, long chain, and very long chain fatty acids

PATHWAY

Substrates: Branched-chain fatty acids

Substrates: Bile acid intermediates

Lignoceryl-CoA (C24) ↓ Acyl-CoA-oxidase

Methyl-palmitoyl-CoA ↓ BC-oxidase

Trihydroxy-coprostanoyl-CoA ↓ BC-oxidase

Lignocerenoyl-CoA ↓ MFP-1

Methy-hexadecanoyl-CoA ↓ MFP-2

Trihydroxy-coprostanoyl-CoA ↓ MFP-2

Hydroxy-lignoceryl-CoA ↓ thiolase

Hydroxy-methyl-palmitoyl-CoA ↓ SCPX

Varanoyl-CoA ↓ SCPX

C22-CoA + Acetyl-CoA

Myristoyl-CoA + Propionyl-CoA

Choloyl-CoA + Propionyl-CoA

MFP = multifunctional protein BC = branched chain SCP = sterol carrier protein Long chain acyl CoA-ligase and lignoceroyl-CoA ligase

Figure 43-1.  Activation and subsequent β-oxidation of very long-chain fatty acids, branched-chain fatty acids, and bile acid intermediates by the l- and d-specific pathways in peroxisomes. CoA, coenzyme A.

BOX 43-1  Peroxisomal Disorders

Suspicion of Peroxisomal Disorder

DISORDERS OF PEROXISOME BIOGENESIS Zellweger Spectrum • Zellweger syndrome • Neonatal adrenoleukodystrophy • Infantile Refsum disease

VLCFA Abnormal

Normal

Plasmalogens

Plasmalogens

Abnormal

Normal

Abnormal

Normal

Zellweger spectrum disorder

ALD or other single-enzyme defect of beta oxidation

RCDP or other single-enzyme defect of plasmalogen synthesis

Phytanic acid

RHIZOMELIC CHONDRODYSPLASIA PUNCTATA (RCDP) • Refsum disease secondary to PEX7 mutation DISORDERS OF SINGLE PEROXISOMAL ENZYMES X-Linked Adrenoleukodystrophy • CADDS • Acyl CoA-oxidase deficiency • Bifunctional enzyme deficiency • DHAP acyltransferase deficiency • Alkyl DHAP synthase deficiency • Hyperoxaluria type 1 • Adult Refsum disease • Acatalasemia • Mulibrey nanism CADDS, contiguous ABCD1 DXS1357E deletion syndrome; CoA, coenzyme A; DHAP, dihydroxyacetone phosphate.

described on a clinical basis before details of the cell and molecular biology of peroxisomal disorders was known; hence, they were assigned names based on the clinical features, pathologic findings, or biochemical defects that identified them.

MOLECULAR ETIOLOGY OF DISORDERS OF PEROXISOME ASSEMBLY These disorders result from defects in the PEX genes. A complex interaction of peroxins is necessary for the biogenesis

Abnormal Adult Refsum’s disease

Figure 43-2.  Diagnostic evaluation of peroxisomal disorders. Confirmatory genetic or biochemical testing may be required.ALD, adrenoleukodystrophy; RCDP, rhizomelic chondrodysplasia punctata; VLCFA, very long-chain fatty acid.

of peroxisomes, and a defect in any of these proteins impairs the process. The final common pathway is peroxisomal dysfunction, with the respective clinical syndromes. Zellweger spectrum disorders are secondary to PTS1-mediated pathways including PEX5, and that rhizomelic chondrodysplasia punctata is secondary to mutations in PEX7, the receptor for PTS2 proteins (Braverman et al., 2013). The most common causes of Zellweger spectrum disorders are mutations in either PEX1 or PEX6, although to date, 13 PEX genes have been identified as potential causes of these disorders. PEX1 and PEX6 encode AAA ATPases. The clinical spectrum is seen in PEX1.



Peroxisomal Disorders

For example, a single base-pair deletion results in a severe phenotype and the common missense mutation G843D allows a milder phenotype (Braverman et al., 2013).

ZELLWEGER SPECTRUM DISORDERS Zellwegers syndrome (cerebrohepatorenal syndrome) was first described by Bowen and associates. Subsequently, the disorders neonatal adrenoleukodystrophy and infantile Refsum disease were described as separate entities. Although classic Zellweger syndrome is the most severe form with a characteristic phenotype, clinical overlap exists between it and the other forms. All of the Zellweger spectrum disorders share morphologic and biochemical abnormalities, and genetic understanding of the underlying mutations has been obtained in many cases. In view of this overlap, it appears prudent at this time to retain a portion of this clinical nomenclature and refer to the group as Zellweger spectrum disorders.

Clinical and Pathologic Features Zellweger Syndrome Zellweger syndrome is a multiple congenital anomaly syndrome characterized by craniofacial abnormalities, eye abnormalities, neuronal migration defects, hepatomegaly, chondrodysplasia punctata, and near-complete absence of peroxisomes. The craniofacial features include a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel (Fig. 43-3). The head circumference usually is normal. Reported ocular abnormalities include cataracts, glaucoma, corneal clouding, Brushfield spots, optic nerve hypoplasia, and pigmentary retinal abnormalities. Severe weakness and hypotonia manifest in the newborn period, often accompanied by seizures and apnea. Most affected infants have oromotor dysfunction and require

A

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tube feeding. Little psychomotor development ensues, and the average life span is limited, with most affected children surviving for 12 to 24 months. The facial appearance, Brushfield spots, and profound hypotonia may lead to a consideration of Down syndrome, although the chromosomal determination will eliminate that as a consideration. Striking abnormalities of neuronal migration unique to Zellweger syndrome are evident in the cerebral hemispheres as areas of pachygyria or polymicrogyria localized to the opercular region. In the cerebellum, the Purkinje cells form scattered heterotopias throughout the cortex and in the granule cell layer. Laminar discontinuities involving the olivary nucleus are noted, which also are unique to Zellweger syndrome. Multiple other abnormalities have been reported. The eyes demonstrate loss of retinal ganglion cells and gliosis of the optic nerve. Retinal pigmentary degenerative changes are associated with absent electroretinograms. Hepatomegaly with periportal fibrosis may result in significant cholestasis and jaundice, micronodular cirrhosis, and hypoprothrombinemia. Renal cortical cysts of varied sizes are present in 97% of patients studied pathologically but may be missed by ultrasound analyses. The adrenal gland demonstrates changes similar to those in X-linked adrenoleukodystrophy, with cytoplasmic lamellar inclusions consisting of cholesterol esterified with very long-chain fatty acids. Skeletal abnormalities include clubfoot, thumb rotation, and stippled chondral calcification of the patella and acetabulum in 50% of patients.

Neonatal Adrenoleukodystrophy and Infantile Refsum Disease We now have a clear understanding that alteration in PEX genes may result in clinical phenotypes that are less severe than in Zellweger syndrome previously termed NALD and IRD. Even in the milder forms, patients generally have

B

Figure 43-3.  Cerebrohepatorenal syndrome of Zellweger. A, Note the prominent forehead, large fontanel, hypertelorism, epicanthal folds, hypotonia, and hepatomegaly. B, Milder form of generalized peroxisomal disorder: 10-year-old boy with ataxia, significant mental retardation, visual loss secondary to retinitis pigmentosa, absence of speech, and sensorineural hearing loss. Liver biopsy showed micronodular cirrhosis and very few, abnormally small peroxisomes.

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intellectual disability, sensorineural hearing loss, retinal degeneration, and motor handicaps. Dysmorphism is less severe than in Zellweger syndrome; renal cysts may be absent, and no radiographic stippling of the cartilage is seen. Although neonatal adrenoleukodystrophy and infantile Refsum disease have in the past been split into distinct clinical presentations, this division can no longer be supported in light of more recent information on the genetic mechanism. This was already apparent from the clear clinical overlap between Zellweger syndrome and neonatal adrenoleukodystrophy and infantile Refsum disease. Attempts to differentiate between these milder phenotypes, either genetically or biochemically, do not reliably predict the clinical course. Patients with milder forms may present in the neonatal period with mild to moderate dysmorphism, hypotonia, poor feeding, and hepatomegaly. Motor and cognitive development usually is delayed. Even with hypotonia, patients may be able to walk, although gait often is ataxic. Retinal pigmentary degeneration may not become evident until the age of 4 to 6 months and often results in visual loss in the first years of life. Electroretinograms show profound abnormalities in nearly all affected persons and do not correlate well with vision in this population. Sensorineural hearing loss is associated with limited language development. Adrenal dysfunction may develop with age. Liver dysfunction often is present and detectable by persistent elevation of liver enzymes. A bleeding diathesis that responds to vitamin K also may develop; in several children, esophageal varices were observed, consistent with portal hypertension. Optic atrophy and retinitis pigmentosa may be seen in patients. The association of retinal pigmentary degeneration and sensorineural hearing loss has led to misdiagnosis as Usher syndrome. Life span is variable, and patients have survived to adulthood. All identified patients have been visually impaired, with sensorineural hearing loss. A progressive leukodystrophy, with variable age at onset, has been reported in a number of patients. This disorder results in loss of previously acquired skills, and, in most cases, progresses to a vegetative state and death. Unlike in X-linked adrenoleukodystrophy, the rate of progression has been more variable. Clinical recognition of these disorders may present some uncertainty because of nonspecific abnormalities and phenotypic variability. Disorders of peroxisome biogenesis commonly manifest in the neonatal period, and patients come to attention because of hypotonia, seizures, or liver disease. Evaluation appropriately focuses on a search for cytogenetic abnormalities, acute treatable metabolic disorders, and structural liver disease. Later in childhood, patients often are mistakenly diagnosed as having cerebral palsy, X-linked adrenoleukodystrophy, mitochondrial disease, or lysosomal disorders. All of the disorders in this group are inherited in an autosomal-recessive fashion, so it is important for genetic counseling that an accurate diagnosis is arrived at expeditiously. Carrier detection is possible only by DNA analysis if the molecular defect has been identified in the index case. Carrier detection is not possible by biochemical determination.

Laboratory Diagnosis The major diagnostic biochemical abnormality is the increased amount of very long-chain fatty acids, which are fatty acids with carbon chains of more than 22. They also are elevated in single-enzyme defects of peroxisomal β-oxidation, so their presence is nonspecific; therefore other studies are required for this diagnosis. Very long-chain fatty acid accumulation here is

due to the reduction of peroxisomal β-oxidation, which is greater in Zellweger syndrome than in milder forms (Wanders, 2014). Because the first two steps of plasmalogen synthesis are peroxisomal functions, a reduction of plasmalogen levels is noted in patients with peroxisome biogenesis defects. An agerelated increase in the levels of phytanic acid occurs in all of the peroxisome biogenesis disorders. With broader genetic tools available such as whole exome sequencing (WES) and other DNA-based panels, the older algorithms for diagnosis may be approaching the end of their utility, but because of the ability to rapidly get biochemical information this approach will be warranted where there is appropriate clinical suspicion.

Prenatal Diagnosis Cultured amniocytes or chorionic villus cells can be used to diagnose all of the disorders of peroxisome biogenesis. A variety of biochemical strategies have been used and focus on the type and degree of biochemical abnormality. Two independent techniques, the measurement of very long-chain fatty acid β-oxidation and plasmalogen synthesis, have demonstrated accurate diagnosis. Molecular genetic techniques may be used in families in which the mutation has been identified and preimplantation genetic diagnosis has been performed.

Therapy Because many of the abnormalities are already present in the affected fetus, potential for therapy is limited at present and likely to remain so. Treatment is primarily supportive, targeting liver dysfunction with vitamin K for prothrombin deficiency, providing nutrition often with tube feeding, and antiepileptic medication. In the milder phenotypes, rehabilitative approaches, including communication training and physical and occupational therapy, are helpful. Attempts to normalize some of the biochemical abnormalities include oral ether lipid therapy and dietary restriction of very long-chain fatty acids or phytanic acid have not met with clinical improvement. Therapy with docosahexaenoic acid replaces low levels in plasma and red blood cells of patients with Zellweger spectrum disorder; however, it is ineffective in improving clinical function.

DEFECTS OF SINGLE PEROXISOMAL ENZYMES Defects of Single Peroxisomal   β-Oxidation Enzymes This is a broad and heterogeneous group of disorders and many are rare. However, this group includes X-linked adrenoleukodystrophy which is the most common peroxisomal disorder and will be discussed here.

Adrenoleukodystrophy The first clinical cases of what is known as X-linked adrenoleukodystrophy (ALD) were described in 1923 by Siemerling and Creutzfeldt (Moser et al., 2007). The X-linked mode of inheritance was suggested by Fanconi and associates. A key observation of characteristic lamellar lipid-soluble cytoplasmic inclusions in the adrenal cortical cells and brain macrophages of patients with childhood adrenoleukodystrophy was made by Powers and colleagues. Similar inclusions were observed in men with Addison disease and spastic paraparesis, and the related condition was named adrenomyeloneuropathy (AMN). Igarashi and associates defined the biochemical defect by demonstrating that the inclusions in the adrenal cortex and cerebral white matter consisted of cholesterol esters



with a striking excess of saturated unbranched fatty acids of 24- to 30-carbon chain length, of which C26:0 and C25:0 were the most abundant. This excess of very long-chain fatty acids in cultured skin fibroblasts, plasma, or red blood cells is the hallmark of the disorder and useful for diagnostic purposes.

Biochemical and Molecular Basis The peroxisomal β-oxidation pathway consists of four enzymatic steps (as outlined in Fig. 43-1). Before the substrates can enter this pathway, the acyl residues require activation by transfer of a coenzyme A. For very long-chain fatty acids entering the l-specific β-oxidation pathway, lignoceryl-CoA ligase (also referred to as lignoceryl-CoA synthetase) is the activating enzyme. Although this enzyme was originally thought to be the cause, it is known that the genetic basis for X-linked adrenoleukodystrophy is mutations of the ABCD1 gene, which encodes a PMP, an ATP-binding cassette protein; the gene for this protein is located on the X chromosome in the Xq28 region. The protein is involved in the transport of appropriate fatty acids into the peroxisome and when this path is disrupted they continue to enter the elongation pathway. Multiple mutations in ABCD1 have been identified in patients with X-linked adrenoleukodystrophy, and no phenotype correlation has been identified. Several mouse models of X-linked adrenoleukodystrophy are now available, but to date none of the animals have manifested a cerebral phenotype.

Clinical and Pathologic Features of   X-Linked Adrenoleukodystrophy and Adrenomyeloneuropathy One of the most intriguing aspects of ALD is the variation in presentations depending on age. All affected individuals demonstrate accumulation of very long-chain fatty acid, and molecular studies have confirmed ABCD1 gene mutations. Various phenotypes have been recognized as occurring within the same pedigree, so neither the genetic mutation nor the biochemical abnormality predicts the clinical presentation.

Childhood Cerebral Form of Adrenoleukodystrophy The childhood cerebral variant is the most common and fulminant form of X-linked adrenoleukodystrophy. Affected boys are normal until 4 to 8 years of age, when they manifest behavior problems and failure in school as a result of rapid regression of auditory discrimination, spatial orientation, speech, and writing. Seizures occur in 30% of patients and, in rare instances, may be the initial sign. The magnetic resonance imaging (MRI) scan reveals parietooccipital white matter lesions (in 85% of patients) or frontal lesions (in 15%) at this stage, with contrast accumulation at the leading edge of the lesion (Fig. 43-5). Rapid clinical deterioration leads to spastic quadriparesis, swallowing difficulty, and visual loss, culminating in a vegetative state usually within 2 years of the initial signs and symptoms. Although males come to medical attention because of the neurologic deficits, impaired adrenal function is seen in the majority of boys at the time of diagnosis.

Adolescent Cerebral Form of Adrenoleukodystrophy Patients with the adolescent cerebral form of adrenoleukodystrophy manifest signs and symptoms of cerebral involvement, as described previously, between 10 and 21 years of age.

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Adult Cerebral Form of Adrenoleukodystrophy In the adult cerebral form of adrenoleukodystrophy, dementia, psychiatric disturbances, seizures, and spastic paraparesis develop after age 21. Patients may be misdiagnosed as having multiple sclerosis, brain tumor, or schizophrenia and demonstrate rapid deterioration similar to that in the childhood cerebral form. Therefore patients with these clinical presentations and adrenal insufficiency or leukodystrophy should be evaluated by plasma very long-chain fatty acids.

Adrenomyeloneuropathy The neurologic manifestations of adrenomyeloneuropathy (AMN), an adult form of adrenoleukodystrophy, consist of an insidious onset and slow progression of spastic paraparesis, impaired vibratory sense in the lower extremity, and bladder or bowel dysfunction. Onset is typically in the third decade of life. The primary pathology involves the spinal cord with loss of myelinated axons in the corticospinal tracts, nucleus gracilis, and dorsal spinocerebellar tracts. Sural and peroneal nerves reveal a loss of large and small myelinated fibers. The development of cerebral demyelination has been seen in approximately 15% to 20% of men with adrenomyeloneuropathy. This pathologic change needs to be differentiated from long tract findings on MRI. Cerebral disease is similar in time course to the childhood form of the disease and leads to dementia, spasticity, blindness, and death. Approximately half of patients with adrenomyeloneuropathy appear to have some degree of cerebral involvement, with mild to moderate abnormalities noted on MRI in 46% (Fig. 43-5). These abnormalities consist most frequently of parietal-occipital white matter and optic radiation involvement. Primary adrenal insufficiency or Addison disease precedes the onset of neurologic symptoms in 42% of patients; in some, this may occur 3 to 35 years earlier. Serum testosterone levels were abnormally low in 22% of our patients, and early onset sexual dysfunction occurred in one-third.

Addison Disease Only The diagnosis of adrenoleukodystrophy with Addison disease only includes the patients who have isolated primary adrenal dysfunction disease in the absence of neurologic signs and symptoms and is more common than was previously recognized. This is not surprising because there is no correlation between adrenal and neurologic dysfunction, so males may come to attention in childhood with adrenal insufficiency and develop neurologic issues decades later. Recognition of these patients is vital for genetic counseling and to monitor for the development of adrenomyeloneuropathy or cerebral symptoms later on.

Asymptomatic Patients With the Biochemical Defect of Adrenoleukodystrophy In asymptomatic patients with the biochemical defect of adrenoleukodystrophy, diagnosis may be accomplished by measurement of plasma very long-chain fatty acids during screening tests of relatives of symptomatic patients. These persons may be of any age and is clearly a function of age. All newborn males are unaffected, and this population appears to decline with age. Whether there are any truly asymptomatic individuals in midadult life is unknown. The elevation of very long-chain fatty acid levels in these males is comparable with that in severely affected family members.

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A

B

C Figure 43-5.  Magnetic resonance imaging (MRI) studies in adrenoleukodystrophy. A, Typical alteration of the blood–brain barrier at the edge of the demyelinated lesion in childhood adrenoleukodystrophy demonstrated on gadolinium-enhanced MRI. B, The discrete but continuous auditory pathway involvement from the lateral lemniscus in the pons to the medial geniculate bodies at the midbrain level to the temporal cortex can be seen. MRI permits precise correlation between the location of the lesion and cognitive deficits; the findings may explain the early auditory comprehension deficiency seen in childhood adrenoleukodystrophy. C, MRI study of the spine in X-linked adrenoleukodystrophy. Views in axial (left) and lateral (right) planes demonstrate cord atrophy, particularly in the thoracic regions.



Symptomatic Heterozygotes Between 10% and 20% of the women who are carriers for the adrenoleukodystrophy gene manifest myelopathy resembling that in adrenomyeloneuropathy between the third and fifth decades of life. Long tract signs and diminished vibration sense in the legs are present in two-thirds of the patients, although only 25% complain of symptoms. Approximately 14% have severe spinal involvement requiring assistance with ambulation, and 5% have dementia. In contrast with males, adrenal insufficiency rarely occurs in these women. In the past, elevation of very long-chain fatty acids in plasma allowed identification of 85% of obligate heterozygotes, but this assay missed 15% of them. Mutation analysis is essential for the accurate identification of females at risk.

Pathogenesis of Adrenoleukodystrophy The main biochemical defect is the striking excess of very long-chain fatty acids, which accumulate in the cholesterol ester fraction, primarily in the adrenal gland and cerebral white matter. The accumulation of very long-chain fatty acids in X-linked adrenoleukodystrophy is not as severe as in disorders of peroxisome biogenesis or single-peroxisomal βoxidation enzyme defects. The resultant accumulation does lead to a variety of issues with membrane dysfunction including issues with red blood cell microviscosity, altered response of adrenal cells to adrenocorticotrophic hormone, and other issues with steroid production. The pathogenesis of the nervous system lesion has been more difficult to discern. It has been presumed that elevation of very long-chain fatty acids results in the axonopathy seen in patients with adrenomyeloneuropathy and in women who are carriers. It is not clear, however, why rapid, inflammatory demyelination affecting the cerebral white matter tracts develops in certain persons. The levels of very long-chain fatty acids in plasma or skin fibroblasts or the capacity to metabolize very long-chain fatty acids in cultured fibroblasts do not differ in males with the childhood form from those in men with adrenomyeloneuropathy or other forms. No correlation exists between severity of the neurologic disease and levels of very long-chain fatty acids. These observations have led to the conclusion that very long-chain fatty acid excess alone is not sufficient to explain cerebral demyelination and that other factors must play a role in the phenotypic variability (Moser et al., 2005). The presence of the perivascular lymphocytic infiltration in the white matter of the cerebral forms provides evidence of immunologic involvement as one additional factor. This is not seen in the adrenal gland or other leukodystrophies. The pattern seen is that of a cellular immune response in the central nervous system, and the collective evidence implies that an immunologic mechanism contributes to the rapid progression of white matter lesions, possibly in response to the altered lipid composition in brain of patients with adrenoleukodystrophy (Mahmood et al., 2007). Recent studies have demonstrated a shift in the production of reactive oxygen species, evidence of mitochondrial dysfunction, and activation of low levels of chronic inflammation in all forms of ALD. It has also been shown that at least one inciting factor is the elevation in very long-chain fatty acids. Further studies in this area may identify factors that contribute to the pathogenesis of the nervous system lesions.

Therapy for Adrenoleukodystrophy Therapy for ALD depends on what manifestations the individual is presenting with; it should also be emphasized that therapy continues to evolve. Adrenal insufficiency should be

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treated with steroid replacement with increased doses at times of physiologic stress. The utility of therapies to lower very long-chain fatty acids remains uncertain. Although dietary restriction alone will not lower very long-chain fatty acids, the addition of monounsaturated fatty acids does lower plasma levels of saturated fatty acids. Dietary therapy with the use of glyceryl trierucate, sometimes referred to as Lorenzo’s oil, does not alter the course of rapidly progressive childhood cerebral disease. The role in AMN remains unknown, but the results in open studies have not been impressive. In one open study, it was shown that the use of glyceryl trierucate lowered the risk of developing childhood cerebral disease when started in asymptomatic boys (Moser et al., 2005). The usage of this therapy, unfortunately, remains uncertain, and it must be emphasized requires a significant lifestyle change in the subject with unclear benefit. Bone marrow transplant has been shown to be effective in boys with early cerebral disease as detected by MRI changes (Mahmood et al., 2007). In patients with more advanced disease, transplantation has not resulted in halting the course and may be associated with worsening of the neurologic status immediately after the procedure; therefore this procedure is not advised in those with neurologic findings. Recently, gene therapy with a lentivirus vector has been successfully used in boys with early cerebral disease. This advancement in the field potentially offers additional avenues of treatment for many individuals who could not previously undergo transplantation. In patients with advanced cerebral disease, neither dietary therapy nor bone marrow transplantation is effective. A variety of therapies including IVIG, cyclophosphamide immunosuppression, and high dose steroids do not arrest the rapid progression of the illness. Males at risk for developing the childhood form of ALD (younger than 10 years of age) require appropriate monitoring. MRI should be performed on a yearly basis. Because MRI abnormalities become evident at least 12 months before onset of neurologic symptoms, periodic neurologic examination is not sufficient for monitoring these patients. Timely assessments are especially important because the best outcomes with bone marrow transplantation are in patients identified at an early stage of cerebral disease. Appropriate adrenal monitoring also is indicated in identified patients.

Newborn Screening for XALD A biochemical assay using tandem mass spectroscopy and the standard newborn blood spot has been developed and has been found to be highly sensitive and specific. This has recently been instituted in New York and may be incorporated in other state panels. If this is subsequently incorporated more broadly into newborn screening programs, it will most likely change the proportion of males coming to attention in the presymptomatic phase and will also improve their care and management.

Current and Future Outlook With expanding clinical phenotypes, peroxisomal disorders are now included as standard considerations in the differential diagnosis for a variety of neurologic findings in infants, children, and adults. As new peroxisomal functions are being identified, they have provided insight into mechanisms involving biogenesis of the organelle and control of protein import. Their vital role encompassing neuronal migration in fetal brain development through membrane integrity in the axons in adults is being appreciated. All of the disorders can be recognized by noninvasive biochemical and genetic tests,

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providing valuable information for genetic counseling. These disorders may be severely debilitating or fatal, but therapeutic options are becoming available. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Braverman, N.E., D’Agostino, M.D., Maclean, G.E., 2013. Peroxisome biogenesis disorders: biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev 17 (3), 187–196. Mahmood, A., Raymond, G.V., Dubey, P., et al., 2007. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study. Lancet Neurol. 6 (8), 687–692. Moser, H.W., Mahmood, A., Raymond, G.V., 2007. X-linked adrenoleukodystrophy. Nat. Clin. Pract. Neurol. 3 (3), 140–151. Moser, H.W., Raymond, G.V., Lu, S.E., et al., 2005. Follow-up of 89 asymptomatic patients with adrenoleukodystrophy treated with Lorenzo’s oil. Arch. Neurol. 62 (7), 1073–1080.

Vamecq, J., Cherkaoui-Malki, M., Andreoletti, P., et al., 2014. The human peroxisome in health and disease: the story of an oddity becoming a vital organelle. Biochimie 98, 4–15. doi:10.1016/j. biochi.2013.09.019; [Epub@2013 Sep 26:4–15]. Wanders, R.J., 2014. Metabolic functions of peroxisomes in health and disease. Biochimie 98, 36–44. doi:10.1016/j.biochi.2013.08.022; [Epub@2013 Sep 3:36–44].

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig 43-4 Rhizomelic chondrodysplasia punctata. Table 43-1 Disorders of Peroxisome Biogenesis Table 43-2 Diagnostic Biochemical Plasma Profile of Peroxisomal Disorders Table 43-3 Phenotypes among X-Linked Adrenoleukodystrophy Hemizygotes

44 

Neurotransmitter-Related Disorders Kathryn J. Swoboda and Melissa A. Walker

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. The term “neurotransmitter disorders” constitutes a broad and increasingly complex spectrum of neurologic conditions associated with defects in the production, transport, release, and reuptake of a variety of chemical compounds involved in neurotransmission. This chapter provides an overview of such disorders, with a primary emphasis on those associated with a dopamine or serotonin deficiency state. Neurologic symptoms associated with dopamine deficiency are broad and range from extremely mild and subtle alterations in mood or gait to a classic exercise-induced dystonic gait abnormality and an infantile-onset parkinsonism syndrome. In recessive inborn errors of dopamine metabolism associated with tetrahydrobiopterin (BH4) deficiencies, neurologic symptoms are often more severe and accompanied by hyperphenylalaninemia, which can be detected on newborn screening. Associated serotonin deficiency is present in most of these disorders. Even when these disorders are ascertained by newborn screening, repletion of neurotransmitter precursors may not be sufficient, resulting in global developmental impairment, fluctuating tone abnormalities, eye movement abnormalities, encephalopathy, ataxia, and seizures. Diseases related to dysfunction of other neurotransmitter systems (i.e., gamma-aminobutyric acid [GABA], glutamate, and glycine, among others) are more difficult to characterize in humans; however, manifestations of these disorders are equally as diverse as in monoaminergic systems, including seizures, ataxia, hypotonia, oculomotor dyspraxia, and developmental delay. Screening for neurotransmitter-related disorders occurs primarily by recognition of key neurologic symptoms, though overlap with other disorders with shared features can make accurate identification and diagnosis of these disorders challenging. The routine availability of increasingly more sophisticated diagnostic tools, including cerebrospinal fluid neurotransmitter metabolite studies, cerebrospinal fluid and urine pterin studies, neuroimaging studies, phenylalanine loading studies, enzymatic assays in blood cells or skin fibroblasts, and molecular studies, have facilitated the diagnosis and treatment of patients with monoaminergic neurotransmitter abnormalities. For ease of classification, neurotransmitter-related disorders can be divided into five groups: 1. Monoaminergic neurotransmitter deficiency states with hyperphenylalaninemia 2. Monoaminergic neurotransmitter deficiency states without hyperphenylalaninemia 3. Amino acid neurotransmitter dysmetabolism 4. Secondary neurotransmitter deficiency states 5. Undefined neurotransmitter deficiency states (Table 44-1)

MONOAMINERGIC NEUROTRANSMITTER DEFICIENCY STATES WITH HYPERPHENYLALANINEMIA Overview The neurotransmitter deficiency in infants in this group arises as a result of defects in BH4 metabolism (Fig. 44-1). Patients

are usually identified by elevated phenylalanine levels on newborn screening, as BH4 is required for phenylalanine hydroxylation in the liver. The accompanying neurotransmitter deficiency results from the lack of BH4, an obligatory cofactor required for the synthesis of catecholamines and serotonin. Although most academic biochemical genetics clinics that monitor children with phenylketonuria systematically perform the additional studies required to diagnose this group of disorders, children occasionally are not identified until they have progressive neurologic symptoms or clear evidence of developmental delay despite a phenylalaninerestricted diet, prompting the earlier designation of “atypical phenylketonuria.” Importantly, newborn screening before an adequate interval of protein intake can lead to a false-negative result. 6-Pyruvoyltetrahydropterinsynthase deficiency results in inadequate BH4 synthesis; dihydropteridine reductase deficiency results in decreased regeneration of BH4 from dihydrobiopterin (see Fig. 44-1). Both are autosomal-recessive disorders in which hyperphenylalaninemia results from a deficiency of BH4. Because of the involvement of BH4 in catecholamine and serotonin synthesis, such infants also have a manifest deficiency of neurotransmitter metabolites in addition to hyperphenylalaninemia. Other conditions in this category include autosomal-recessive guanosine triphosphate cyclohydrolase (GTPCH) deficiency and primapterinuria (Table 44-2).

Role of BH4 in the Central Nervous System Because BH4 is required for the hydroxylation of aromatic amino acids, its importance in the central nervous system (CNS) becomes immediately apparent, as catecholamine and serotonin synthesis require tyrosine and tryptophan. A BH4dependent process can be strongly suspected when plasma phenylalanine levels return to normal after BH supplementation. The greater requirement of tyrosine hydroxylase for BH4 in comparison with tryptophan hydroxylase may explain the more severe impairment in the catecholaminergic system compared with the serotonergic system.

6-Pyruvoyltetrahydropterin   Synthase Deficiency 6-Pyruvoyltetrahydropterin synthase catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate to form 6-pyruvoyltetrahydropterin. Patients have elevated neopterin to biopterin ratios in urine and plasma. Reduced 6-pyruvoyltetrahydropterin synthase activity can be documented in red blood cells. In the classic form of the disorder, patients have reduced catecholamine and serotonin metabolites and an increased neopterin to biopterin level in cerebrospinal fluid. Patients are usually detected by newborn screening, as with phenylketonurics, and demonstrate progressive neurologic involvement in the first few months of life, including extrapyramidal signs, axial and truncal hypotonia, hypokinesia, feeding difficulties, choreoathetotic or dystonic limb movements, and autonomic symptoms. Many of these patients, despite early diagnosis and supplementation with

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TABLE 44-1  Primary Monoaminergic Neurotransmitter Deficiency Disorders Disorder ELEVATED PLASMA PHENYLALANINE 6-Pyruvoyltetrahydrobiopterin synthase deficiency* Dihydropteridine reductase deficiency* GTP cyclohydrolase deficiency* Primapterinuria NORMAL PLASMA PHENYLALANINE GTP cyclohydrolase deficiency* GTP cyclohydrolase deficiency* Sepiapterin reductase deficiency* Tyrosine hydroxylase deficiency* Tryptophan hydroxylase deficiency* Dopamine b-hydroxylase deficiency* Monoamine oxidase A deficiency Dopamine Transporter Deficiency* Vesicular Monoamine Transporter2 Deficiency*

Phenotypic Features

Locus

Inheritance

Encephalopathy, dystonia, spasticity, axial hypotonia, autonomic symptoms, oculogyric crises, seizures

11q22.3–23.3

AR

4p15.31 14q22.1–22.2 10q22

AR AR AR

14q22.1–22.2

AD

7p11

AR

2p14p12

AR

11p15.5

AR

11p15.3

AR

9q34 Xp11.23

XR

5p15.33

AR

10q25.3

AR

Benign hyperphenylalaninemia Exercise-induced dystonia, gait disorder, writer’s cramp, restless leg syndrome, tremor Dystonia, spasticity, torticollis, axial hypotonia, limb rigidity, autonomic symptoms, psychomotor retardation, oculogyric crises Parkinsonian symptoms, psychomotor retardation, behavioral disturbances Gait disturbance, infantile parkinsonism, dystonia, speech delay Ataxia, speech delay, hypotonia, psychomotor retardation Orthostatic hypotension, lethargy, ptosis Mild mental retardation, tendency to violent or aggressive behavior Hyperkinetic movement disorder progressing to parkinsonism dystonia Mixed hyperkinetic and hypokinetic movement disorder, oculogyric crises, dysautonomia, developmental delay, behavioral and sleep disturbances

*Disorder associated with a dopamine deficiency state. AD, autosomal-dominant; AR, autosomal-recessive; GTP, guanosine triphosphate; XR, X-linked recessive.

TABLE 44-2  Metabolite Patterns Observed in Urine, Plasma, and Cerebrospinal Fluid in the Inherited Disorders Affecting Dopamine and Serotonin Metabolism Phe

BH4

BH2

Neop

Sep

Prim

HVA

5-HIAA

3OMD

GTPCH (Recessive)

↑ (P)

↓ (U, CSF)

N

↓ (U, CSF)

N

N

↓ (CSF)

↓ (CSF)

N

GTPCH (Dominant)

N

↓ (CSF)

N

↓ (CSF)

N

N

↓ (CSF)

± ↓ (CSF)

N

6PTPS

↑ (P)

↓ (U, CSF)

N

(U, CSF)

N

N

↓ (CSF)

(CSF)

N

6PTPS (Mild)

(P)

(U)

N

(U)

N

N

N

N

N

SR

N

(CSF)

(CSF)

N

↑ (CSF)

N

(CSF)

(CSF)

N

PCD

↑ (P)

↓ (U)

N

N

N

(U)

N

N

N

DHPR

(P)

↓ (U) ± ↓ (CSF)

↑ (U, CSF)

N

N

N

↓ (CSF)

↓ (CSF)

N

TH

N

N

N

N

N

N

↓ (CSF)

N

N

AADC

N

N

N

N

N

↓ (CSF)

↓ (CSF)

↑ (P, CSF, U)

AADC, aromatic L-amino acid decarboxylase; BH2, 7,8-dihydrobiopterin; DHPR, dihydropteridine reductase; 5-HIAA, 5-hydroxyindoleacetic acid; GTPCH, guanosine triphosphate cyclohydrolase; HVA, homovanillic acid; N, normal; Neop, neopterin; P, plasma; PCD, pterin α-carbinolamine dehydratase; Phe, phenylalanine; Prim, primapterin; Sep, sepiapterin; 6PTPS, 6-pyruvoyltetrahydropterin synthase; SR, sepiapterin reductase; TH, tyrosine hydroxylase; 3OMD, 3-O-methyldopa; U, urine; ↓, decreased; ↑, elevated. (With permission from Hyland, K., 2007. Inherited disorders affecting dopamine and serotonin: Critical neurotransmitters derived from aromatic amino acids. J Nutr 137, 1568–1572S.)

BH4 and neurotransmitter precursors, continue to manifest delay in development. A “peripheral” form of the disorder is associated with nearly one-third of known mutations with the human PTS gene and is characterized by normal central neurotransmitter levels and less significant or transient hyperphenylalaninemia. Patients with the peripheral form have an excellent prognosis for normal neurologic development, provided the hyperphenylalaninemia is corrected by diet or BH4 administration.

Dihydropteridine Reductase Deficiency Dihydropteridine reductase deficiency manifests in a variety of phenotypes, all with hyperphenylalaninemia. The clinical presentation is similar to that of central 6pyruvoyltetrahydropterin synthase deficiency. Without folinic acid to restore methyltetrahydrofolate status in the CNS, these patients can have progressive calcification of the basal ganglia and subcortical regions, despite treatment with BH4 and



Neurotransmitter-Related Disorders

neurotransmitter precursors. Diagnosis can be confirmed by the pattern of urine pterins and documentation of abnormal dihydropteridine reductase activity in skin fibroblasts. Results of phenylalanine loading tests are abnormal, and phenylalanine status improves or returns to normal with BH4 supplementation. Cerebrospinal fluid neurotransmitter and pterin analysis reveals reduced concentrations of homovanillic acid and 5-hydroxyindoleacetic acid, decreased or normal BH4 levels, and elevated dihydrobiopterin levels.

Autosomal-Recessive Guanosine Triphosphate Cyclohydrolase Deficiency Patients with the autosomal-recessive form of GTPCH deficiency (in contrast to autosomal-dominant dopa-responsive dystonia) present similarly to patients with dihydropteridine reductase deficiency and 6-pyruvoyltetrahydropterin synthase deficiency with severe global developmental impairment, marked axial hypotonia, eye movement abnormalities, limb hypertonia, convulsions, and autonomic symptoms. GTPCH activity is absent in blood cells, liver, and skin fibroblasts. Cerebrospinal fluid neurotransmitter metabolite analysis reveals low homovanillic acid, 5-hydroxyindoleacetic acid, neopterin, and biopterin levels.

Pterin-4a-Carbinolamine Dehydratase Deficiency (Primapterinuria) Pterin-4a-carbinolamine dehydratase deficiency, or primapterinuria, causes mild hyperphenylalaninemia these in­­ fants are usually identified on newborn screening but generally have a benign course with normal development (Thöny and Blau, 2006).

MONOAMINERGIC NEUROTRANSMITTER DEFICIENCY STATES WITHOUT HYPERPHENYLALANINEMIA Overview Neurotransmitter deficiency disorders not associated with hyperphenylalaninemia span a complex clinical spectrum. The lack of newborn screening and increasingly diverse phenotypes make these disorders challenging to recognize. Excepting autosomal-dominant dopa-responsive dystonia and monoamine oxidase a deficiency, these disorders are inherited

A

B

357

in an autosomal-recessive fashion. Heterozygous carriers very rarely have a discernible phenotype.

Segawa Disease or Autosomal-Dominant Dopa-Responsive Dystonia The best-described and most widely identified entity among this group of disorders is autosomal-dominant doparesponsive dystonia caused by GTPCH deficiency, or Segawa disease. Patients with a classic presentation of exercise-induced dystonia are easily recognized; however, the diagnosis should also be considered in patients with spastic diplegia, particularly with diurnal variation, as well as in more atypical presentations resulting from incomplete penetrance such as writer’s cramp, asymmetric limb dystonia, tremor, or restless leg-type symptoms. Patients often benefit greatly from directed treatment of the associated dopamine deficiency state and clinical response to L-DOPA/carbidopa may aid in diagnosis. Cerebrospinal fluid neurotransmitter metabolite (low homovanillic acid, normal or low 5-hydroxyindoleacetic acid, and reduced BH4) and pterin studies as well as phenylalanine loading can be helpful in confirming the diagnosis in these patients and can help characterize the degree of associated dopamine and serotonin deficiency. GTPCH activity can be measured in skin fibroblasts. Urine biopterin levels are low.

Aromatic L-Amino Acid Decarboxylase or Dopa-Decarboxylase Deficiency Aromatic L-amino acid decarboxylase is a pyridoxinedependent enzyme that decarboxylates L-DOPA and 5hydroxytryptophan to make dopamine and serotonin, respectively. Patients with this disorder typically present in the first few months of life with dystonia or intermittent limb spasticity, axial and truncal hypotonia, oculogyric crises, autonomic symptoms, and ptosis. Cerebrospinal fluid neurotransmitter metabolites demonstrate a characteristic pattern: low homovanillic acid and 5-hydroxyindoleacetic acid levels; markedly elevated 3-Omethyldopa, 5-hydroxytryptophan, and L-DOPA; and normal biopterin and neopterin levels. Plasma L-DOPA is markedly elevated. Urine catecholamines may be reduced or elevated, specifically with vanillactic acid, despite normal preliminary organic acid results (Fig. 44-2). Although some children benefit in terms of the underlying movement disorder, treatment is complex, and these patients

C

Figure 44-2.  Episodic neurologic manifestations in aromatic L-amino acid decarboxylase deficiency. A, Ocular convergence spasm, ptosis, and orofacial dystonia. B, Torticollis and limb dystonia. C, Torticollis and limb rigidity.

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are vulnerable to an array of medication-related side effects. Overall clinical outcomes in aromatic L-amino acid decarboxylase deficiency have remained poor, though emerging gene therapies may hold promise.

Sepiapterin Reductase Deficiency Sepiapterin reductase catalyzes the (NADP) reduction of carbonyl derivatives, including pteridines, and plays an important role in BH4 biosynthesis. It is likely that low dihydrofolate reductase activity in the brain allows accumulation of dihydrobiopterin that inhibits tyrosine and tryptophan hydroxylases and uncouples neuronal nitric oxide synthase, leading to neurotransmitter deficiency and neuronal cell death. Thus identification of low cerebrospinal fluid neurotransmitter levels and the presence of elevated cerebrospinal fluid dihydrobiopterin are essential, and the diagnosis can be confirmed with low skin fibroblast enzyme activity or sequencing of the SPR gene. Few patients have been described. In the largest published series, motor delay, axial hypotonia, language delay, diurnal fluctuation of symptoms, dystonia, sleep benefit, weakness, oculogyric crises, dysarthria, parkinsonian signs, hyperreflexia, and psychiatric of behavioral signs were observed in more than half of the 38 patients surveyed. Other significant neurologic manifestations included autonomic disturbances, eye movement abnormalities, chorea, ataxia, dysphagia, hyporeflexia, seizures, and myoclonus. In all cases receiving treatment, significant motor improvement resulted from low-dose L-DOPA/carbidopa.

Tyrosine Hydroxylase Deficiency or AutosomalRecessive Dopa-Responsive Dystonia Tyrosine hydroxylase deficiency, sometimes referred to as autosomal-recessive Segawa disease, displays diverse phenotypes that can be classified as mild, moderate, or severe. Mild cases may demonstrate clumsy gait, toe-walking, tight heel cords, or abnormal posturing that may worsen at the end of the day and may progress with age. Attention or articulation difficulties are sometimes seen. All children with mild symptoms are readily treated with medication. Moderately affected cases demonstrate an abnormal gait often with dystonic posturing with stressed gait, sometimes accompanied by ataxic, spasticity, speech delay, involuntary eye movement problems (brief upward eye-rolling movements with stress or fatigue), or frank oculogyric crises. Most have an excellent response to treatment, but full benefit may take many months. In the most severe cases, referred to as the infantile Parkinson’s disease variant, children are severely disabled and affected from early infancy, demonstrating muscle tightness and rigidity, arching, tremor and poor muscle control, and involuntary eye movements. Ptosis, speech delay, feeding difficulty, and constipation are also common. Less commonly, there are children with generalized low tone, with poor head control and inability to sit unsupported. They often demonstrate torticollis. Dysautonomia can occur, frequently during illness. Severe cases are more difficult to treat, often requiring multiple medications and being unusually vulnerable to side effects of dopaminergic agonists or precursors. Response may be slow, with some continued benefit during months to years. Some cases show persistent mental retardation, encephalopathy, and motor disability despite of treatment. Cerebrospinal fluid concentration of homovanillic acid is low whereas 5-hydroxyindoleacetic acid, neopterin, and biopterin are normal. Phenylalanine loading studies are normal, and enzymatic assays for confirmation of a suspected

diagnosis are not presently available, making confirmation by molecular testing is extremely helpful. A recent analysis has identified mostly missense and compound heterozygous TH mutations, consistent with prior reports of autosomal recessive inheritance. Patients variably respond to L-DOPA/carbidopa, and some have complete reversal of symptoms. The exception to this is the patient with the severe infantile parkinsonism form, who typically tolerates L-DOPA poorly. Addition of dopamine agonists such as selegiline or anticholinergic agents such as trihexyphenidyl can provide significant benefit and help promote the gradual ongoing attainment of motor skills and ability to ambulate independently, but such achievements may occur over years, rather than months or weeks, in the most severely affected patients (Marecos et al., 2014).

Tryptophan Hydroxylase Deficiency Tryptophan hydroxylase catalyzes the BH4-dependent hydroxylation of tryptophan to 5-hydroxytryptophan, which is then decarboxylated to form serotonin. Tryptophan hydroxylase expression is limited to certain cells in the CNS and periphery. Although clinically suspected, no confirmed cases have yet been identified.

Dopamine B-Hydroxylase Deficiency Dopamine b-hydroxylase converts dopamine to norepinephrine. Patients with severe deficiency cannot synthesize norepinephrine, epinephrine, and octopamine in CNS or peripheral autonomic neurons. Dopamine acts as a false neurotransmitter for noradrenergic neurons. Neonates with dopamine b-hydroxylase deficiency can have episodic hypothermia, hypoglycemia, and hypotension, leading to early death. Survivors do fairly well until late childhood, when overwhelming orthostatic hypotension profoundly limits their activities (Robertson et al., 1991). Most patients have been identified as young adults. Observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than 1 supports the diagnosis. Orthostatic hypotension, particularly after exercise, and ptosis are constant features. General lethargy and lassitude improve dramatically, and blood pressure becomes normal with treatment with D,L-threo-dihydroxyphenylserine, a synthetic amino acid that is converted to norepinephrine by aromatic L-amino acid decarboxylase. Patients may undergo personality change, becoming more “aggressive” with treatment.

Monoamine Oxidase Deficiency Monoamine oxidase is a mitochondrial enzyme involved in the catabolism of biogenic amines. Monoamine oxidase A, the primary type in fibroblasts, preferentially degrades serotonin and norepinephrine. Monoamine oxidase B, the primary type in platelets and in the brain, preferentially degrades phenylethylamine and benzylamine. These enzymes are critical in the neuronal metabolism of catecholamine and indoleamine neurotransmitters. The genes are closely linked on the X chromosome, near the Norrie’s disease locus, and only affected boys have been identified to date.

Monoamine Oxidase A Deficiency Brunner described a family with an X-linked nondysmorphic mild mental retardation and a tendency to severe aggressive or violent behavior and urine studies consistent with marked disturbance of monoamine metabolism (Brunner et al., 1993). No additional patients have been identified to date.



Monoamine Oxidase B Deficiency Isolated monoamine oxidase B deficiency has not yet been reported in a patient. Two brothers with a microdeletion, including the Norrie locus and monoamine oxidase B, however, had features consistent with Norrie disease alone. These patients had neither abnormal behavior nor mental retardation, leading the authors to conclude that monoamine oxidase A plays a more significant role than does monoamine oxidase B in the metabolism of biogenic amines, and monoamine oxidase B deficiency alone may have a primarily neurochemical phenotype: that of increased phenylethylamine in urine (Lenders et al., 1996).

Monoamine Oxidase A and B Deficiency A small number of cases of MAO A and B deficiency (with intact Norrie locus) have been reported, all male. Affected individual’s demonstrated episodic hypotonia, intellectual disability and stereotyped movements (Saito et al. 2014).

Dopamine Transporter Deficiency The presynaptic dopamine transporter (DAT) encoded by SLC6A3 modulates the intensity and duration of dopaminergic signaling by synaptic dopamine reuptake. Individuals with dopamine transporter deficiency syndrome classically present with a hyperkinetic movement disorder of infantile onset that progresses to parkinsonism dystonia and characteristic elevated CSF homovanillic acid to 5-hydroxyindoleacetic acid (HV to 5-HIAA). Inheritance has been consistent with an autosomal recessive pattern. Treatment generally involves ropinirole, L-dopa, and/or selegiline therapy, but most cases are refractory to medical or surgical management (Marecos et al., 2014).

Vesicular Monoamine Transporter 2 Deficiency A syndrome of mixed hyperkinetic and hypokinetic movement disorder with oculogyric crises, dysautonomia, developmental delay, behavioral and sleep disturbances with no CSF neurotransmitter deficiency has been described in a single family. Affected individuals additionally demonstrate elevated urine 5-HIAA, HVA, and decreased urine norepinephrine and dopamine and were found to carry single family has been described with homozygous missense mutations in SLC18A2, the gene encoding the vesicular monoamine transporter 2. Treatment with pramipexole improved dopamine-related symptoms markedly, and to a lesser extent, other symptoms (Marecos et al., 2014).

DISORDERS OF AMINO ACID NEUROTRANSMITTERS Overview Amino acid neurotransmitters are the main inhibitory and excitatory messengers in the nervous system; however, few have been implicated in human disease. GABA and glycinerelated disorders are best studied yet incompletely understood. Glycine has ubiquitous function and both excitatory and inhibitory properties. Glycine encephalopathy, formerly referred to as nonketotic hyperglycinemia, will be touched on briefly, as more extensive review occurs elsewhere in this text. Disorders of GABA degradation will also be reviewed (Fig. 44-3), with specific emphasis on succinic semialdehyde dehydrogenase deficiency, the most common and best characterized.

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Gamma-Aminobutyric Acid   Transaminase Deficiency GABA is the major inhibitory neurotransmitter of the brain, derived primarily from glutamate, the major excitatory neurotransmitter. The first step of the GABA degradation pathway involves GABA transaminase, which removes an amino group from GABA and adds it to alpha-ketoglutarate, thus replenishing glutamate and reestablishing the closed loop system known as the GABA shunt. GABA transaminase deficiency is a rare, autosomal-recessive disorder characterized by abnormal development, seizures, and high levels of CSF GABA betaalanine, both of which are also elevated in serum. Cases to date have presented with neonatal seizures, lethargy, hypotonia, hyperreflexia, developmental retardation, and high pitched cry, all with poor outcomes (Definitive diagnosis can be made by measurement enzyme activity in various cell types [Parviz et al., 2014]).

Succinic Semialdehyde Dehydrogenase Deficiency Succinic semialdehyde dehydrogenase deficiency is an autosomal-recessive inborn error of metabolism associated with a defect in the metabolism of GABA. Phenotypic features range from nonspecific global developmental delay and hypotonia to ataxia, severe mental retardation, visual impairment, and seizures. Somewhat uniquely among neurotransmitterrelated disorders, disease course is not intermittent or episodic. Neuropsychiatric symptoms (i.e., sleep disorders, inattention, hyperactivity, obsessive-compulsive disorder, and anxiety) are prominent. MRI is commonly abnormal. Urine organic acid screening to detect elevated 4-hydroxybutyric acid is the most easily available screening strategy, but GABA levels in cerebrospinal fluid and urine are also elevated. Treatment is generally symptomatic and targeted at seizure management (Lapalme-Remis et al., 2015).

Secondary Neurotransmitter Deficiency States Menkes disease is an X-linked recessive disorder in which multiple copper-dependent enzymes can be secondarily affected, including dopamine b-hydroxylase, leading to secondary autonomic involvement and norepinephrine deficiency (Kaler et al., 2008). Hyperekplexia, or “startle disease,” is a heterogeneous disorder caused by defects in the a1 subunit of the glycine receptor occurring in autosomal-dominant and autosomalrecessive forms, characterized by stimulus-sensitive myoclonus. Transient hypertonia and hypokinesia in infancy in some families with the disorder has led to the designation “stiff baby syndrome.” Dubowitz and colleagues described an infant with classic startle disease, with markedly decreased cerebrospinal fluid GABA levels (Dubowitz et al., 1992). Infants with hyperekplexia have higher than expected rates of sudden infant death syndrome. An exaggerated startle response persists throughout life; sudden, acoustic or tactile stimuli can precipitate a brief attack of intense rigidity with falling. Dramatic improvement of symptoms occurs in most patients with clonazepam. Neurodegenerative disorders are sometimes associated with reduced neurotransmitter metabolites. Such abnormalities have been seen in patients with leukodystrophy and progressive encephalopathy phenotypes in which a primary defect in neurotransmitter or pterin metabolism could not be identified but who still may benefit from directed treatment of the underlying neurotransmitter deficiency.

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Periods of hypoxia or ischemia can lead to secondary deficiencies of serotonin and dopamine.

UNDEFINED NEUROTRANSMITTER   DEFICIENCY STATES Increasingly, with more widespread testing of cerebrospinal fluid neurotransmitter metabolites, patients are being identified with documented neurotransmitter deficiency states that do not fit easily into any of the preceding diagnostic categories, and the nature of their underlying defects remains unknown. These include patients with a wide variety of movement disorder phenotypes, encephalopathy, or seizures. Additional studies are needed to determine the precise defects affecting neurotransmitter levels and to ascertain whether they are primary or secondary.

APPROACH TO TREATMENT IN   PATIENTS WITH NEUROTRANSMITTER DEFICIENCY STATES Because patients with neurotransmitter deficiency disorders caused by tyrosine hydroxylase or BH4 deficiency have been deficient for prolonged periods before treatment, they can be extremely sensitive to initiation of neurotransmitter precursors. Starting with extremely conservative dosages, increasing the dosage slowly during weeks or months, and ensuring that peripheral aromatic L-amino acid decarboxylase is fully blocked by providing ample carbidopa can make the transition to treatment much easier. The rate or degree to which children respond depends on a variety of factors, including age at diagnosis, specific disorder and mutation, presence or absence of associated hyperphenylalaninemia, and presence or absence of central BH4 deficiency. In general, optimism about improvement is warranted. Institution of neurotransmitter precursor treatment may lead to new problems, such as intermittent dyskinesia related to a peak dose effect, changes in appetite, gastroesophageal reflux, diarrhea, and constipation. These problems, greatest in the first few weeks of institution of treatment, tend to improve with time. With regard to replacement of L-DOPA, use of a slow-release form of the medication may theoretically be ideal. However, such formulations are dosed, not for use in children, but for use in adults with Parkinson’s disease. In addition, dividing standard dosage forms marketed for adults makes adequate dosing in infants and young children a significant challenge. Thus ideal dosage forms may need to be formulated in compounded preparations, rather than through commercially marketed dosage preparations. Support for parents and children during this often difficult period of transition from initiation of treatment to adjustment of medications is critical because these patients will likely require neurotransmitter precursor replacement throughout their lifetimes. In a disorder such as aromatic L-amino acid decarboxylase deficiency, in which direct receptor agonists may be indicated, only adult formulations of these often-potent medications are available, making the use of compounding necessary. Giving more frequent and lower doses throughout the day may be necessary in some children. Although patients with primary neurotransmitter deficiency states are more likely to respond optimally to treatment, patients with secondary neurotransmitter deficiency may have some symptomatic benefit from directed treatment of their underlying neurotransmitter deficiency state.

NEUROLOGIC DISORDERS CHARACTERIZED BY EXCESS NEUROTRANSMITTER LEVELS Glycine Encephalopathy Glycine encephalopathy, formerly referred to as nonketotic hyperglycinemia, is a heterogeneous disorder associated with insufficient activity of various components of the mitochondrial glycine cleavage system. The enzyme system for cleavage of glycine is composed of four protein components: P protein, a pyridoxal phosphate-dependent glycine decarboxylase; H protein, a lipoic acid-containing protein; T protein, a tetrahydrofolate-requiring enzyme; and L protein, a lipoamide dehydrogenase. Nonketotic hyperglycinemia may be caused by a defect in any one of these enzymes. It is an autosomalrecessive disorder with several reported phenotypes, including the classic severe neonatal form, an infantile variant, a mildepisodic childhood variant, a late-onset form, and a benign reversible form. Most patients described to date have the neonatal and most severe phenotype, likely because it is the most distinctive phenotype. These patients present shortly after birth with lethargy, encephalopathy, hypotonia, myoclonic jerks, and apnea. EEG generally reveals a burst-suppression pattern. Those who survive the neonatal period generally develop intractable seizures and profound mental retardation. Patients with the infantile form have seizures and variable cognitive impairment after a short period of apparently normal development. In the mild, episodic form, patients typically present some time after infancy with mild psychomotor retardation and may manifest episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, children present with progressive spastic diplegia and optic atrophy. They generally do not have seizures, and intellectual function is preserved. Diagnosis is best made by documenting an increased cerebrospinal fluid to plasma glycine ratio. At present, confirmation of diagnosis requires enzyme analysis in liver or transformed lymphoblasts. Treatment with dextromethorphan and sodium benzoate has led to variable improvement in seizure control and behavioral problems in some patients. It is additionally advisable to avoid valproate, as it may increase serum and CSF glycine levels (Hoover-Fong JE et al., 2004). REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Brunner, H.G., Nelen, M., Breakefield, X.O., et al., 1993. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 62, 578–580. Dubowitz, L.M., Bouza, H., Hird, M.F., et al., 1992. Low cerebrospinal fluid concentration of free gamma-aminobutyric acid in startle disease. Lancet 340, 80–81. Hoover-Fong, J.E., Shah, S., Van Hove, J.L., et al., 2004. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology 63, 1847–1853. Kaler, S.G., Holmes, C.S., Goldstein, D.S., et al., 2008. Neonatal diagnosis and treatment of Menkes disease. N. Engl. J. Med. 358, 605–614. Lapalme-Remis, S., Lewis, E.C., De Meulemeester, C., et al., 2015. Natural history of succinic semialdehyde dehydrogenase deficiency through adulthood. Neurology 5, 861–865. Lenders, J.W., Eisenhofer, G., Abeling, N.G., et al., 1996. Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes. J. Clin. Invest. 97, 1010–1019.

Marecos, C., Ng, J., Kurian, M.A., 2014. What is new for monoamine neurotransmitter disorders? J. Inherit. Metab. Dis. 37, 619–626. Parviz, M., Vogel, K., Gibson, K.M., et al., 2014. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies. J Pediatr Epilepsy 3, 217–227. Robertson, D., Haile, V., Perry, S.E., et al., 1991. Dopamine betahydroxylase deficiency. A genetic disorder of cardiovascular regulation. Hypertension 18, 1–8. Saito, M., Yamagata, T., Matsumoto, A., et al., 2014. MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus. Brain Dev. 36, 64–69. Thöny, B., Blau, N., 2006. Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase. Hum. Mutat. 27, 870–878.

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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 44-1 Synthesis and catabolism of catecholamine and indoleamine neurotransmitters. Fig. 44-3 The gamma-aminobutyric acid metabolism pathway.

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Phakomatoses and Allied Conditions Elizabeth A. Thiele and Bruce R. Korf

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

The disorders referred to as phakomatoses are notable for their dysplastic nature and tendency to form tumors in various organs, particularly the nervous system. Some of these conditions have been referred to as “neurocutaneous disorders” because of the frequent involvement of the skin in addition to the nervous system. Cutaneous features are not present in all phakomatoses, however (e.g., von HippelLindau syndrome), and many include features outside the skin and nervous system (Table 45-1 summarizes the phakomatoses).

THE NEUROFIBROMATOSES The neurofibromatoses consist of three distinct disorders: NF1 (Ferner and Gutmann, 2013), NF2 (Lloyd and Evans, 2013), and schwannomatosis (Plotkin et al, 2013).

Neurofibromatosis Type 1 Neurofibromatosis type 1 (NF1) is transmitted as an autosomal-dominant trait and is notable for its great variability of expression. It can involve not only the peripheral and central nervous systems, but also the skin, bone, endocrine, gastrointestinal, and vascular systems. Diagnostic criteria for NF1 are presented in Box 45-2.

Clinical Characteristics In NF1, the usual presenting signs are cutaneous manifestations. Skin changes include café-au-lait macules, cutaneous neurofibromas, nevus anemicus, patchy and diffuse areas of hyperpigmentation, and juvenile xanthogranulomas. Six or more café-au-lait macules measuring at least 5 mm across before puberty or 15 mm after puberty constitute one diagnostic criterion for NF1. Individuals with mutation in the SPRED1 gene may also present with multiple café-au-lait macules, skinfold freckles, and macrocephaly but do not develop neurofibromas or other tumor-related NF1 complications. This condition is referred to as Legius syndrome. Usually the second sign to appear is skinfold freckling. Freckles begin in the inguinal region in children at 3 to 4 years of age and eventually appear in the axillae, at the base of the neck, and in the inframammary region in females. Cutaneous neurofibromas are a prominent finding in NF1 and are located in or adjacent to the dermis. They are discrete, soft or firm papules, ranging in size from a few millimeters to several centimeters, can be flat, sessile, or pedunculated, and can be readily impressed into the skin below. Neurofibromas can develop at any time and in any location, and may affect any component of the peripheral nervous system, from the dorsal root ganglion to the terminal nerve twigs. Plexiform neurofibromas represent tumors involvinga longitudinal section of nerve or multiple branches of a major nerve. Near the surface of the body they can cause thickening and hypertrophy of the skin and soft tissues. They may occur deeper in the body and be detected only by imaging. Tumors of the orbit

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or limbs can cause major physical deformity. Plexiform neurofibromas can be congenital lesions, often growing rapidly in the early years of life; they then may remain quiescent for long periods of time or grow unpredictably. The tumors are easily visualized by magnetic resonance imaging (MRI), and display a characteristic “target sign.” Neurofibromas originating at the dorsal roots may grow in a dumbbell shape and invade the spinal canal, sometimes causing spinal cord compression. The gastrointestinal tract can also be affected by growth of neurofibromas or ganglioneuromas causing intestinal obstruction or bleeding. Ophthalmologic features of NF1 include Lisch nodules, glaucoma, and optic glioma. Iris Lisch nodules are melanocytic hamartomas that are highly specific to NF1. Optic pathway gliomas are found in approximately 15% of patients. Most are asymptomatic, but these tumors can manifest with decreased visual acuity, visual field defects, or precocious puberty. Visual symptoms do not necessarily correlate with the size or growth of the tumor radiographically. The glioma can involve the optic nerves, chiasm, optic radiations, and hypothalamus; it may manifest rarely as the diencephalic syndrome of infancy or more commonly with precocious puberty. Optic gliomas are pilocytic astrocytomas, but usually are slow-growing. Aside from optic gliomas, astrocytomas of the cerebrum, brainstem, and cerebellum are the most common intracranial tumors encountered in NF1. Malignant peripheral nerve sheath tumor occurs in 8% to 13% of affected persons. These manifest with pain or sudden growth, usually within a preexisting plexiform neurofibroma. Various other neoplastic disorders occur more frequently in patients with NF1 than in the general population, including leukemia, especially juvenile myelomonocytic leukemia and pheochromocytoma. Macrocephaly and short stature are common in NF1 and scoliosis has been reported to occur in 10% to 40% of patients. Bowing of the tibia, fibula, and other long bones can be present in early life, with occurrence of spontaneous fractures at the junction of the middle and distal thirds of the bone shaft, resulting in pseudarthrosis. Nonossifying fibromas may occur and can present with pain or fracture. Children with NF1 manifest an increased frequency of migraine, and these may be associated with features of abdominal pain, nausea, and vomiting. Constipation has also been reported at increased frequency in affected children. Approximately 50% of patients have learning disabilities, with no specific pattern unique to those with NF1. Both verbal and nonverbal disabilities occur, as well as attention-deficit disorder, hypotonia, and expressive and language problems. Those with attention deficit disorder do tend to respond to stimulant medication. Problems with motor coordination and balance are also seen, and correlate with the presence of other neurocognitive dysfunctions. Children with NF1 may also have problems with sleep. Fewer than 10% have severe intellectual disability, and most of these patients have large deletions of the NF1 gene. There is also an increased frequency of symptoms consistent with autism spectrum disorders.



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BOX 45-2  Diagnostic Criteria for Neurofibromatosis 1 • Six or more café-au-lait macules more than 5 mm in greatest diameter in prepubertal children, and more than 15 mm in greatest diameter in postpubertal children • Two or more neurofibromas of any type or one plexiform neuroma • Freckling in the axillary or inguinal regions • Optic pathway glioma • Two or more Lisch nodules (iris hamartomas) • A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis • Diagnosis of NF1 in a first-degree relative (parent, sibling, or offspring) according to foregoing criteria (Modified from: Stumpf, D., 1988. Consensus development conference of neurofibromatosis. Arch Neurol 45, 575–578; Gutmann, D.H., et al., 197. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278, 51–57.)

Seizures occur in approximately 6–10% of patients, are often focal, and may be associated with structural changes in the brain. Vascular anomalies in NF1 can occur in peripheral or cerebral vessels and include regions of intimal proliferation and fibromuscular changes in small arteries. Renal artery stenosis can lead to hypertension in children, and involvement of other vessels can cause vascular insufficiency or hemorrhage as a result of arterial wall dissection. Stenosis of the internal carotid artery can lead to moyamoya disease and stroke, although lesions often are asymptomatic. Surgical revascularization has been shown to be effective in prevention of ischemic episodes in instances of internal carotid stenosis.

Pathology Neurofibromas consist of a mixture of cell types, including Schwann cells, fibroblasts, perineurial cells, and mast cells. In plexiform neurofibromas, the pathologic process extends across multiple nerve fascicles instead of occurring at a focal site in a nerve and may extend across branches of a larger nerve. Malignant peripheral nerve sheath tumor manifests as a malignant tumor of Schwann cell origin, although sometimes rhabdoid elements are present in such tumors. Most, if not all, of these neoplasms arise from preexisting tumors, usually plexiform neurofibromas.

Genetics NF1, inherited as an autosomal-dominant trait, has an estimated prevalence of 1 in 3000 in all populations; about half of cases are new mutations. The NF1 gene is located at 17q11.2 and encodes a 3818-amino-acid protein referred to as neurofibromin. The protein includes a functional GTPase-activating protein (GAP) domain that regulates conversion of RASguanosine triphosphate to Ras-guanosine diphosphate. Neurofibromin functions as a tumor suppressor gene with respect to neurofibroma formation. Transformation to malignancy requires additional genetic changes, such as mutation of p53. NF1 exhibits a wide range of variability of expression and complete penetrance. Mutations are widely scattered across the gene and include a wide variety of mutational mechanisms. Approximately 50% of cases of NF1 occur sporadically, as a result of a new mutation of the NF1 gene. Because of the high penetrance of the disorder, unaffected parents of a sporadically affected child have a low risk of recurrence, barring the rare instance of germline mosaicism. Somatic mosaicism

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for NF1 may manifest with segmental distribution of features. Genetic testing for diagnosis of NF1 is available on a clinical basis. The discovery of mutation in the SPRED1 gene accounting for patients with multiple café-au-lait spots but lacking other features of NF1 (referred to as “Legius syndrome”) and provides additional rationale for genetic testing in young children with multiple café-au-lait spots. The majority of mutations in children with multiple café-au-lait spots are found in the NF1 gene, making it cost-effective to begin with NF1 testing, followed by SPRED1 testing if no NF1 mutation is found.

Management Treatment of patients with neurofibromatosis is symptomatic. Affected persons should be followed on a regular basis by a physician who is familiar with the disorder to recognize treatable complications early and to provide anticipatory guidance and counseling. Genetic counseling should be provided. Controversy surrounds the use of imaging, especially MRI, in screening patients with NF1. Most of the lesions that will be identified are not amenable to treatment, so such testing may create needless anxiety and risks associated with sedation. The value of the “baseline” examination is questionable because most of the lesions of NF1 are slow-growing and will be followed both clinically and by imaging once they come to attention. Current consensus guidelines do not recommend routine imaging, although care should be individualized for specific clinical needs (Gutmann et al., 1997). Neurofibromas of the peripheral nerves need not be removed unless they are subject to repeated irritation and trauma or develop signs of malignant change. Some plexiform neuromas can be removed for cosmetic reasons, although complete resection is difficult and regrowth is common. Malignant tumors are managed with appropriate surgical measures and often radiation therapy and chemotherapy. Optic gliomas tend to behave in an indolent manner and therefore are followed clinically without treatment in asymptomatic children. Symptomatic tumors most often are treated with chemotherapy; radiation therapy may be associated with second malignant tumors or moyamoya disease. Malignant peripheral nerve sheath tumors tend to be highly malignant, so early diagnosis is essential. Patients with unexplained pain or growth of a neurofibroma should be evaluated, with consideration of biopsy. Positron emission tomography (PET) scanning may be helpful in distinguishing a malignant peripheral nerve sheath tumor from plexiform neurofibroma. Clinical trials of drugs to treat specific complications are ongoing but no definitive medical therapy has been identified.

Neurofibromatosis Type 2 Clinical Characteristics and Pathology Diagnostic criteria for NF2 are presented in Box 45-3. The defining feature of NF2 is the occurrence of bilateral vestibular schwannomas. Vestibular schwannomas commonly present with tinnitus and/or hearing loss, and may cause problems with balance. Audiology and auditory brainstem-evoked response testing can be helpful, but definitive diagnosis is based on MRI findings. Schwannomas can occur along any other cranial nerve, the fifth being most common after the eighth. Schwannomas also may occur along spinal nerves, with the potential for causing radiculopathy or cord compression, or along peripheral nerves. In some patients, a polyneuropathy develops as a result of Schwann cell proliferation around peripheral nerves. Dermal schwannomas appear as plaquelike lesions, often with associated hair growth. Café-au-lait

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BOX 45-3  Diagnostic Criteria for Neurofibromatosis 2 CONFIRMED NF2* • Bilateral vestibular schwannomas or • A first-degree relative with NF2 and either • Unilateral vestibular schwannoma before age 30 years or any two of • Meningioma, schwannoma, ependymoma, juvenile lens opacity PRESUMPTIVE NF2 • Unilateral vestibular schwannoma before age 30 years and at least one of: meningioma, schwannoma, ependymoma, juvenile lens opacity or • Two or more meningiomas and unilateral vestibular schwannoma before age 30 years or at least one of: meningioma, schwannoma, ependymoma, juvenile lens opacity MANCHESTER CRITERIA† • Bilateral vestibular schwannomas or • A first-degree relative with NF2 and either • Unilateral vestibular schwannoma or any two of: meningioma, schwannoma, ependymoma, neurofibroma, posterior subcapsular lenticular opacity or • Unilateral vestibular schwannoma and any two of: meningioma, schwannoma, ependymoma, neurofibroma, posterior subcapsularlenticular opacity or • Two or more meningiomas and unilateral vestibular schwannoma or any two of: meningioma, schwannoma, ependymoma, neurofibroma, posterior subcapsular lenticular opacity *Based on: Gutmann, D.H., et al., 1997. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278, 51–57. †Baser, M.E., et al., 2002. Evaluation of clinical diagnostic criteria for neurofibromatosis 2. Neurology 59(11), 1759–1765.

macules may occur but are not a reliable indicator of NF2, unlike in NF1. Other central nervous system tumors associated with NF2 are meningiomas and ependymomas. Virtually the entire NF2 phenotype is characterized by proliferative lesions; the one exception is the occurrence of posterior subcapsular cataracts or cortical wedge opacities.

Genetics NF2 is transmitted as an autosomal-dominant trait with complete penetrance and variable expression. Prevalence is estimated at approximately 1 in 60,000, and birth incidence at 1 in 30,000. Approximately half of cases occur sporadically as a result of new mutation. The NF2 gene was mapped to chromosome 22, and the responsible gene is variously referred to as schwannomin or merlin. Merlin is a cytoskeletal protein that appears to play a role in the control of cell growth in tissues. Schwannomas are clonal tumors, and the NF2 gene acts as a tumor suppressor in formation of these tumors, as well as other NF2-associated tumors. Genetic testing for NF2 is available for diagnostic purposes. Some genotype-phenotype

correlations have been identified; missense or splicing mutations tend to predict milder disease than do mutations that lead to protein truncation. Somatic mosaicism for NF2 mutation may produce localized disease or ameliorate disease severity.

Management Patients benefit from multidisciplinary care at a center with experience in dealing with the varied manifestations of the disorder. Management of tumors associated with NF2 is primarily surgical. Timing of surgery and the decision to treat one or both vestibular tumors depends on tumor size, degree of hearing loss, and involvement of other cranial nerves or compression of the brainstem. Stereotactic radiosurgery is also used for the treatment of vestibular schwannomas, although there may be an increased risk of malignancy in residual tumor. Use of auditory brainstem implants can be helpful in some patients in restoring some hearing due to tumor progression or surgery. Treatment with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab have shown promising results in reduction in size of vestibular schwannomas and improvement of hearing. Meningiomas are less likely to respond to bevacizumab treatment. Reduction in tumor size in some patients and improvement in hearing has also been observed with lapatinib treatment.

Schwannomatosis Schwannomatosis is a more recently recognized entity, characterized only by the occurrence of schwannomas on cranial and spinal nerves other than the vestibular nerve. It often presents with pain or nerve compression. Diagnostic criteria are provided in Box 45-4. Schwannomatosis is transmitted as a dominant trait with incomplete penetrance. About 10% of cases are familial; the remainder are sporadic, presumably due to new mutation or incomplete penetrance. The first gene found to be responsible for the disorder is SMARCB1 and encodes a protein component of a chromatin remodeling complex. It is located on chromosome 22 near the NF2 locus but is distinct from that locus. Although schwannomas are the hallmark feature, meningiomas may also occur in some families with SMARCB1 mutation. Mutation of SMARCB1 do not account for all cases of schwannomatosis. A second gene, LZTR1 has been found to account for some cases of schwannomatosis without germline SMARCB1 mutation. Schwannomas in schwannomatosis patients with germline mutation of either SMARCB1 or LZTR1 have, in addition, mutation of NF2 on the same copy of chromosome 22 and loss of NF2 and either SMARCB1 or LZTR1 on the other chromosome. Not all cases of schwannomatosis are associated with loss of heterozygosity on chromosome 22, indicating that still other genes are involved. Treatment of schwannomatosis is surgicalt. There is one report of a favorable response to bevacizumab, though no additional studies of the use of this drug have been reported to date.

TUBEROUS SCLEROSIS COMPLEX (TSC) Tuberous sclerosis complex is a disorder of autosomaldominant inheritance that affects multiple organ systems, resulting in manifold clinical expressions. TSC is currently recognized as one of the most common single-gene disorders seen in children and adults, with an estimated incidence of 1 in 5800 live births. The first description of tuberous sclerosis complex was by von Recklinghausen, who described a newborn



Phakomatoses and Allied Conditions

BOX 45-4  Diagnostic Criteria for Schwannomatosis MOLECULAR DIAGNOSIS: Two or more pathologically proved schwannomas or meningiomas AND genetic studies of at least two tumors with loss of heterozygosity (LOH) for chromosome 22 and two different NF2 mutations; if there is a common SMARCB1 mutation, this defines SMARCB1-associated schwannomatosis Or One pathologically proved schwannoma or meningioma AND germline SMARCB1 pathogenic mutation CLINICAL DIAGNOSIS: * Two or more nonintradermal schwannomas, one with pathological confirmation, including no bilateral vestibular schwannoma by high-quality MRI (detailed study of internal auditory canal with slices no more than 3mm thick). Recognize that some mosaic NF2 patients will be included in this diagnosis at a young age and that some schwannomatosis patients have been reported to have unilateral vestibular schwannomas or multiple meningiomas. * One pathologically confirmed schwannoma or intracranial meningioma AND affected first-degree relative * Consider as possible diagnosis if there are two or more nonintradermal tumors but none has been pathologically proven to be a schwannoma; the occurrence of chronic pain in association with the tumor(s) increase the likelihood of schwannomatosis Patients with the following characteristics do not fulfill diagnosis for schwannomatosis: * Germline pathogenic NF2 mutation * Fulfill diagnostic criteria for NF2 * First-degree relative with NF2 * Schwannomas in previous field of radiation therapy only (With permission from: Plotkin, et al., 2013. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria.)

who had died of respiratory distress and was found at postmortem examination to have multiple cardiac tumors and a “great number of cerebral scleroses.” Bourneville usually is credited with the first detailed description of the cerebral manifestations of the disease, describing “sclérose tubéreuse,” indicating the superficial resemblance of the lesions of a potato. He attached no significance to the facial skin rash of his first patient, calling it acne rosacea, but he and Brissard believed that the renal tumors and cerebral scleroses were associated findings. Facial angiofibromas, previously referred to as adenoma sebaceum, were independently described in several reports, but Vogt emphasized the association of adenoma sebaceum and the cerebral scleroses described by Bourneville. He also described a “classic” triad of clinical features comprising mental retardation, intractable epilepsy, and adenoma sebaceum, which is now known to be present in less than one-third of patients with TSC.

Clinical Characteristics Diagnostic criteria are provided in Box 45-5. The clinical presentation of TSC depends on the age of the patient, the organs involved, and the severity of involvement. Of importance, both the brain and the skin have more than one major criterion for diagnosis; therefore a diagnosis of definite tuberous sclerosis complex can be based on skin findings alone, or on neuroimaging findings alone.

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BOX 45-5  Diagnostic Criteria for Tuberous Sclerosis Complex MAJOR FEATURES • Hypomelanotic macules (≥3, at least 5-mm diameter) • Angiofibromas (≥3) or fibrous cephalic plaque • Ungual fibromas (≥2) • Shagreen patch • Multiple retinal hamartomas • Cortical dysplasias* • Subependymal nodules • Subependymal giant cell astrocytoma • Cardiac rhabdomyoma • Lymphangioleiomyomatosis (LAM)† • Angiomyolipomas (≥2)† MINOR FEATURES • “Confetti” skin lesions • Dental enamel pits (>3) • Intraoral fibromas (≥2) • Retinal achromic patch • Multiple renal cysts • Nonrenal hamartomas DIAGNOSTIC CERTAINTY CRITERIA Definite TSC • 2 major features or • 1 major feature + 2 or more minor features • Identification of a known pathogenic mutation in TSC1 or TSC2 Probable TSC • 1 major feature or • 2 or more minor features *Includes tubers and cerebral white matter radial migration lines. †A combination of the two major clinical features (LAM and angiomyolipomas) without other features does not meet criteria for a definite diagnosis. (With permission from Northrup H, Krueger DA on behalf of the International Tuberous Sclerosis Complex Consensus Group. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference, Pediatr Neurol. 2013; 49(4): 243–254.)

Epilepsy is the most common presenting symptom in tuberous sclerosis complex and also is the most common medical disorder. In up to 80% to 90% of persons with TSC, seizures will develop during their lifetime, with the onset most frequently in childhood. A majority of children with TSC have the onset of seizures during the first year of life, and approximately one-third develop infantile spasms. Almost all seizure types can be seen in persons with tuberous sclerosis complex, including tonic, clonic, tonic-clonic, atonic, myoclonic, atypical absence, partial, and complex partial. Only “pure” absence seizures are not observed. Infantile spasms will develop in approximately one-third of children with TSC, although some reports suggest an incidence as high as 75%. TSC is thought to be the most common single cause of infantile spasms, and in some series, 25% of symptomatic infantile spasms are secondary to TSC. Partial complex seizures precede infantile spasms in approximately one-third of patients with tuberous sclerosis complex in whom infantile spasms develop. A strong association between the presence of infantile spasms in tuberous sclerosis complex and subsequent developmental impairment has been noted, although children with tuberous sclerosis complex and infantile spasms can have a normal cognitive outcome.

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The electroencephalogram (EEG) in infantile spasms associated with TSC often demonstrates hypsarrhythmia or modified hypsarrhythmia. It is important to realize, however, that the EEG, although usually abnormal, frequently does not have the features of hypsarrhythmia; in some series, up to 70% of children with tuberous sclerosis complex and infantile spasms did not have the characteristics of hypsarrhythmia. Several reports have characterized the EEG patterns of persons with TSC and have found a high incidence of abnormalities, including diffuse slowing and epileptiform features. TSC is associated with a wide range of cognitive and behavioral manifestations. Approximately one-half of persons with TSC have normal intelligence, whereas the other half have some degree of cognitive impairment, ranging from mild learning disabilities to severe mental retardation. A bimodal distribution of cognitive abilities is evident, with affected persons falling into a severely cognitively impaired group or a group with normal intelligence. Risk factors for cognitive impairment include a history of infantile spasms, intractable epilepsy, and a mutation in the TSC2 gene. Persons with TSC, particularly those with cognitive impairment, also are at high risk for developmental disorders. Autistic spectrum disorders affect up to 50% of persons with tuberous sclerosis complex, and attention-deficit hyperactivity and related disorders also are common, affecting approximately 50% of the patients. During adolescence and adulthood, anxiety disorders, depression, or mood disorders develop in a majority of patients with TSC. Cutaneous manifestations are found in up to 96% of patients with TSC. Angiofibroma, the skin manifestation initially described in the disorder as adenoma sebaceum, typically appears between the ages of 1 and 4 years and can progress through childhood and adolescence. These lesions typically are pink or red papules that appear in patches or in a butterfly distribution on or about the nose, cheeks, and chin (Fig. 45-10). Hypopigmented, oval, or leaf-shaped macules, ranging from a few millimeters to several centimeters in length and scattered over the trunk and limbs, are commonly seen. The lesions often are apparent at birth and can appear more prominent during the first several years of life. In fair-skinned

Figure 45-10.  Typical angiofibroma in an adult with tuberous sclerosis complex. (Courtesy of Dr. TN Darling, Uniformed Services University of Health Sciences, Bethesda, MD.)

persons, visualization of these hypopigmented spots is facilitated by using a Wood’s light. At least three types of hypopigmented macules occur: polygonal (similar to a thumbprint) is the most frequent shape (0.5 to 2 cm); an ash leaf-shaped hypopigmented macule is characteristic but is not the most common shape (1 to 12 cm); and a confetti-shaped arrangement of multiple, tiny white macules (1 to 3 mm) (Fig. 45-11). Histologic assessment of the hypopigmented spots usually demonstrates a normal number of melanocytes, and on electron microscopy, a reduction in the number, diameter, and melanization of melanosomes in the melanocytes from the white macule is seen. If hypopigmented macules occur on the scalp, the affected person will have poliosis, or a patch of gray or white hair. Another skin manifestation currently considered a major criterion for clinical diagnosis of TSC is the shagreen patch, a connective tissue hamartoma that is distributed asymmetrically on the dorsal body surfaces, particularly on the lumbosacral skin (Fig. 45-12). In a majority of the cases, the shagreen patch is characterized by multiple and small areas of connective tissue hamartoma, ranging in size from a few millimeters to 1 cm. Present from birth, the shagreen patch is more easily identified as the child grows. Subungual or periungual fibromas (Koenen tumors) are present in at least 20% of patients and usually first appear during adolescence, although they can be seen earlier. These typically involve the toes more often than the fingers (Fig. 45-13). Oral fibromas or papillomas occur in about 10% of patients and usually are found on the anterior aspect of the gingiva. Dental enamel pits have been found in all adult patients with TSC, compared with 7% of controls. The kidneys are frequently affected in persons with TSC, and after neurologic manifestations, renal involvement is the most common cause of morbidity and mortality. The two main types of renal lesions are angiomyolipoma and renal cysts. Angiomyolipoma are present in up to 80% of patients with TSC and can develop in either childhood or adulthood. Persons with TSC can have multiple small angiomyolipomas on the surface of the kidneys, throughout the kidney, or one or more larger lesions. The larger lesions are considered to be at greater risk of becoming symptomatic, particularly when they reach 4 to 6 cm in size. They can produce nonspecific complaints such as flank pain, but they also carry a risk of potentially lifethreatening hemorrhage from rupture of dysplastic, aneurysmal blood vessels in the angiomyolipoma. Renal cysts are seen in fewer than 20% of persons with tuberous sclerosis complex and are rarely, if ever, symptomatic. Polycystic kidney disease occurs in 3% to 5% of patients with tuberous sclerosis complex and, when present, usually reflects a contiguous gene syndrome, because the polycystic kidney disease gene is adjacent to the TSC2-tuberin gene on chromosome 16. The cardiac manifestation, rhabdomyoma, is seen in 50% to 60% of persons with TSC. Typically, rhabdomyomas, which can frequently be detected prenatally, are maximal at birth and early childhood and undergo spontaneous regression during the first few years of life. If symptomatic, they result in outflow tract obstruction or valve dysfunction. If the lesions involve the cardiac conduction system, they can predispose the patient to dysrhythmias not only in infancy and childhood, but also throughout life. Pulmonary involvement in includes lymphangioleiomyomatosis, multifocal micronodular pneumocyte hyperplasia, and pulmonary cysts. Although multifocal micronodular pneumocyte hyperplasia is seen fairly commonly in both men and women with tuberous sclerosis complex, lymphangioleiomyomatosis is thought to occur almost exclusively in women. Although lymphangioleiomyomatosis was once thought to be quite rare, affecting less than 1% of women, recent studies



have found such abnormalities in up to 40% of women with, many of whom are asymptomatic. Retinal hamartomas are relatively common, affecting at least 50% of patients, although typically they are not clinically significant. A nodular (mulberry) tumor can be seen on or about the optic nerve head, and round or oval gray-yellow glial patches can be central or peripheral. The large retinal tumors can be cystic. Papilledema is not present, except in those patients with an intracranial mass lesion that obstructs the normal circulation of the cerebrospinal fluid, resulting in increased intracranial pressure. Hamartomas also can be found in other organ systems, including stomach, intestine, colon, pancreas, and liver. Hepatic angiomyolipoma and cysts have been reported in up to 24% of persons with and are thought to be asymptomatic and nonprogressive. Sclerotic and hypertrophic lesions of bone often can be seen, although these typically are not symptomatic.

Clinical Laboratory Testing Due to multiorgan involvement in TSC, a variety of clinical testing is recommended both at time of diagnosis and subsequently, to monitor for involvement and allow appropriate intervention (Table 45-2). MRI and also computed tomography (CT), are important in confirming the diagnosis of TSC, demonstrating cortical tubers, subependymal nodules (Fig. 45-14), and subependymal giant cell tumors (Fig. 45-15). Brain MRI is the preferred imaging modality, because it allows better delineation of cortical tubers and other cortical abnormalities, such as radial migration lines. The imaging characteristics of tubers change with age, related to myelination state. In neonates, tubers appear hyperintense on T1 sequences and hypointense on T2. With increasing age, tubers appear isointense on T1 and hyperintense on T2. In addition to T1-weighted and T2-weighted MRI sequences, fluid-attenuated inversion recovery (FLAIR) sequences appear most useful for identifying tubers and other cortical and subcortical abnormalities. Both CT and MRI can identify subependymal nodules; calcification of the nodules is apparent on CT scan. Development of subependymal nodules into subependymal giant cell tumors occurs in 5% to 10% of persons with TSC; yearily neuroimaging is until the age of 20 years.

Pathology TSC is a multisystem disorder of cellular migration, proliferation, and differentiation, resulting in the development of hamartias and hamartomas. The major pathologic features in the brain include cortical tubers, subependymal nodules, and subependymal giant cell tumors. Cortical tubers are found in the cortex and subcortical white matter, typically located at the gray-white junction. They vary widely in size and distribution among patients with TSC and may extend centrally in a linear or wedge-shaped zone spanning the full thickness from the ventricular wall to the cortical surface. Histologically, tubers consist of dysplastic, hypomyelinated aggregates of abnormal glial and neural elements, with glia-derived cells and astrocytes predominating. A distinguishing feature of cortical tubers is the giant cell, an enlarged, bizarre-appearing neuron or large cells with both neuronal and glial characteristics. Many children with TSC may experience learning difficulties, as a result of mental retardation or autistic spectrum disorders. Risk factors include early seizure onset, infantile spasms, and an intractable seizure disorder. Correlation between the severity of cognitive deficits and epilepsy with tuber burden is thought

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probable, although the data are limited. Distinct from cortical tubers, subependymal nodules do have growth potential and are located around the wall of the lateral ventricle, consisting of astrocytes arising from the subependymal zone and protruding into the ventricles. Subependymal nodules most commonly occur at the caudothalamic groove in the vicinity of the foramen of Monro, and it is thought that they arise from remnants of the germinal matrix in that region.

Genetics TSC is transmitted as an autosomal-dominant trait with variable penetrance and an estimated incidence of 1 in 5800 live births worldwide. Wide phenotypic variability of clinical manifestations and severity has been noted, even within families having the same mutation. Currently, no known effect of paternal or maternal age or of birth order on disease phenotype has been recognized. Approximately two-thirds of cases are sporadic and the result of apparent spontaneous mutations. Both somatic and germline mosaicism have been described in many patients. Two genes, TSC1 and TSC2, have been identified for tuberous sclerosis complex. A disease causing mutation in one of these two genes can be identified in approximately 85% of persons with definite tuberous sclerosis complex according to current criteria. TSC1 located at 9q34; it was cloned in 1997, and the protein product, hamartin, was identified and characterized. The TSC2 gene is located on 16p13 and encodes a protein referred to as tuberin. Tuberin and hamartin interact with one another and function as tumor suppressor molecules. Loss of heterozygosity has been identified in hamartomas from persons with TSC1 and TSC2 mutations, particularly in kidney and lung tissue, but less commonly in cortical tubers or subependymal giant cell astrocytomas. Tuberin has GTPase-activating properties, similar to the NF1 protein product. Hamartin and tuberin are components of the mammalian target of rapamycin (mTOR) pathway, which is involved in many functions, including regulation of cell size. In vivo, it appears that tuberin can be phosphorylated by Akt, at least in part regulating its activity. In normal cells, the tuberin/hamartin complex acts as an inhibitor of mTOR activity. On growth factor stimulation or other stimuli, tuberin is phosphorylated by Akt, which leads to the inactivation of inhibitory activity of TSC1/TSC2 and resultant cell growth. In cells containing mutations affecting the function of hamartin or tuberin, mTOR and S6 kinase activities are significantly increased, and cell growth is no longer regulated by the PI3kinase-TSC1/TSC2 signaling pathway, which is thought to lead to the development of hamartoma.

Management TSC affects most organ systems, and management and treatment recommendations vary according to organ manifestations (Table 45-2). Affected persons, both children and adults, should be managed with regular follow-up evaluations by a physician who is familiar with tuberous sclerosis complex, to recognize treatable manifestations early and to provide anticipatory guidance and counseling. With regard to neurologic manifestations, management focuses on treatment of epilepsy and behavioral disorders and on identification of learning disabilities. Treatment of epilepsy in TSC is similar to that for partial epilepsies resulting from other causes and includes antiepileptic medications, the vagus nerve stimulator, and the ketogenic diet. Vigabatrin is particularly effective in treating infantile spasms in patients with tuberous sclerosis complex. Epilepsy surgery has a very

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important role in the management of patients who have pharmacoresistant epilepsy. Rapamycin, an mTOR antagonist, has been shown to reduce the size of subependymal giant cell tumors and renal angiomyolipoma in tuberous sclerosis complex and may also reduce the progression of pulmonary lymphangioleiomyomatosis. In animal models of TSC, rapamycin has also been shown to prevent epilepsy if given prenatally and to improve cognitive deficits. Ongoing multicenter trials are evaluating the role of rapamycin and other mTOR antagonists in the management of TSC. One rapamycin-like drug, everolimus, is FDA approved for treatment of progressive subependyal giant cell astrocytoma or renal angiomyolipoma.

VON HIPPEL-LINDAU DISEASE (VHL) Von Hippel-Lindau disease is inherited as an autosomaldominant trait and is characterized by retinal, cerebellar, and spinal hemangioblastomas, cystic tumors of the pancreas, kidney, and epididymis, renal cell carcinoma, endolymphatic sac tumors, and, in some families, pheochromocytoma (Maher et al., 2011).

Clinical Characteristics Retinal hemangioblastoma is one of the earliest manifestations of the disease. The early retinal lesion has the appearance of an aneurysmal dilatation of a peripheral retinal vessel; typically, tortuous vessels later manifest, with an arteriovenous pair leading to small, elevated retinal lesions. These lesions commonly are located in the retinal periphery and can easily be overlooked unless careful ophthalmoscopy is performed. Fluorescein angiography is helpful in demonstrating the lesion. Although they usually affect the cerebellum, central nervous system hemangioblastomas sometimes are found in the medulla and spinal cord; they rarely occur in the cerebral hemispheres. The tumor usually is found in patients after the third decade of life but has been reported to occur rarely in children; initial symptoms and signs are those of a spaceoccupying lesion of the posterior fossa. A variety of renal lesions has been found in VHL, including benign cysts, hemangiomas, adenomas, and malignant hypernephromas. Cystic lesions vary in size, ranging from a few millimeters to several centimeters across, and, although they can occur unilaterally, these lesions are more often bilateral and multiple. Renal cell carcinoma is a prominent cause of morbidity and mortality, occurring with a frequency next to that of the retinal and cerebellar hemangioblastoma. Cystic lesions can also occur in the pancreas, adrenal gland, and epididymis. Other organs less commonly affected with cystic changes include the liver, spleen, and lung. Endolymphatic sac tumors associated with VHL can cause hearing loss. Pheochromocytomas occur more often in patients with von VHL than in the general population and tend to cluster in certain families. The retinal hemangioblastoma diagnosis usually is established by careful ophthalmoscopy with fluorescein retinal angiography, revealing the vascular characteristics of the lesions. Cranial MRI scans demonstrate the cerebellar hemangioblastoma or those tumors affecting the medulla and spinal cord. Intraabdominal cystic lesions can be visualized by CT, MRI, or ultrasonography. Other laboratory studies that can assist in diagnosis include erythrocyte count and hematocrit determination, which can be elevated in patients with cerebellar hemangioblastoma or renal carcinoma because of the increased erythropoietin activity of the cyst fluid.

Pathology The tumors usually are well circumscribed, can be solid or cystic, and usually are found in the paramedial aspect of the cerebellar cortex. Characteristic microscopic features include large numbers of thin-walled, closely packed blood vessels lined by plump endothelial cells; the cells are separated by large, pale cells and incorporated in the elaborate network of reticulin fibers.

Genetics VHL disease is inherited as an autosomal-dominant trait. The birth incidence is about 1 in 36,000 persons, and point prevalence has been estimated at 1 in 91,000. Penetrance is nearly complete on careful evaluation. The gene is located on 3p25–26, and encodes a protein that regulates a cellular system that senses and responds to hypoxia. The VHL gene functions as a tumor suppressor; hence, homozygous mutation occurs in tumors, leading to loss of function and constitutive activation of the hypoxia-sensing pathway. Genetic testing is available and has revealed that specific mutations tend to be found in families with von Hippel-Lindau disease associated with pheochromocytoma. VHL disease has been subdivided into type 1, in which all of the manifestations may be present except for pheochromocytoma, and type 2, which includes the full set of features. Type 2 is further divided into 2A (pheochromocytoma and other manifestations, but not renal cell carcinoma), 2B (all features), and 2C (isolated pheochromocytoma).

Management Affected individuals should be provided a program of surveillance to insure early recognition of treatable complications. Recommendations of the VHL Family Alliance are provided in Table 45-3. Retinal hemangioblastomas should be carefully followed by serial ophthalmologic evaluations when the lesions are small. If, however, visual loss or retinal detachment occurs, the lesions can be treated by either laser photocoagulation or cryocoagulation. Central nervous systems lesions are usually treated surgically or with stereotactic radiation therapy. Medical therapy for the various complications of VHL is currently under investigation.

STURGE-WEBER SYNDROME (ENCEPHALOFACIAL ANGIOMATOSIS) (SWS) Sturge-Weber syndrome is characterized by presence of a facial angioma (port-wine stain, or nevus flammeus) and an ipsilateral leptomeningeal angioma; it has an incidence currently estimated at 1 case in 20,000 to 50,000 persons. Schirmer initially described a patient with a facial vascular nevus who had associated buphthalmos, but he did not mention the central nervous system lesion. Sturge initially described this syndrome by providing the clinical findings of a 6-year-old girl with a facial nevus who also had angiomas of the lips, gingiva, palate, floor of the mouth, uvula, and pharynx. The child had buphthalmos and was hemiparetic, and Sturge suggested that she had a similar vascular nevus of the underlying brain. Not until 1897, however, did Kalischer perform the first neuropathologic study of a patient with similar findings, demonstrating that Sturge’s initial contention of cerebral involvement by vascular nevus was correct. Associated intracranial calcification was later described by Weber.



Clinical Characteristics SWS, which occurs sporadically, is characterized by angiomas involving the leptomeninges and ipsilateral skin of the face, typically in the ophthalmic (V1) and maxillary (V2) distributions of the trigeminal nerve. It can extend to other facial areas, including the lips, gingiva, palate, tongue, pharynx, and larynx. The neck, trunk, and extremities also can be involved, either ipsilaterally or contralaterally to the facial angioma. The angioma also can involve the nasopharynx, mucous membrane, and ocular choroidal membrane, resulting in glaucoma in approximately 25% of patients (Fig. 45-17). Additional ocular findings include iridic heterochromia, strabismus, optic atrophy, and dilated retinal veins. In the brain, the associated ipsilateral leptomeningeal angioma most commonly involves the parietal and occipital regions, but also may involve the temporal region and, on occasion, can affect both hemispheres. Dimitri reported that these patients had intracranial calcifications observed on the skull radiographs and described the typical serpentine “tram-track sign” of calcific intracranial densities. Neurologic manifestations vary and depend on location and extent of the leptomeningeal angioma. Seizures occur in 75% to 90% of patients with SWS and may be refractory to treatment. It is hypothesized that the seizure activity results from cortical irritability caused by the leptomeningeal angioma, resulting in regional hypoxia, ischemia, and gliosis, although associated cortical dysgenesis also may be involved. Seizure manifestations are primarily partial motor (40%), although some patients can have primary or secondary generalized tonic-clonic (20%) and both partial and generalized seizures (40%). Other types of seizure activity occur less frequently. Unfortunately, refractory epilepsy develops in a significant number of patients with Sturge-Weber syndrome, ranging in series from 11% to 83%. Surgical procedures, including focal cortical resection, hemispherectomy, and corpus callosotomy, should be considered if seizure activity proves medically intractable. Persons with SWS also are at risk for hemiparesis contralateral to the leptomeningeal angioma, seen in approximately 33% of patients. The hemiparesis can result from ischemia with venous occlusion and thrombosis due in part to venous congestion resulting from failure of cortical vein development. Transient weakness also may result from seizure activity and may become more severe and less transient with recurrent seizure activity. Leptomeningeal venous angiomas can arise in the absence of any facial angioma; although secondary cerebral signs and symptoms similar to those of SWS can occur, these patients are more appropriately considered to have leptomeningeal angiomatosis. Persons with SWS also are at risk for developmental delay and mental retardation (50% to 60%) and are more likely in those with bilateral leptomeningeal involvement and in those with a history of seizures. Headaches also are common, occurring in up to 60% of affected persons, and are thought to be secondary to the vascular abnormalities, giving symptoms consistent with migraine. EEG studies document decreased amplitude and frequency of electrocerebral activity over the affected hemisphere. Diffuse, multiple, and independent spike foci commonly are present. Hemianopsia in young patients also is difficult to determine but is believed to occur in about one-quarter to one-half of patients. About one-third of patients have glaucoma, and approximately half of these have buphthalmos ipsilateral to the facial angioma. Glaucoma can be unilateral or bilateral, regardless of whether the facial angioma is bilateral. Intracranial calcification is evident on radiographs in 90% of adult patients. Calcifications uncommonly are present at

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birth but are manifest in virtually all patients by the end of the second decade of life. The intracranial calcifications typically assume a linear, parallel configuration (“tram-track sign”), or a convolutional pattern most commonly seen in the parietal or parietooccipital regions (Fig. 45-18). Cranial CT and MRI scans are complementary in evaluating the cerebral changes of SWS, in that the MRI demonstrates thickened cortex, decreased convolutions, and abnormal white matter, whereas cranial CT scans demonstrate more definitively the characteristic calcification. Cranial MRI scans (T2-weighted images) reveal smaller, nonspecific foci of hypointense signal. Gadolinium enhancement may reveal pial angioma, thereby allowing early diagnosis of SWS before calcification. Cerebral angiography discloses decreased cerebral venous drainage with dilatation of the deep cerebral veins. Various other vascular abnormalities have been demonstrated in approximately one-third of patients and include thrombotic lesions, dural venous sinus abnormalities, and arteriovenous malformations. PET provides a sensitive measure of the extent of cerebral metabolic impairment. Serial PET scans in children with SWS can be useful and, when used with other neuroimaging studies, document the progression of the disease.

Pathology SWS is thought to be caused by the presence of residual embryonal blood vessels and their secondary effects on surrounding tissues. During development, a vascular plexus develops around the cephalic portion of the neural tube, under the ectoderm that subsequently becomes facial skin. This plexus forms during the sixth week of gestation and regresses at approximately the ninth week. It is thought that failure of this regression results in residual vascular tissue, subsequently forming the angiomata of the leptomeninges, face, and ipsilateral eye. Neuropathologic studies have demonstrated thickened, hypervascularized leptomeninges that involve the occipital, parietal, or temporoparietal region primarily (Fig. 45-19). These meningeal vessels generally are small and tortuous and rarely enter the underlying brain substance. Calcific deposits are present in the walls of some small cerebral vessels but more commonly are found in the outer pyramidal and molecular cortical layers. Biochemical assays have demonstrated increased calcium content of the gray and white matter, with normal iron content. The pathophysiology of the deposition of intracerebral calcium is not well understood.

Management Treatment for the neurologic manifestations of SWS includes management of seizure activity and headaches. Approximately 50% of children with seizures achieve control with administration of appropriate antiepileptic drugs. Those patients with seizure disorders refractory to medical treatment should be carefully considered for epilepsy surgery with resection of the affected lobe(s) or hemispherectomy. Rochkind and colleagues reported that seizure control after surgery was better in those patients who received antiepileptic drugs. Aspirin therapy may reduce the incidence of strokelike episodes and is typically used in individuals with either recurrent vascular events or progressive neurologic deficits. Treatment options for the facial angioma include laser therapy using various pulsed-dye lasers, as well as pulsed-light sources, and other laser therapies. The current recommendation is to begin treatment as early as possible; infants have received treatment during the first week of life. Treatment of glaucoma, if present, consists of control of intraocular pressure, to prevent optic nerve injury, by

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medical or surgical intervention. The management of patients with SWS requires the skill of an attentive physician, psychologist, and social worker.

MAFFUCCI SYNDROME Maffucci syndrome is a rare congenital disease characterized by multiple enchondromas with secondary hemangiomas, phlebolithiasis, and malformations of bone. Occasionally, associated skin changes, including patches of vitiligo, café-aulait spots, and other hyperpigmented patches and nevi, are seen. A related disorder, Ollier disease, is characterized by multiple endochondromas without hemangiomas. Both are sporadic and have been found to be due to somatic mosaicism of IDH1 or IDH2 genes. No single treatment plan exists, because each patient must be individually managed.

EPIDERMAL NEVUS SYNDROME Epidermal nevus syndrome is a heterogeneous group of disorders characterized by patchy cutaneous hamartomatous lesions, central nervous system abnormalities, and various other manifestations (Table 45-4) (Happle, 2010a; Happle, 2010b). Most of these disorders occur sporadically and are highly variable in their presentation. Central nervous system manifestations include unilateral lissencephaly, a paucity of white matter, excessive and heterotopic gray matter, apparent schizencephaly, unilateral colpocephaly, and hemimegalencephaly. Associated neurologic abnormalities include intellectual disability and convulsive disorders. Cortical resection has been helpful in some instances, but no other definitive treatment exists. The patchy manifestations of these disorders have suggested the possibility that they result from somatic mosaicism; this has been demonstrated in some instances of PTEN hamartoma syndrome, in which mosaicism for PTEN has been found. In the past, these patients were erroneously described as having Proteus syndrome, but it is now known that Proteus syndrome results from mosaic mutations in AKT1.

PARRY-ROMBERG SYNDROME   (FACIAL HEMIATROPHY) Parry-Romberg syndrome, which typically has onset between 5 and 15 years of age, is characterized by a progressive ipsilateral loss of facial soft tissue, cartilage, and bone. This tissue loss usually involves the tissues between the nose and nasolabial fold or above the maxilla, but progresses to affect most of the ipsilateral face during the ensuing years. The tongue, the gums, and the soft palate may also become involved. The eyelashes, eyebrows, and hair on the involved side can be affected, and ipsilateral blanching of the hair or alopecia can occur. Progression of this atrophic process generally lasts between 2 and 10 years and is believed to cease by the end of the second or beginning of the third decade of life. In addition to atrophy of the facial tissues, various other neurologic deficits have been reported, including recurrent headaches, trigeminal neuralgia, ipsilateral Horner syndrome, contralateral partial seizures, and hemiparesis. Moreover, an unusual association of the syndrome with multiple benign tumors has been described. Scleroderma and lipodystrophy must be clinically differentiated from this disease. Cranial imaging can be normal or document cerebral atrophy, encephalomalacia, and abnormal T2 signal intensities. No typical or consistent neuropathologic findings have been reported. No specific treatment for the syndrome exists; however, various reconstructive surgical procedures, often using grafts of autogenous fat after

disease stabilizes, can result in reasonably good cosmetic results.

NEUROCUTANEOUS MELANOSIS Neurocutaneous melanosis is a rare, nonfamilial, embryonic, neuroectodermal dysplasia characterized by abnormally pigmented cutaneous areas (e.g., giant hairy pigmented nevi, multiple hyperpigmented cutaneous nevi, large congenital melanocytic nevi) and leptomeningeal melanosis (Gerami and Paller, 2013). Diagnosis is usually made in infants and children younger than 2 years of age; however, the condition is present at birth. No gender predilection exists. All patients have areas of abnormal skin hyperpigmentation, the most common pattern of which is multiple giant hairy pigmented nevi. Giant hairy nevi usually have a “bathing suit” or capeshaped distribution. The presence of multiple satellite lesions, large size, and midline location for pigmented lesions are predictive of neurologic involvement. Mosaicism for specific mutations in the NRAS oncogene have been identified as the underlying cause of this disorder. This suggests the possible use of drugs that block RAS signaling in therapy. The clinical presentation of neurocutaneous melanosis depends on the location and extent of involvement of this leptomeningeal lesion. Hydrocephalus is commonly encountered because of cerebrospinal fluid pathway obstruction in the basilar cisterns, the arachnoid villi over the cerebral hemispheric convexities, or both, and intraspinal melanotic arachnoid cyst, lipoma, and intraspinal lipoma have been described as obstructed. Association with Dandy-Walker malformation has been reported. Behavioral abnormalities and recurring seizures can occur, as well as cranial nerve dysfunction and signs of spinal cord and root involvement. Attempts to treat hydrocephalus by a shunting procedure are palliative. There is a risk of melanoma.

KLIPPEL-TRÉNAUNAY-WEBER   SYNDROME (KTW) Klippel-Trénaunay-Weber syndrome initially was believed to be characterized only by cutaneous and/or subcutaneous hemangiomas, varicosities, and hypertrophy of the soft tissues and bone of a limb. Additional associated anomalies later recognized included macrocephaly; hydrocephalus; lymphangiomas; hemangiomas of the trunk, intestine, and bladder; and abnormalities of the digits. KTW usually occurs sporadically. Another disorder associated with vascular malformations as well as skeletal anomalies, lipomatous overgrowth, and epidermal nevi, referred to as CLOVES syndrome, is associated with mosaic PIK3CA mutations. Limb hypertrophy usually is apparent at birth. Lymphedema can be present. An inordinately progressive growth of the affected body part eventually occurs, leading to the development of various other abnormalities. Abnormal growth of one leg, for example, can result in a pelvic tilt and scoliosis, but the patient’s overall height is not significantly changed. The legs are affected more commonly than the arms. Additional abnormalities include megalocornea, glaucoma, iridic heterochromia, syndactyly, polydactyly, macrodactyly, and clinodactyly. Hemangiomas of the tongue, pharynx, larynx, and bladder have been described, and labial and scrotal lesions are common. Macrocephaly often is present, and seizures and mental retardation have been reported. Any treatment plan for these patients must be individualized and requires a multidisciplinary team. Nonsurgical management involves compression of the involved limb. MRI or CT venography can be performed if any vascular surgical



procedure is contemplated. Some vascular lesions can be treated with cryotherapy, laser therapy, or sclerotherapy, whereas others can be surgically removed. An osteotomy or epiphyseal stapling procedure can occasionally benefit patients with limb hypertrophy, but limb amputations may be required in others.

INCONTINENTIA PIGMENTI (BLOCHSULZBERGER SYNDROME) Incontinentia pigmenti is transmitted as an X-linked dominant trait, predominantly affecting females. Most hemizygous males apparently die in utero. The gene responsible for disorder is IKBKG/NEMO, which regulates nuclear factor kappa b signaling. Most mutations lead to loss of function with the most common, accounting for 78% of cases, an intragenic deletion involving exons 4 to 10. The syndrome is characterized by various hyperpigmented skin lesions that can be apparent at birth and by commonly associated abnormalities involving the central nervous system, eyes, hair, teeth, and bone (Minić et al., 2014). The skin manifestations have been described as having three stages. The first stage typically is characterized by vesiculobullous lesions present at birth or during the first several weeks of life. These lesions appear in groups or in a linear distribution over the trunk and limbs, following the lines of Blaschko. A preponderance of eosinophils is found in the vesicular fluid, and the peripheral blood also can exhibit an eosinophilia. The lesions rupture, resulting in oozing and crusting, and can persist for months. The second stage is characterized by evolution into verrucous lesions beginning after the sixth week of life. The third stage typically is characterized by hyperpigmented brown or gray-brown macular lesions that follow the lines of Blaschko. These pigmented skin lesions usually become more prominent during the first few years of life and then gradually fade. The decrease of abnormal pigmentation may continue throughout adolescence, and in some patients the pigmentation can completely disappear. One-third to one-half of patients have symptoms and signs of neurologic abnormalities manifested by developmental disability, corticospinal tract dysfunction, and seizures. Microcephaly and hydrocephaly may occur. Approximately onethird of patients have ocular abnormalities, including optic atrophy, papillitis, abnormal retinal pigmentation, nystagmus, strabismus, and cataracts. Visual loss occurs in about 8% of patients. The most common ocular abnormalities are retinal detachment and a fibrovascular retrolental membrane. There are often associated ectodermal and skeletal anomalies. Skin changes include atrophic scarring and alopecia, and nails can be flat and thin, commonly with transverse ridges. Skeletal abnormalities include spina bifida, hemivertebrae, accessory ribs, and syndactyly. Delayed dentition, pegged teeth, and abnormal crown formation are also seen. Treatment remains symptomatic and supportive.

INCONTINENTIA PIGMENTI ACHROMIANS (HYPOMELANOSIS OF ITO) Incontinentia pigmenti achromians has been known as systemic achromic nevus and hypomelanosis of Ito (Pavone et al., 2015). Typical skin changes occur as hypopigmented lesions on any part of the head, trunk, or limbs, either unilaterally or bilaterally. The configuration of the hypopigmented lesions may manifest as linear streaks or whorls of hypopigmentation that follow the lines of Blaschko. The skin lesions are congenital. Multiple associated anomalies are common and can involve the central nervous system or the peripheral

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nervous system, eyes, and bone. Common central nervous system abnormalities include mental retardation, language disabilities, seizures, and motor system dysfunction. Ocular abnormalities include strabismus, epicanthic folds, myopia, optic nerve hypoplasia, and hypopigmentation of the fundus; rarely, corneal asymmetry, pannus, and atrophic irides with irregular pupillary margins have been reported. Cataracts and retinal detachments also have been reported. Characteristic histologic features of skin biopsy specimens include dyskeratosis, increased dermal mastocytes, and pilosebaceous abnormalities. Hypomelanosis of Ito occurs sporadically and in many cases has been found to be associated with mosaicism for chromosomal abnormalities. The abnormal cells may be confined to the skin lesions and therefore are detected only by cytogenetic analysis of cultured fibroblasts obtained by skin biopsy. No single chromosome abnormality accounts for all cases; rather, it appears that the streaky hypopigmentation associated with the disorder, or sometimes patches of hyperpigmentation following Blaschko’s lines, are the cutaneous manifestation of mosaicism for various genes or chromosomal regions.

WYBURN-MASON SYNDROME   (RETINOCEPHALIC ANGIOMATOSIS) Although known as Bonnet-Dechaum-Blanc syndrome in Europe and as Wyburn-Mason syndrome in the United Kingdom and the United States, the condition is more appropriately called a retinocephalic vascular malformation (Fileta et al., 2014). The syndrome is thought to result from an embryonic abnormality in the development of the optic nerve pathway and related vessels from its origin in the mesencephalon all the way to the projection to the retina. The intracranial vascular malformation usually is deep within the brain substance and can involve the mesencephalon, diencephalon, and basal ganglia, extending to the visual pathways and chiasm. Variable involvement of the cranial nerves occurs, including the third, sixth, seventh, and eighth nerves; nystagmus and Parinaud syndrome have been reported. Corticospinal tract dysfunction can be unilateral or bilateral, and some patients are ataxic. Approximately one-half of patients have vascular malformations that affect the palate, oral mucosa, maxilla, and mandible. Cutaneous lesions also can occur, manifesting as angiomas or punctate erythematous lesions. The diagnosis of this syndrome is initially considered when the retinal vascular lesion is observed. Cranial CT and MRI scans clearly demonstrate arteriovenous malformation, but only cerebral angiography reliably delineates the extent of the lesion. No beneficial treatment method is currently available for this syndrome. The surgical removal of part or all of the extensive vascular malformation cannot be performed with any practical success, and the use of rigorous radiologic interventional techniques has been unsuccessful. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Ferner, R.E., Gutmann, D.H., 2013. Neurofibromatosis type 1 (NF1): diagnosis and management. Handb. Clin. Neurol. 115, 939– 955. Fileta, J.B., Bennett, T.J., Quillen, D.A., 2014. Wyburn-Mason syndrome. JAMA Ophthalmol 132 (7), 805.

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Gerami, P., Paller, A.S., 2013. Making a mountain out of a molehill: NRAS, mosaicism, and large congenital nevi. J. Invest. Dermatol. 133 (9), 2127–2130. Gutmann, D.H., Aylsworth, A., Carey, J.C., et al., 1997. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278 (9207339), 51–57. Happle, R., 2010a. The group of epidermal nevus syndromes Part I. Well defined phenotypes. J. Am. Acad. Dermatol. 63 (1), 1–22, quiz, 23–24. Happle, R., 2010b. The group of epidermal nevus syndromes Part II. Less well defined phenotypes. J. Am. Acad. Dermatol. 63 (1), 25–30, quiz, 31–32. Lloyd, S.K.W., Evans, D.G.R., 2013. Neurofibromatosis type 2 (NF2): diagnosis and management. Handb. Clin. Neurol. 115, 957–967.

Maher, E.R., Neumann, H.P., Richard, S., 2011. Von Hippel-Lindau disease: a clinical and scientific review. Eur. J. Hum. Genet. 19, 617–623. Minić, S., Trpinac, D., Obradović, M., 2014. Incontinentia pigmenti diagnostic criteria update. Clin. Genet. 85 (6), 536–542. Pavone, P., Praticò, A.D., Ruggieri, M., et al., 2015. Hypomelanosis of Ito: a round on the frequency and type of epileptic complications. Neurol. Sci. 36 (7), 1–8. Plotkin, S.R., Blakeley, J.O., Evans, D.G., et al. 2013. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Renard, D., Campello, C., Taieb, G., et al., 2013. Neurologic and vascular abnormalities in Klippel-Trénaunay-Weber syndrome. JAMA Neurol 70 (1), 127–128.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 45-1 Multiple café-au-lait spots. Fig. 45-2 Axillary freckling. Fig. 45-3 Multiple cutaneous neurofibromas. Fig. 45-4 Truncal plexiform neurofibroma with overlying hyperpigmentation. Fig. 45-5 Magnetic resonance imaging scan showing bilateral spinal tumors with displacement of the cord by the larger tumor on the right side of the photo. Fig. 45-6 Orbital plexiform neurofibroma associated with buphthalmos. Fig. 45-7 Sagittal magnetic resonance imaging scan of brain showing a glioma of the optic chiasm (arrow). Fig. 45-8 Area of enhanced T2 signal intensity in cerebellum (arrow). Fig. 45-9 Magnetic resonance imaging scan of brain from a person with NF2 showing a meningioma (arrow 1) and two vestibular schwannomas (arrows 2 and 3). Fig. 45-11 Hypopigmented macule in a child with tuberous sclerosis complex. Fig. 45-12 Shagreen patch (arrows) over the lumbosacral region of an adolescent with tuberous sclerosis complex. Fig. 45-13 Periungual fibroma on finger of a patient with tuberous sclerosis complex.

Fig. 45-14 Magnetic resonance imaging scan of brain in tuberous sclerosis complex, showing cortical tubers (black arrows) and subependymal nodules (white arrows). Fig. 45-15 Computed tomography scan of brain in tuberous sclerosis complex, showing subependymal giant cell tumor. Fig. 45-16 Von Hippel-Lindau disease. Fig. 45-17 A 20-month-old girl with Sturge-Weber syndrome. Fig. 45-18 Lateral skull radiograph from a young child with Sturge-Weber syndrome, demonstrating parallel linear calcifications (the “tram-track sign”). Fig. 45-19 Section of the cerebellum and brainstem in Sturge-Weber Syndrome. There is notable cerebeller atrophy. Fig. 45-20 Multiple enchondromas of the digits, typically observed in Maffucci syndrome. Fig. 45-21 Hemifacial atrophy as manifested in Parry-Romberg syndrome. Box 45-1 Neurocutaneous Disorders: Specific Cutaneous Abnormalities and Associated Disorders Table 45-1 Phakomatoses and Their Clinical Features Table 45-2 Diagnostic and Follow-Up Management in Tuberous Sclerosis Complex Table 45-3 Recommendations for Surveillance of Individuals with von Hippel-Lindau Disease Table 45-4 Classification of Epidermal Nevus Syndrome

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Disorders of Vitamin Metabolism Barbara Plecko and Robert Steinfeld

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Vitamins are essential nutritional compounds and work as cofactors of various enzymes. Vitamin deficiency disorders are seen in developing countries and in patients with chronic disease and can affect the central and/or peripheral nervous system, often in the context of a multisystem disease (Kumar, 2010). The vitamin supply of breastfed infants is directly related to maternal nutrition. Hypervitaminoses are seen in faddists and in cases of long-term overdose of vitamin supplements. Nutritional sources, cofactor function, age-dependent daily allowances, signs of deficiency, dosages for treatment of respective vitamin deficiencies, and signs of hypervitaminosis are given in Table 46-1. In addition to nutritional disorders of vitamin metabolism, there is a growing number of inherited inborn errors of metabolism (IEMs) that affect specific steps of vitamin transport and processing or lead to selective vitamin inactivation. Rapid recognition and treatment of the underlying cause are warranted to avoid irreversible damage.

THIAMINE (VITAMIN B1) Thiamine is absorbed in the upper small intestine and is transported across cell membranes by two transporters, encoded by SLC19A2 and SLC19A3. Within the cell, thiamine is phosphorylated to its active form, thiamine pyrophosphate (TPP), and works as a cofactor of the cytosolic transketolase. Another solute carrier, encoded by SLC25A19, imports TPP into mitochondria, where it finally acts as a cofactor of the pyruvate dehydrogenase complex, the branched chain ketothiolase dehydrogenase, and the alpha-ketoglutarate dehydrogenase. Two diseases are linked to vitamin B1 deficiency: beriberi and the more severe Wernicke’s syndrome. Wernicke’s disease is still one of the more frequently encountered vitamin deficiency syndromes, and in developed countries, it occurs in patients with severe chronic disorders, malnutrition, or chronic alcohol abuse. In infancy, thiamine deficiency has been reported with breastfeeding by thiamine-deficient mothers and in infants fed with soybean or other formulas in which the thiamine was presumably heat-inactivated during preparation. Infantile thiamine deficiency is characterized by a multisystem presentation, with vomiting, aphonia, abdominal distention, diarrhea, cyanosis, tachycardia, and convulsions. In less fulminant cases, infants have failure to thrive and developmental delay followed by edema, oliguria, constipation, cardiomegaly, and hepatomegaly. Cranial imaging may show signal hyperintensities in T2-weighted images localized in the periventricular gray matter around the third ventricle, sylvian aqueduct, fourth ventricle, and mammillary bodies. Increased lactate in plasma or cerebrospinal fluid (CSF) and urinary excretion of less than 120 mg of thiamine per gram of creatinine would support the diagnosis. Clinical response to the administration of thiamine is the best confirmatory test. Oral administration of 10 to 50 mg of thiamine daily will reverse clinical symptoms in a few weeks. Serious life-threatening neurologic manifestations or congestive heart failure should be treated with the parenteral administration

of 5 to 20 mg of thiamine and may lead to severe long-term sequelae. Genetic disorders affecting thiamine transport or activation present with surprisingly divergent symptoms and variable age (Brown, 2014).

Rogers Syndrome Rogers syndrome (Online Inheritance in Man [OMIM] 249270) is caused by autosomal-recessive mutations in the SLC19A2 transporter and manifests with thiamine-responsive megaloblastic anemia, type 2 diabetes mellitus, and sensorineural deafness. Thiamine levels in plasma are normal, but the presence of sideroblasts in bone marrow suggests the diagnosis. Treatment consists of 25 to 75 mg of oral thiamine per day. Although most manifestations are thiamine responsive, hearing loss may be irreversible.

Biotin- or Thiamine Responsive Basal Ganglia Disease Biotin- or thiamine-responsive basal ganglia disease (BTBGD; OMIM 607483) is a panethnic, autosomal-recessive disease that is triggered by febrile infections, stress, or trauma. The typical onset is during early childhood, but onset can range from the neonatal period to adulthood. Major symptoms are subacute-onset encephalopathy, confusion, dystonia, ataxia, dysarthria, dysphagia, pyramidal tract signs, external ophthalmoplegia, and partial or generalized seizures. Episodes are followed by slow subtotal recovery and subsequent relapses. If left untreated the disease can lead to coma and, ultimately, death. T2-weighted magnetic resonance imaging (MRI) reveals bilateral signal intensities of the striatum in addition to cortical and subcortical lesions. Chronic changes include atrophy, necrosis, and gliosis (Ortigoza-Escobar et al.., 2014). BTBGD is caused by mutations in the SLC19A3 gene, which encodes a thiamine transporter, and a rapidly growing phenotypic spectrum—from neonatal encephalopathy with lactic acidosis to seizures with generalized dystonia—has been described. The partial response to biotin is not fully understood to date. Routine metabolic testing is normal, with the exception of elevated lactic acid during the acute phase, but measurement of free thiamine in CSF may become a valuable diagnostic screening tool. Confirmation is by genetic analysis of the SLC19A3 gene. Treatment consists of regular oral supplementation of thiamine, 300 to 900 mg/day. During subsequent exacerbation the usual thiamine dose may be doubled and given intravenously. An add-on of biotin, 5 to 10 mg/kg per day, may lead to faster recovery. Antipyretics are essential because fever may trigger decompensation.

Thiamine Pyrophosphokinase Deficiency Autosomal-recessive thiamine pyrophosphokinase deficiency (OMIM 606370) presents with a late-onset Leigh-like disease and basal ganglia changes on MRI. During acute episodes,

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elevated blood and CSF lactate and enhanced excretion of α-ketoglutarate are consistent findings. Thiamine pyrophosphate (TPP) concentrations in blood and muscle are reduced, and diagnosis is confirmed by sequencing of the TPK1 gene. Thiamine supplementation at 100- to 200 mg/day was of limited benefit in symptomatic patients. Earlier intervention with doses around 500 mg/day may be associated with better prognosis.

Amish Lethal Microcephaly and Bilateral Striatal Necrosis Resulting   From SLC25A19 Mutations Amish lethal microcephaly and bilateral striatal necrosis (OMIM 607196) is caused by mutations in the SLC25A19 gene, which encodes the transport of TPP into the mitochondria. The Amish founder mutation is associated with severe microcephaly at birth and a very short life span. Patients typically show excretion of α-ketoglutarate and lactic acidosis during febrile infections. A few patients with different SLC25A19 mutations have been described outside the Amish community; these patients presented with associated CNS malformation or bilateral striatal necrosis but a normal head circumference. In addition to these primary defects in thiamine transport and activation, some enzyme defects may have a favorable response to thiamine administration. Among these are pyruvate dehydrogenase complex and pyruvate carboxylase deficiency and some forms of maple syrup urine disease.

RIBOFLAVIN (VITAMIN B2) Riboflavin is the precursor of the metabolically active forms flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which function as cofactors for at least 90 different flavin-dependent proteins (flavoproteins). Flavin-dependent enzymes catalyze oxidation–reduction processes in primary metabolic pathways such as the citric acid cycle, β-oxidation, and degradation of amino acids. Flavin-dependent proteins also play an important role in the biosynthesis or regulation of other essential cofactors and hormones, such as coenzyme A, coenzyme Q, heme, pyridoxal 5′-phosphate, folate, cobalamin, steroids, and thyroxine.

Riboflavin Deficiency Symptomatic riboflavin deficiency commonly occurs in association with deficiencies of other vitamins. Details are described in Table 46-1.

Riboflavin-Dependent Enzymatic Reactions At least 50 different deficiencies of flavoproteins have been associated with an inherited human disease. Because a significant proportion of mutations in flavoproteins affect the affinity to their cofactors, a supranormal intake of riboflavin can lead to functional rescue. Disorders that may respond to high riboflavin doses (100-300 mg) include deficiencies of multiple acyl-CoA dehydrogenase, dihydrolipoamide dehydrogenase, and acyl-CoA dehydrogenase-9 (Table 46-2).

DISORDERS OF RIBOFLAVIN TRANSPORT At least three distinct riboflavin transporters, SLC52A1 through SLC52A3, are involved in riboflavin uptake via the human intestine. The relative contribution and role of these transporters are currently unclear, but deficiency of SLC52A2 and SLC52A3 is associated with genetic neuronopathies.

Riboflavin Deficiency Haploinsufficiency of the SLC52A1 riboflavin transporter has been reported with mild riboflavin deficiency (OMIM 615026) in a mother whose newborn child developed transient severe symptoms resembling clinical and biochemical features of multiple acyl-CoA dehydrogenase deficiency. Oral supplementation of 100 mg riboflavin per day rapidly normalized the biochemical parameters and clinical condition. The mother was treated with 50 mg of riboflavin per day.

Riboflavin Transporter Deficiency Neuronopathy Type 1 riboflavin transporter deficiency neuronopathy, also referred to as Brown–Vialetto–Van Laere syndrome-1 (BVVLS1) or Fazio–Londe disease (OMIM 211530), is an autosomalrecessive progressive neurologic disorder that is caused by mutations in the SLC52A3 gene. Type 2 riboflavin transporter deficiency neuronopathy, also referred to as Brown–Vialetto–Van Laere syndrome-2 (BVVLS2; OMIM 614707) is an autosomal-recessive progressive neurologic disorder that is caused by mutations in the SLC52A2 gene. Both types of riboflavin transporter deficiency neuronopathy are associated with very similar clinical features. More than two-thirds of patients carry pathogenic mutations in the SLC52A3 gene. Onset of symptoms ranges from a few months of age to the early teenage years and rarely can occur in adulthood. Peripheral nerves are the main site of pathology, manifesting as motor, sensory, and cranial neuronopathy, which can be proven by neurophysiological investigations. Cognition is usually preserved (Foley et al., 2014). The acylcarnitine profile in blood may show accumulation of shortand medium-chain (and sometimes long-chain) acylcarnitines in some but not all affected individuals. Oral riboflavin supplementation starting from 10 mg/kg per day, divided into three single doses, is gradually increased to 50 mg/kg per day to establish the optimum individual dose. All treated patients have improved after the initiation of riboflavin therapy.

NIACIN (VITAMIN B3) Niacin (also nicotinic acid) and its active forms, the nicotinamides (NAD+), function in a variety of oxidation–reduction reactions and serve as main electron donors in the respiratory chain. Niacin deficiency occurs in alcoholics, in adolescents with anorexia nervosa, in individuals following dietary fads, and in patients infected with human immunodeficiency virus, most often confounded with other micronutrient deficiencies. Signs and symptoms of niacin deficiency are outlined in Table 46-1.

NIACIN DEPENDENCY Hartnup’s disease (OMIM 234500) is caused by autosomalrecessive mutations of the neutral amino acid transporter SLC6A19. Low tryptophan levels lead to secondary niacin deficiency and Pellagra-like clinical features, which may improve after administration of 50 to 300 mg/day of NAD.

VITAMIN B6 Vitamin B6 is derived from the diet in different vitamers as pyridoxine, pyridoxal, or pyridoxamine and their phosphorylated esters (Fig. 46-1). Pyridox(am)ine 5′-phosphate is further oxidized to pyridoxal 5′-phosphate (PLP) by pryidox(am)ine



Disorders of Vitamin Metabolism

5′-phosphate oxidase (PNPO). PLP works as the active cofactor for more than 200 enzymatic reactions in amino acid and neurotransmitter synthesis and degradation. It is a cofactor of the glutamate decarboxylase and of the GABA transaminase and the aromatic acid decarboxylase. PLP thus plays a crucial role in brain metabolism. Some drugs (isoniazide, penicillamine, cycloserine, hydralazine, etc.) interact with pyridoxine and warrant preventive pyridoxine supplementation in dosages of 25 to 50 mg/day. Nutritional vitamin B6 deficiency is rarely seen. Signs and symptoms are outlined in Table 46-1.

Vitamin B6 Deficiency, Dependency, and Responsiveness In contrast to nutritional vitamin B6 deficiency, dependency indicates a lifelong hyperphysiologic demand of pyridoxine or PLP as a result of different IEMs with autosomal-recessive inheritance, which cause reduced availability of PLP by different mechanisms (Table 46-3). In all entities, seizures are a hallmark of the disease. In addition, patients with classical homocystinuria, gyrate atrophy, or X-linked sideroblastic anemia can show pyridoxine response as a result of a chaperone effect. Vitamin B6 responsiveness has also been described in single individuals with West syndrome or idiopathic epilepsy of unclear genetic background.

Pyridoxine-Dependent Epilepsy Pyridoxine-dependent epilepsy (PDE; OMIM 266100) is characterized by the onset of neonatal myoclonic or bilateral tonic-clonic seizures that are resistant to antiepileptic drugs and may evolve into status epilepticus. About 30% of patients have encephalopathic signs such as sleeplessness and irritability or show low Apgar scores. Late onset up to 3 years of age has been described. Electroencephalogram (EEG) findings can range from nonspecific slowing and discontinuity to focal discharges or, rarely, burst-suppression patterns. Neuroimaging may be normal or reveal a variety of unspecific changes. About 85% of patients show a prompt cessation of seizures after a single administration of pyridoxine (50-100 mg intravenously), followed by a stepwise normalization of the EEG. The first administration of pyridoxine can lead to prolonged apnea or a comatose state, and thus resuscitation equipment should be at hand. Approximately 15% of patients have an ambiguous clinical response to a single pyridoxine administration.

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Therefore a pyridoxine trial with 30 mg/kg per day in two to three standard doses over 3 consecutive days is recommended. Some patients develop systemic signs that resolve upon specific treatment with pyridoxine (Stockler et al., 2011). In 2006, antiquitin (ALDH7A1) deficiency was identified as the major molecular background of PDE (Fig. 46-2). Antiquitin encodes α-aminoadipic semialdehyde dehydrogenase, and its deficiency results in the accumulation of α-aminoadipic semialdehyde (AASA), which is in equilibrium with piperidine 6-carboxylate (P6C). P6C inactivates PLP and leads to a lifelong hyperphysiologic pyridoxine demand. Elevated AASA in urine (plasma or CSF) serves as a reliable biomarker even when on pyridoxine. AASA is also elevated in molybdenum cofactor deficiency (MOCOD) and warrants simultaneous determination of urinary sulfocysteine to avoid false diagnoses. Infants with PDE are supplemented with pyridoxine at dosages of 20 to 30 mg/kg per day in two to three standard doses. Beyond infancy, usual total daily pyridoxine doses vary from 100 mg/day to 300 mg/day. In the case of febrile breakthrough seizures, doubling of the daily pyridoxine dose over 3 to 5 days is recommended in subsequent infections. Longterm pyridoxine dosages above 300 to 500 mg/day can cause (reversible) sensory neuropathy. Approximately 75% of children with PDE show mild to moderate cognitive impairment. Future trials will show whether reduced formation of α-AASA by a lysine-restricted diet or competitive inhibition of lysine uptake by high-dose arginine supplementation may lead to better outcome. In 2009, folinic acid–responsive seizures, a previously distinct entity of unknown molecular background, was shown to be allelic to antiquitin deficiency. Of note is that no patient on folinic acid monotherapy survived, but an add-on of folinic acid at dosages of 3 to 5 mg/kg per day has been beneficial in neonates with PDE and initial incomplete pyridoxine response. A minority of PDE cases are caused by etiologies other than antiquitin deficiency, such as pyridoxine-responsive PNPO deficiency, hyperprolinemia type II, and severe neonatal hypophosphatasia. Recently, pyridoxine responsiveness has been described in severe forms of KCNQ2 deficiency.

Pyridox(am)ine 5′-Phosphate Oxidase Deficiency The clinical presentation of pyridox(am)ine 5′-phosphate oxidase (PNPO) deficiency (OMIM 610090) is indistinguishable from antiquitin deficiency, except for the higher rate of

TABLE 46-3  Biomarkers of Vitamin B6–Dependent Epilepsies Resulting From Inborn Errors of Metabolism and Their Response to Treatment IEM- and PLP-related mechanisms

Urine

Plasma

CSF

Response to Vitamin B6

PNPO deficiency Reduced PLP formation

Vanillactate*

↑ PM and PM/PA

↓ PLP° sek. NT changes*

Mainly to PLP, in certain mutations also pyridoxine

Congenital hypophosphatasia Reduced PLP uptake

↓ AP, ↓ Ph, ↑ Ca

To pyridoxine (or PLP)

Congenital hyperphosphatasia Reduced PLP uptake

↑ AP

Unknown

Antiquitin deficiency (PDE) PLP inactivation

↑ AASA and P6C

↑ AASA and P6C ↑ Pipecolic acid

Hyperprolinemia II PLP inactivation

↑ Proline, P5C

↑ Proline, P5C

↑ AASA ↓ PLP° sek. NT changes*

To pyridoxine (or PLP) To pyridoxine (or PLP)

AP, alkaline phosphatase; AASA, alpha aminoadipic acid; Ca, calcium; CSF, cerebrospinal fluid; IEM, inborn errors of metabolism; NT, neurotransmitter; PA, pyridoxic acid; PDE, pyridoxine-dependent epilepsy; P5C, pyrrolin-5-carboxylate; Ph, phosphate; PLP, pyridoxal 5′-phosphate; PM, pyridoxamine; PNPO, pyridox(am)ine 5′-phosphate oxidase; P6C, piperideine-6-carboxylate. *Inconsistent findings. °Before specific treatment with vitamin B6.

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PART VI  Genetic, Metabolic and Neurocutaneous Disorders L-lysine H2N

COOH NH2

H 2N

COOH

2-keto 6-amino caproic acid

O

HOOC N piperideine-2-carboxylate

COOH

NH2

H

saccharopine

HOOC

pipecolic acid

COOH

N

N

COOH

O N

COOH

COOH NH2

piperideine-6-carboxylate

alpha aminoadipic semialdehyde

HOOC

COOH NH2 alpha aminoadipic acid

Figure 46-2.  Lysine degradation pathway. Antiquitin deficiency causes accumulation of alpha-aminoadipic semialdehyde, which is in a nonenzymatic equilibrium with its cyclic form, Δ1-piperideine-6-carboxylate. Δ1-piperideine-6-carboxylate inactivates PLP by a Knoevenagel condensation.

prematurity observed in 60% of patients. The majority of infants have low Apgar scores and may require intubation. Myoclonic jerks and severe tonic-clonic convulsions are associated with a burst-suppression pattern in about 60% of cases. With the duration of symptoms, brain MRI may reveal whitematter changes and atrophy. In 2005 this disorder was found to be caused by mutations in the PNPO gene resulting in reduced PLP formation. Patients were initially characterized as being resistant to pyridoxine but dependent on PLP supplementation, but this paradigm has recently been contradicted by novel pyridoxine-responsive PNPO mutations. Surprisingly, some of these patients showed clear worsening of seizures when pyridoxine was replaced by PLP. In contrast to antiquitin deficiency, PNPO deficiency leads to severe systemic PLP deficiency with anemia and failure to thrive, and most patients die if untreated. Aside from secondary changes of

plasma and CSF amino acids and neurotransmitters or inconsistently elevated vanillactate in urine, PNPO lacks a specific biomarker (Mills et al., 2014). Patients with classical PNPO deficiency need lifelong treatment with PLP (unlicensed outside of Asia), 30 to 60 mg/kg per day in four to six standard doses. To avoid oxidation, PLP should be dissolved immediately before oral administration. The first administration can cause severe apnea and coma, and thus resuscitation equipment should be at hand. Many patients are sensitive to exact dose intervals even during the night, and seizure recurrence is frequent. Because of potential PLP liver toxicity, transaminases should be monitored regularly, and the lowest effective dose should be used. Patients with pyridoxineresponsive PNPO mutations may be treated with pyridoxine alone. Residual seizures necessitate a switch to PLP, which can be successful if performed slowly.



Hyperprolinemia Type II Hyperprolinemia type II (OMIM 239510) is generally considered benign because only 50% of patients present with seizures, which often respond to common anticonvulsants. Hyperprolinemia type II is caused by a deficiency of Δ1pyrroline-5-carboxylate dehydrogenase leading to the accumulation of Δ1-pyrroline-5-carboxylate (P5C), which inactivates PLP (Fig. 46-2). The diagnosis can be made by marked elevation of plasma proline and the presence of P5C in urine. The action of pyridoxine in this disorders is less clear.

Congenital Hypophosphatasia Congenital hypophosphatasia (OMIM 241500) is caused by deficient tissue-nonspecific alkaline phosphatase (TNSALP). In addition to its function in bone metabolism, TNSALP is responsible for the cellular uptake of PLP (Fig. 46-1). Patients with severe deficiency may thus present with pyridoxineresponsive neonatal seizures and burst-suppression pattern before recognition of the bone disease. The availability of enzyme replacement therapy will hopefully prevent the osteomalacia and early death associated with severe forms of the disease.

Pyridoxine Versus PLP to Test for Vitamin B6 Responsiveness Neonates with seizures of unclear etiology who fail to respond to common anticonvulsants should receive a standardized pyridoxine trial with 30 mg/kg per day over 3 consecutive days. In responders, withdrawal is obsolete and is replaced by molecular workup according to the presence or absence of respective biomarkers. In case of failure, folinic acid, 3 to 5 mg/kg per day, might be added and pyridoxine switched to PLP, with monitoring of liver function tests from day 2. This suggestion is based on the relatively higher frequency of pyridoxine-responsive entities compared with classical PLPdependent PNPO deficiency, the licensed drug status of pyridoxine in most developed countries, its availability as an IV drug, and the potential liver toxicity of high-dose PLP. Treatment effects have to be observed closely. Confirmation diagnosis in prospectively treated siblings of children affected by antiquitin or PNPO deficiency should be performed as quickly as possible.

VITAMIN B12 (COBALAMINE) Vitamin B12 (cobalamin; Cbl) is derived from animal food sources only and follows a complex mechanism of absorption, transport, and intracellular modification to finally act as one of the two active cofactors, methylcobalamin (MeCbl) for the recycling of homocysteine to methionine and adenosylcobalamin (AdoCbl) for the conversion of methylmalonyl-CoA to succinyl-CoA. The estimated daily losses of Cbl are minute compared with body stores. Hence, even in the presence of severe malabsorption, 2 to 5 years may pass before Cbl deficiency develops.

Cobalamin Deficiency Infants of strictly vegan mothers are at special risk of developing nutritional Cbl deficiency. Rarer causes include intestinal bacterial overgrowth (e.g., Helicobacter pylori) or parasites (e.g., Diphyllobothrium latum), malabsorption as a result of intestinal disease, and inherited defects affecting absorption and trans-

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port. B12 deficiency also has been reported with exposure to anesthesia by nitrous oxide. Megaloblastic anemia and neurologic manifestations are the hallmarks of Cbl deficiency (Table 46-1), but they can occur irrespective of each other. Infants show a consistent pattern of irritability, failure to thrive, and simultaneous growth deceleration, apathy, and anorexia, accompanied by developmental regression. Severe cases may develop acute decompensation with metabolic acidosis, hyperammonemia, and coma. This is clearly distinct from manifestations later in life with glossitis, myelopathy, painful paresthesia, disturbed proprioception, dementia, and neuropsychiatric disorders. CNS symptoms may partly be attributable to secondary disruption of the folate cycle and low methionine levels. In infants, the main MRI abnormality, if present, is delayed myelination or supratentorial atrophy, which may reverse upon treatment. The diagnosis of Cbl deficiency rests on a thorough history and measurement of biochemical parameters in plasma and urine. Severe deficiency requires injections of hydroxocobalamin (OHCbl), whereas oral treatment with (Cyano) Cbl is sufficient if intestinal absorption is intact. Dietary counseling is of utmost importance, especially in vegan families, and regular Cbl supplementation is the option of choice if dietary habits remain unchanged. Symptoms of nutritional Cbl deficiency are reversible if recognized early. Treatment delay may result in poor cognitive outcome and microcephaly. Some infants showed a transient movement disorder consisting of tremor and myoclonus, particularly involving the face, tongue, and pharynx, which appeared 48 hours after the initiation of treatment with intramuscular cobalamin.

Cobalamin Dependency The genetic defects of Cbl metabolism can affect absorption, transport, cellular uptake, or intracellular processing. Hereditary intrinsic factor (IF) deficiency (OMIM 261000) and Imerslund–Graesbeck syndrome (OMIM 261100) lead to reduced intestinal absorption and poor renal reabsorption of Cbl and can manifest from infancy to adulthood with symptoms indistinguishable from those of nutritional Cbl deficiency. TC II deficiency (OMIM 275350) presents with additional symptoms of immunodeficiency and recurrent infections, glossitis, and oral ulcerations. Disorders of absorption lead to reduced Cbl plasma levels, whereas in TC II defects, the Cbl plasma concentrations are normal (Table 46-3). All disorders result in elevated concentrations of homocysteine and methylmalonic acid (MMA) in plasma and urine. Disorders of intracellular Cbl processing can be classified into combined disorders of metCbl and AdoCbl metabolism, those with isolated metCbl deficiency, also called remethylation defects, and those with isolated adoCbl deficiency. The clinical picture and the presence of elevated homocysteine and MMA, alone or in combination, and the presence of anemia are important biomarkers to guide the molecular workup (Table 46-3).

CblC, CbD-MMA/HC, CbF, and CblJ Deficiency (Combined Defects of Ado- and MetCbl) The combined defects of Ado- and MetCbl include CblC (OMIM 609831), CbD-MMA/HC (OMIM 77410), CbF (OMIM 277380), and CblJ deficiency; CblC deficiency is by far the most severe and the most common. Most patients have an early onset during infancy, with feeding difficulties, failure to thrive, microcephaly, hypotonia, seizures, ataxia, megaloblastic

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anemia or pancytopenia, and visual problems such as nystagmus or early-onset retinopathy. Acute symptoms in addition to chronic, such as thromboembolic vasculopathy, renal failure resulting from atypical hemolytic uremic syndrome (HUS), cardiomyopathy, or metabolic crisis with hyperammonemia and ketoacidosis, may occur. MRI reveals delayed myelination and global atrophy or hydrocephalus. Symptom severity seems to correlate with the reduction of methionine levels rather than with MMA or homocysteine concentrations. In late-onset cases, psychiatric problems and myelopathy prevail. The few patients described with CblF deficiency had a milder phenotype but suffered from recurrent infections. Treatment by regular injections of hydroxocobalamin up to 1 mg two to three times weekly, folinic acid 5 to 20 mg/day, betaine at 100 mg/kg per day in four standard doses, and eventually supplementation of methionine improves acute manifestations, but cognitive outcome is often impaired.

CblE, CblG, and CblD-HC Deficiency (Defects of MetCbl; Remethylation Defects) Most patients with so-called remethylation defects, which include CblE, CblG, and CblD-HC deficiency, manifest in the first year of life with feeding difficulties, hypotonia, developmental delay, and megaloblastic anemia. Infection-related deterioration, thromboembolism, or late-onset disease may occur. Plasma homocysteine is elevated, whereas MMA excretion in urine is normal. Delayed diagnosis can lead to irreversible myelopathy with spastic paraparesis. Anemia may not be present in early phases of the disease. Treatment of isolated MetCbl defects is identical to the treatment of combined deficiencies, and responses can be excellent.

CblA-MMA, CblB-MMA, and CblD-MMA Deficiency (Defects of AdoCbl) CblA-MMA (OMIM 251100), CblB-MMA (OMIM 251110), and CblD-MMA (OMIM 277410 variant 2) deficiency cause isolated AdoCbl deficiency. Most patients present with acute metabolic decompensation and encephalopathy during early life, often triggered by febrile infections, with metabolic acidosis, variable hyperammonemia, and high MMA excretion but normal homocysteine (Table 46-3). In the acute phase, MRI may show bilateral T2-weighted basal ganglia hyperintensities or metabolic stroke. The neurologic manifestations range from acute extrapyramidal movement disorders or comatose state to more chronic presentations with hypotonia, developmental delay, or optic atrophy. Metabolic crises can lead to irreversible brain damage and need emergency treatment in metabolic centers. A considerable proportion of patients respond to parenteral administration of hydroxocobalamin, 1 mg twice weekly, whereas the remainder will need a protein-restricted diet.

TOCOPHEROL (VITAMIN E) Vitamin E, including alpha-tocopherol, is the generic term for a group of fat-soluble compounds that function as scavengers of free radicals and protect polyunsaturated fatty acids from oxidation. It is stored predominantly in adipose tissue. Blood levels reflect recent dietary intake and absorption rather than body stores. Nutritional vitamin E deficiency occurs predominantly in disorders associated with either chronic fat malabsorption (e.g., cystic fibrosis, celiac disease, chronic cholestatic hepatobiliary disorders, short bowel syndrome) or a deficiency of plasma lipoproteins (e.g., abetalipoproteinemia, Tangiers disease). Details are described in Table 46-1.

Disorders of Vitamin E Metabolism Ataxia With Vitamin E Deficiency (= Familial Isolated Vitamin E Deficiency) Ataxia with vitamin E deficiency (AVED; OMIM 277460) is an autosomal-recessive neurologic disorder that is caused by mutations in the TTPA gene coding for the tocopherol transfer protein. Clinical signs comprise progressive spinocerebellar ataxia, areflexia, pyramidal tract lesion, loss of proprioception, retinopathy, ophthalmoplegia, mental retardation, cardiac arrhythmias, xanthelasma, and tendon xanthomas. Laboratory findings include extremely low vitamin E levels and high serum cholesterol, triglycerides, and beta-lipoprotein. With daily alpha-tocopherol supplementation of 20 to 40 mg/kg po, plasma vitamin E levels will normalize and cognitive function rapidly improves; however, neurologic symptoms often show slow and incomplete recovery.

BIOTIN (VITAMIN H) Biotin is absorbed through the intestine by active transport mechanisms and serves as a cofactor for five carboxylation enzymes that are involved in carbohydrate, lipid, and amino acid metabolism: pyruvate carboxylase, acetyl-CoA carboxylase (α and β), propionyl-CoA carboxylase, and 3-methylcrotonyl carboxylase. Biotinidase is an important enzyme for the release of protein-bound biotin and for the recycling of biotin from biocytin, which is formed in the degradation of the carboxylases. Nutritional biotin deficiency is extremely rare.

Biotinidase Deficiency Because of its excellent treatability, biotinidase deficiency (OMIM 253260) is included in most newborn screening programs worldwide. Severe biotinidase deficiency (residual activity [RA] < 10%) presents in the first half year of life with hypotonia; tonic-clonic, myoclonic, and partial seizures or infantile spasms; skin rash; and alopecia. EEG findings vary from normal to burst suppression pattern or hypsarrhythmia. Brainstem auditory-evoked potentials (BAEPs) can show findings consistent with sensorineural hearing loss. MRI can show (reversible) diffuse white-matter changes, edema of the putamen and caudate nuclei, and varying degrees of cerebral atrophy with ventriculomegaly. If untreated, the disease can result in coma or death. Partial biotinidase deficiency (RA 10%-30%) manifests in older children with ataxia or spastic paraparesis, developmental delay, hearing loss, or optic atrophy. Metabolic ketoacidosis with an increased anion gap, elevated lactate, and abnormal analysis of organic acids is present in severely affected patients, whereas attenuated forms may only be detected by measurement of biotinidase activity in serum. Symptomatic children with biotinidase deficiency improve when supplemented with 5 to 20 mg of oral biotin per day, irrespective of age and weight, and require lifelong treatment. Hearing loss and optic atrophy are usually not reversible.

Biotin-Dependent Holocarboxylase Synthetase Deficiency (Multiple Carboxylase Deficiency) Multiple carboxylase deficiency (OMIM 253270) is indistinguishable from biotinidase deficiency, but biotinidase activity in serum is normal, whereas the activity of various carboxylases is impaired. Patients are supplemented with higher doses of biotin, approximately 20 mg/day (Baumgartner, 2013).



Disorders of Vitamin Metabolism

379

Biotin-Responsive Basal Ganglia Disease

Nutritional Folate Deficiency

See the section on thiamine (vitamin B1).

Folate deficiency can be encountered along with multivitamin deficiencies or with increased folate requirements such as in pregnancy, lactation, prematurity, or diseases associated with abnormalities of folate absorption, use, or excretion. Drugs such as aminopterin, methotrexate, pyrimethamine, trimethoprim, and triamterene act as folate antagonists and produce folate deficiency by inhibiting dihydrofolate reductase, which is essential for the regeneration of tetrahydrofolate (see Fig. 46-3). Signs of deficiency and treatment are described in Table 46-1.

FOLATE Folates are essential micronutrients and derivatives of pteridine compounds. Three major folate coenzymes are involved in catalytic one-carbon-transfer reactions: 10-formyl-THF functions as formyl donor in the purine synthesis; 5,10methylen-THF mediates the methyl transfer to dUMP; and 5-methyl-THF participates in the methylation of homocysteine (Fig. 46-3). The latter reaction is crucial for the synthesis of S-adenosyl-methionine (SAM), which represents the preferred methyl group donor in the majority of methylation pathways. Thus lack of folate coenzymes affects a multitude of metabolic routes and will eventually compromise the synthesis of nucleic acids, amino acids, neurotransmitters, and biomolecules that are essential for myelin formation. The dependency of the brain on the external supply of 5-methylTHF can be explained by the low concentration of dihydrofolate reductase that is required to regenerate 5-methyl-THF (see Fig. 46-3). A comparative summary of the characteristic laboratory findings of the folate pathway and transport disorders is illustrated in Table 46-3.

Histidine

DISORDERS OF FOLATE METABOLISM Dihydrofolate Reductase Deficiency Dihydrofolate Reductase (DHFR) deficiency (OMIM 613839) has an autosomal-recessive inheritance pattern. As a consequence of DHFR deficiency, dihydrofolate accumulates and tetrahydrofolate diminishes, resulting in inhibition of pyrimidine and purine synthesis (see Fig. 46-3). DHFR is a major target of methotrexate, a commonly used chemotherapeutic for leukemias, and thus DHFR deficiency initially affects erythropoiesis and myelopoiesis but eventually may compromise cerebral folate supply and all THF-dependent reactions within the brain.

N-Formimidoyl-Glutamate

N-Formyl-Glutamate

NADPH

THF

FTCD

DHFR

FTCD

NADP+

Glutamate

5-Formyl-THF

THF + Formate ATP

5-Formimidoyl-THF

AMT

MTHFS or FTCD

+H2O

10-Formyl-THF

MTHFD1

NADP+ MTHFR

MTHFD1

MTHFD1

NADPH

Transport across intestinal mucosa and choroid plexus

ADP +P–

FTCD 5, 10-Methenyl-THF

5MTHF Transport

Folic acid

DHF

Purine nucleotides

5, 10-Methylene-THF dUMP Glycine

5-Methyl-THF

SHMT1

dTMP DHF

Serine MeCbl

Homocysteine SAM + Methyl-

Methionine synthase

THF Methionine

Pyrimidine nucleotides DHFR

NADP+ NADPH

SAM

Figure 46-3.  Schematic illustration of the folate metabolic pathways. The key metabolites histidine, serine, glycine, homocysteine, and methionine are highlighted in red. Enzymes are depicted in blue. Several enzymes are multifunctional, containing subdomains with distinct enzymatic activities. 5-methyl-THF is the major metabolite that is transported across the mucosa of the small intestine and the choroid plexus.AMT, aminomethyltransferase (EC 2.1.2.10); DHF, dihydrofolate; DHFR, dihydrofolate reductase (EC 1.5.1.3); FTCD, formiminotransferase (bifunctional enzyme, EC 2.1.2.5 + EC 4.3.1.4); MeCbl, methylcobalamin; MTHFD1, 5,10-methylenetetrahydrofolate dehydrogenase (trifunctional enzyme, EC 1.5.1.5 + EC 3.5.4.9 + EC 6.3.4.3); MTHFR, methylenetetrahydrofolate reductase (EC 1.5.1.20); MTHFS, 5,10-methenyltetrahydrofolate synthetase, 5-formyltetrahydrofolate cyclo-ligase (EC 6.3.3.2); SAH, S-adenosyl-homocysteine; SAM, S-adenosyl-methionine; SHMT, serine hydroxymethyltransferase (EC 2.1.2.1); THF, tetrahydrofolate.

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All reported patients show infantile onset of symptoms comprising megaloblastic anemia, failure to thrive, and secondary microcephaly. Neurologic symptoms follow shortly and include profound developmental delay, central hypotonia with poor head control, inability to fix and follow, and frequent focal seizures. At later stages, learning difficulties and short episodes of involuntary blinking and winking may develop, eventually with impaired consciousness. The EEG may indicate atypical childhood absence epilepsy with eyelid myoclonia. Brain imaging demonstrates cerebellar and cerebral atrophy, thin corpus callosum, and poor myelination of white matter. Serum folate and plasma homocysteine concentrations are in the normal range (Table 46-4). However, there is a marked depletion of 5-methyl-THF in the CSF and a moderate decrease in tetrahydrobiopterin and neurotransmitter concentrations (homovanillic acid and 5-hydroxyindoleacetic acid) in the CSF. Folic acid should be avoided in the treatment of DHFR deficiency because DHFR constitutes the only enzyme that catalyzes the conversion of folic acid to dihydrofolate. Infants should be promptly supplemented with 5 to 10 mg/kg body weight of oral folinic acid given daily as a single dose. Dosing for an affected individual should be adjusted to achieve a normal CSF concentration of 5-methyl-THF considering the age-dependent normal range.

Methylenetetrahydrofolate Reductase Deficiency Methylenetetrahydrofolate reductase (MTHFR) deficiency (OMIM 236250) has an autosomal-recessive inheritance pattern and is the most common inherited disorder of folate metabolism. MTHFR catalyzes the NADPH-dependent reduction of 5,10-methylene-THF to 5-methyl-THF, which in turn is required for the conversion of homocysteine to methionine (Fig. 46-3). The onset and severity of symptoms vary significantly but correlate with the degree of enzyme deficiency. The most common clinical finding in MTHFR deficiency is developmental delay, followed by motor and gait abnormalities, incoordination, cerebral seizures, paresthesias, stroke, muscular weakness, and psychiatric disturbances, including memory deficits. The majority of patients show EEG abnormalities, and about half of them develop microcephaly. In severe early-onset MTHFR deficiency, the infant may present with infantile spasms, developmental regression, and hydrocephalus.

Adult-onset MTHFR deficiency may manifest with the combination of progressive spastic paraparesis and polyneuropathy, variable behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy. Other clinical signs may be quite variable, for example, marfanoid habitus resembling classical homocystinuria. Betaine supplementation is the first choice in the treatment of MTHFR deficiency and improves the prognosis of severe MTHFR deficiency when initiated early. Patients should receive daily 100 mg/kg body weight per day (infants up to 250 mg/kg per day and older children up to 20 g/d) of oral betaine, divided in four single dosages. In case of psychomotor regression or epilepsy, the 5-methyl-THF concentrations in CSF should be monitored. Because of the limited folate transport across the blood–CSF barrier and the increased demand of choline for the biosynthesis of myelinated membranes, the concentration of 5-methyl-THF in the CSF is significantly reduced in most early-onset patients and roughly correlates with the severity of the neurologic symptoms in MTHFR deficiency. In cases where betaine supplementation fails to achieve the aimed therapeutic effect, treatment with folinic acid or MTHF, riboflavin, methionine, pyridoxine, and cobalamin can be tried.

MTHFD1-Encoded Enzyme Deficiency (Methylenetetrahydrofolate Dehydrogenase Deficiency) The MTHFD1 defect is inherited as an autosomal-recessive trait. In eukaryotes, the MTHFD1 gene encodes a single cytoplasmic protein, a homodimer of 100-kD polypeptides, with three distinct enzymatic activities (Fig. 46-3). All five reported patients presented with megaloblastic anemia in addition to leukopenia or signs of immune deficiency. Hyperhomocystinuria and mildly decreased synthesis of intracellular methylcobalamin in the presence of exogenous [57Co]cyanocobalamin were common findings. Cobalamin and folate levels in serum were within the normal range. Three patients were treated with intramuscular hydroxocobalamin, oral folate or folinic acid, and oral betaine or thiamine. In one patient, 5-methyl-THF and methylcobalamin were later empirically added to the regimen at the age of 23 months. One patient had mild mental retardation at the age of 6 years, whereas two other patients had normal cognitive development.

TABLE 46-4  Laboratory and Imaging Findings of Cobalamin or Folate Pathway and Transport Disorders Disorder

Serum Folate

CSF 5MTHF

Blood Count

Plasma Homocysteine

Brain Imaging

FCTD deficiency

Normal

Low

Normal

Normal

No abnormalities reported

DHFR deficiency

Normal

Low

Macrocytic anemia

Normal

Hypomyelination, thin corpus callosum, brain atrophy

MTHFR deficiency

Normal

Low to normal

Normal

Increased

Periventricular demyelination

MTHFD1 deficiency

Normal

Low

Anemia

Increased

Bilateral small hippocampi, T2 signal changes in lobes

PCFT deficiency

Low

Low

Macrocytic anemia

Increased

Calcifications in the cortex or basal ganglia

CFT deficiency

Normal

Low

Normal

Normal

Hypomyelination, cerebellar (+ cerebral) atrophy

Methylcobalamin deficiency

High to normal

Normal

Macrocytic anemia

Increased

Thin corpus callosum, cortical atrophy, hypomyelination

CFT, cerebral folate transport; CSF, cerebrospinal fluid; DHFR, dihydrofolate reductase; FCTD, formiminotransferase; PCFT, proton-coupled folate transporter; MTHFD1, methylenetetrahydrofolate dehydrogenase-1; MTHFR, methylenetetrahydrofolate reductase.



Disorders of Vitamin Metabolism

381

Formiminotransferase Deficiency

Cerebral Folate Transport Deficiency

Formiminotransferase (= glutamate formimidoyltransferase, FTCD) deficiency (OMIM 229100) is an autosomal-recessive inherited disorder caused by mutations in the FCTD gene. FTCD catalyzes the formation of 5,10-methenyl-THF (Fig. 46-3) in the histidine degradation pathway. The clinical relevance of formiminotransferase deficiency is presently unclear. Patients carrying missense mutations in the FCTD gene show developmental or speech delay, muscular hypotonia, and breathing difficulties with late infantile onset. Additional findings are abnormal electroencephalograms and significantly increased urinary excretion of formiminoglutamate (FIGLU). Because of the poor correlation between clinical phenotype, residual enzymatic activity, and biochemical findings, no specific treatment is currently recommended.

Cerebral folate transport deficiency (CFTD; OMIM 613068) is an autosomal-recessive inherited disorder associated with mutations in the FOLR1 gene, which encodes folate receptor alpha (FRα). CFTD is characterized by the failure of FRα-mediated folate transport in the CSF that differentiates it from other types of cerebral folate deficiency (see Table 46-3). Folic acid possesses a very high affinity for FRα and thus may block 5-methyl-THF transport across the choroid plexus. The most consistent clinical finding in CFTD is developmental regression, with onset typically before the age of 3 years. Short drop attacks resembling infantile spasms may precede frequent myoclonic epileptic seizures that are often resistant to antiepileptic medication. Ataxia, truncal hypotonia, and lower limb spasticity are frequent neurologic signs. Most patients appear to lose their social contact skills and develop an autistic-like behavior. Some patients present a milder phenotype with developmental delay, ataxia, and autistic features only (Grapp, 2012). Many patients become microcephalic in the course of the disease. Brain imaging reveals delayed myelination, hypomyelination, and cerebellar and cerebral atrophy. Magnetic resonance (MR) spectroscopy indicates low concentration of inositol and choline in the cerebral white matter. Focal T2 hyperintensities of the white matter can be detected in cranial MR imaging at later stages of the disease. Slow background together with multifocal epileptiform activities are commonly found in the EEG. Very low CSF concentrations of 5-methyl-THF are the biochemical hallmark of CFTD, and concentrations have been below 5 nM in all patients reported so far. Plasma folate concentrations of untreated patients are measured in the lower normal range, and intraerythrocytic folate concentration is typically normal. Oral supplementation with 5 to 10 mg/kg of folinic acid results in normalization of cerebral choline and inositol and correction of 5-methyl-THF. In cases of incomplete clinical response, additional intravenous injections of 50 to 100 mg folinic acid once per week should be considered. In selected patients, intrathecal administration of folinic acid may be beneficial. Early treatment is mandatory to achieve complete correction of clinical symptoms.

DISORDERS OF FOLATE TRANSPORT Hereditary Folate Malabsorption Hereditary folate malabsorption (HFM; OMIM 229050) is an autosomal-recessive inherited trait caused by mutations in the proton-coupled folate transporter (PCFT = SLC46A1), which cotransports folates together with protons. Affected individuals fail to absorb sufficient folates in the small intestine to match the daily requirements of about 0.4 mg. In addition, the frequent failure to correct 5-methyl-THF levels in CSF even under normalized plasma folate concentration indicates impaired folate transport across the blood–CSF barrier in a proportion of patients with HFM. Patients may show poor feeding and failure to thrive during very early infancy. The folate deficiency results primarily in megaloblastic anemia but may develop into pancytopenia. Anemia may be normocytic in case of poor nutrition and/or concomitant iron deficiency and may be accompanied by diarrhea and/or oral mucositis. Infants with HFM may initially present with profound immunodeficiency, which includes humoral and cellular immunity and mimics severe combined immune deficiency (SCID). Neurologic signs may be part of the initial manifestation of HFM or may develop later and include developmental delay, cognitive and motor impairment, behavioral abnormalities, ataxia and other movement disorders, peripheral neuropathy, and seizures with onset in infancy or early childhood (Zhao et al., 2007). Calcifications in the cortex or basal ganglia have been reported for several individuals with HFM. Serum folate concentrations are very low or even undetectable. Oral folate supplementation does not result in significant increase in serum folate concentration, and a single oral load of 5-formyl-THF (= folinic acid) shows no or little effect on serum folate concentration over a minimum of 4 hours. CSF 5-methyl-THF concentrations in affected individuals are frequently low (< 5 nM) and remain below the normal range even after correction of the serum folate concentration. Treatment aims to prevent hematologic and immunologic defects and to optimize the psychomotor development of children (Diekman et al., 2014). Infants should immediately receive 10 to 20 mg/kg body weight of oral folinic acid given daily as a single dose. Dosing should be adjusted to achieve a normal CSF concentration of 5-methyl-THF considering the age-dependent normal range. In case of insufficient response to oral treatment, intramuscular injections of levofolinic acid, either daily 1 mg or 5 mg twice per week or, alternatively, intravenous injection of 50 to 100 mg of levofolinic acid should be tried.

REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Baumgartner, M.R., 2013. Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E. Handb. Clin. Neurol. 113, 1799– 1810. Review. Brown, G., 2014. Defects of thiamine transport and metabolism. J. Inherit. Metab. Dis. 37 (4), 577–585. Review. Diekman, E.F., de Koning, T.J., Verhoeven-Duif, N.M., et al., 2014. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurol. 71 (2), 188–194. Foley, A.R., Menezes, M.P., Pandraud, A., et al., 2014. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 137 (Pt 1), 44–56. Grapp, M., Just, I.A., Linnankivi, T., et al., 2012. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain 135 (Pt 7), 2022–2031. Kumar, N., 2010. Neurologic presentations of nutritional deficiencies. Neurol. Clin. 28 (1), 107–170.

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Mills, P.B., Camuzeaux, S.S., Footitt, E.J., et al., 2014. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain 137 (Pt 5), 1350– 1360. Ortigoza-Escobar, J.D., Serrano, M., Molero, M., et al., 2014. Thiamine transporter-2 deficiency: outcome and treatment monitoring. Orphanet J. Rare Dis. 9, 92. Stockler, S., Plecko, B., Gospe, S.M. Jr., et al., 2011. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol. Genet. Metab. 104 (1–2), 48–60. Review. Zhao, R., Min, S.H., Qiu, A., et al., 2007. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood 110 (4), 1147–1152.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 46-1 Vitamin B6 is absorbed in different vitamers that are dephosphorylated by intestinal alkaline phosphatases (IPs) and rephosphorylated to their 5'-phosphate esters by phosphate kinase (PK). Table 46-1 Dietary Reference Allowances of Vitamins Table 46-2 Riboflavin-Responsive Disorders With Predominantly Neurologic Symptoms

47 

Nutrition and the Developing Brain María Victoria Escolano-Margarit and Cristina Campoy

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. The important role that optimal early nutrition has in brain development has been stressed for years. Some authors have stated that nutrition may be the environmental variable with the widest range of effects on brain development. Diet is responsible for both the provision of substrates from which the brain is constructed and the energy required for its function. The central nervous system is most vulnerable to nutritional influence at the periods when growth, development, and plasticity are higher; in the case of human beings this extends from the beginning of the third trimester of pregnancy until 2 years of age. At age 2 years, the volume of the human brain has reached 80% to 90% of adult size (Isaacs, 2013). Between the 24th and 42nd weeks of gestation white- and gray-matter structures undergo a rapid increase in volume, with the cerebellum and cortical gray matter being the structures with highest growth rates. Although the brain initially grows rapidly, its development continues into the teenage years, raising the possibility that the nature of diet at later stages may also be influential. The effects of malnutrition are based on the timing and magnitude of the nutrient deficit and on the brain’s need for the particular nutrient at the time of the deficit. It is important to note that insults early in life when the brain is developing could have long-lasting effects.

PROTEIN-CALORIE MALNUTRITION Studies based on animal models at the beginning of the last century have demonstrated that undernutrition in early life has dramatic anatomic and biochemical effects on the brain. It seems that the primary effect of protein-calorie deprivation involves replication and growth of cells in those elements most actively proliferating during the insult, rather than cell destruction. Box 47-1 lists major neuropathologic abnormalities resulting from malnutrition described in animal experimental studies. Table 47-1 summarizes the most important nutrients required for brain growth during late fetal and neonatal brain development and the particular brain structure or function that they regulate. The major aspects of the anatomic and biochemical changes associated with malnutrition in animals have been observed in malnourished children. Malnutrition during brain development leads to reduction in brain cells, number of synapses, dendritic arborization, and myelin production, which result in decreased brain size and macrostructure and alterations in neurotransmitter systems. The structures that are most affected are the hippocampus, cerebellum, and neocortex. All of these alterations are associated with delays in motor and cognitive functions, such as impaired school performance, decreased IQ scores, decreased memory, learning disorders, attention deficit disorders, and reduced social skills (Laus et al., 2011). A combination of intrauterine and extrauterine malnutrition has the greatest effect on brain structure composition and function. The fetus takes the critical nutrients it needs irrespective of the nutritional status of the mother. This ensures proper delivery of substrates for growth. Only in extreme situations of nutrient deprivation is the placental transfer of nutrients

affected. Severe deficiencies in nutrition are widespread in developing countries, and there is evidence that these defi­ ciencies affect brain structural maturation and long-term functioning of the brains of children, resulting in cognitive functional delays and permanent cognitive impairments. Maternal protein-calorie malnutrition can restrict uterine blood flow and growth of the uterus, placenta, and the fetus. Intrauterine growth restriction is associated with many adverse fetal and neonatal outcomes, including delayed neurologic development. After birth, stunting affects one third of children under age 5 years in low-income and middle-income countries. Ninety percent of the worldwide burden of child stunting is attributable to 36 countries. The highest prevalence of stunting occurs in central Africa and south-central Asia, with an approximate prevalence of 40%. Childhood stunting has been linked to poor mental development and school achievements as well as behavioral abnormalities (Laus et al., 2011). Whether some of these effects are reversible remains a matter of debate. Optimal development of the fetal and infant brain depends on adequate maternal nutritional intake. Stunting early in life has been reported to have lasting effects school performance and IQ scores up to the age of 15 years. Some other authors state that children can recover from an early nutritional insult and improve cognition. Nutrient deficiencies are more likely to occur in disadvantaged environments, which themselves have additional adverse effects on children’s behavior and development. An unstimulating home environment could exacerbate the effects of malnutrition on neurologic development. The extent to which nutrition as an independent risk factor influences brain development and its future function is difficult to elucidate (Laus et al., 2011). Neuroimaging techniques have shown that infants with intrauterine growth restriction that reflects a deficient prenatal nutrition have reduced total brain tissue volumes and reduced cortical gray and hippocampus volumes, compared with children with the same gestational age but appropriate intrauterine growth (Isaacs, 2013). Intrauterine growth restriction has been associated with lower IQ, academic underachievement, reduced social skills, and behavioral problems such as attention deficit and hyperactivity disorder. Although it seems clear that nutrition plays a role in the genesis of brain tissue abnormalities, the effects of other contributing factors, such as dysfunction of fetal-placental perfusion leading to hypoxia and acidosis in fetal circulation, cannot be excluded in these children (Von Beckerath et al., 2013). Recent advances in perinatal and neonatal intensive care have led to an increase in the survival of preterm extremely low birth weight infants, although undernutrition occurs frequently during hospitalization in these infants. Undernutrition in extremely low birth weight infants is associated with extrauterine growth restriction and other adverse outcomes, such as bronchopulmonary dysplasia, sepsis, and neurodevelopmental impairment. Preterm infants with extremely low birth weight can encounter cognitive problems such as poorer school performance, behavioral and learning problems, and deficits in higher order neurocognitive functions. Studies in preterm infants have shown that those fed high nutrient

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BOX 47-1  Nutrition and Brain Development EFFECTS OF MALNUTRITION ON THE DEVELOPING BRAIN • Reduction in brain volume • Sparing of cortical neurons • Increased cell packing • Disruption of cortical pyramidal cells • Reduction in cortical dendritic spines • Decrease in width of cortical neurons • Decreased dendritic branching in cortex • Reduced number of cortical glial cells • Reduced number of cortical synapses • Reduced number of synaptic reactive zones EFFECTS OF RESTORING NUTRITION ON REVERSIBILITY OF BRAIN LESIONS • Increase in brain weight and volume: “catch-up” head growth • Prolongation of period of mitotic activity • Prolongation of period of protein synthesis • Reversal of cell packing • Reduced cortical glial cell density • Persistence of reduced number of cortical dendrites and synaptic spines • Persistence of reduced myelination • Increase in number of mitochondria in neurons • Increase in synaptic density (Modified from Levitsky, D.A., Strupp, B.J., 1995. Malnutrition and the brain: changing concepts, changing concerns. J. Nutr. 125, 2212S.)

formulae have larger brain volumes and a better performance in intelligence tests. The effects of breastfeeding have also been studied. Increasing the percentage of breast milk in the early diet of preterm infants increases the amount of white matter relative to gray and has also been associated with better performance in intelligence tests (Isaacs, 2013; Hsiao et al., 2014). Thus early administration of optimal postnatal nutrition can help to prevent neurodevelopmental impairment in preterm infants, but up to 75% of extremely premature infants do not receive the recommended nutrition and develop extrauterine growth retardation (Hsiao et al., 2014). The limit of viability for preterm infants is around the 23rd to 24th week of gestation. Thus nutritional deficits in preterm infants will be introduced earlier during development compared with intrauterine growth restricted children. Therefore in preterm infants differences are observed mainly in the white matter, whereas intrauterine growth restricted children tend to show differences in gray matter structures (Isaacs, 2013). White-matter injury is the most common pattern of brain injury after preterm birth. The third trimester of gestation is critical for brain de­­ velopment, especially for white-matter structures. During this period, preoligodendroglial progenitors differentiate to mature myelin-producing oligodendrocytes, axons develop and form connections, and neurons proliferate and migrate to the cortex and deep nuclear gray-matter structures. The main pathogenic mechanisms of white-matter injury are inflammation and ischemia. Both activate the microglia, which leads to release of free radicals and proinflammatory cytokines,

TABLE 47-1  Important Nutrients During Late Fetal and Neonatal Brain Development Nutrient

Brain Requirement for Nutrient

Described Brain Abnormalities or Disorders

Protein-energy

Cell proliferation, cell differentiation Synaptogenesis Growth factor synthesis

Global Cortex Hippocampus

Iron

Myelin Monoamine synthesis Neuronal and glial energy metabolism

White matter Striatal-frontal Hippocampal-frontal

Zinc

DNA synthesis Neurotransmitter release

Autonomic nervous system Hippocampus, cerebellum

Copper

Neurotransmitter synthesis, neuronal and glial energy metabolism, antioxidant activity

Cerebellum

LC-PUFAs

Synaptogenesis Myelin

Eye Cortex

Choline

Neurotransmitter synthesis DNA methylation Myelin synthesis

Global Hippocampus White matter

Iodine

Cerebral development Cerebellar development

Reduced brain weight, including cerebellum Reduced number of neurons in cerebrum, cerebellum, and brainstem Increased thickness of cerebellar external germinal layer Regional increases in neuronal density in cerebral hemisphere and decreased in synaptic counts visual cortex

Vitamin A

Regulation of gene and protein expression controlling neural growth and differentiation Regulion of patterning of neural tube development Modulion of neurogenesis, neural survival, and synaptic plasticity

Hydrocephalus Microcephaly Retinal and optic nerve defects

Vitamin B12

DNA synthesis Formation and maintenance of myelin sheaths Neurotransmitter synthesis

White-matter degenerative lesions in brain, spinal cord, and peripheral nerves Spinal cord posterior and lateral column involvement

LC-PUFAs, long-chain polyunsaturated fatty acids. (Adapted from Georgieff, M.K., 2007. Nutrition and the developing brain: nutrient priorities and measurement. Am. J. Clin. Nutr. 85, 614S–620S.)



ultimately resulting in degeneration of preoligodendrocytes. As a consequence there is a failure in the differentiation of preoligodendrocytes into mature myelinating oligodendrocytes, and hypomyelination occurs. Perinatal infection, which is frequent in preterm infants in intensive care units, has been recognized as an important risk factor for white-matter injury. Infection leads to systemic inflammation, and it is often associated with hemodynamic instability with reduced brain flow, which subsequently potentiates the two main pathogenic mechanisms of white-matter injury previously mentioned. Nutrition in preterm infants not only influences brain growth and maturation, but nutritional supplements that would reduce systemic infections and attenuate inflammation could also protect the brain against injury in this period of high vulnerability. There are some specific nutrients such as glutamine and probiotics that may be of interest as potential neuroprotective agents for preterm infants. Probiotics have shown to improve gut mucosal barrier integrity, regulate adequate bacterial colonization, enhance intestinal innate immune response, and modulate intestinal inflammation, which results in a reduction of necrotizing enterocolitis, bacterial translocation, and inflammation. Although probiotics have failed to improve neurodevelopmental outcomes, they may attenuate white-matter injury because of a favorable alteration of the immune response, resulting in less inflammation (Hsiao et al., 2014). In addition, they may be able to produce beneficial effects through the recently described microbiome–gut–brain axis. The exact mechanisms by which the gut microbiome modulates brain development are not yet clear, but the immune system seems to play a key role. Glutamine supplementation has also been shown to reduce the risk of serious neonatal infections and systemic inflammation, thereby leading to a reduction of white-matter injury. The mechanism through which glutamine enteral supplementation exerts its effects is yet to be unraveled. The postulated benefits of these nutritional supplements warrant further investigation. Studies have shown that animals may recover from periods of undernutrition. However, if stunting continues during the entire period of cell replication, there is a persistent reduction in cell numbers, irrespective of the diet subsequently provided. Evidence of recovery in humans is less direct. An adequate calorie and protein intake certainly ends the insult, but it is not clear whether supplements always improve brain function, as genetic and environmental factors play a role in the potential for recovery. Studies evaluating the relationship between nutrition and cognition that took into account the social environment demonstrated that both factors are significantly correlated with cognitive performance. In interventional studies, both treatments, nutrition, or psychosocial stimulation alone seem to improve cognition. Combined treatments are the most effective at preventing large losses of potential cognitive performance, however, with greater effect the earlier the treatment begins. Some authors have stated that malnourished children have less energy to explore their environment and take advantage of opportunities for social contacts and learning processes; thus an unstimulating home environment can exacerbate the effects of malnutrition. There is evidence that in developing countries clinical deficiencies in nutrition affect the structure and long-term functioning of children’s brains. These clinically evident deficiencies are less likely to occur in industrialized countries, where a balanced diet is generally available. In industrialized countries, special attention should be paid to preterm children and those with intrauterine restricted growth who are often nutritionally deprived during critical stages of brain development. Concern should also be focused on those children with malabsorption, metabolic diseases, or increased demands of

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nutrients caused by underlying pathologies, as well as on those receiving vegan diets.

MICRONUTRIENTS There is widespread belief that micronutrient intake in industrialized countries is deficient because of changes in nutritional habits. Some studies conclude that in general average intake of nutrients is above reference nutrient intakes, but it is often marginal for some micronutrients, such as iron, folic acid, and vitamins D and B12. Whether such a marginal intake is a matter of concern remains under discussion. In industrialized countries, it is therefore necessary to distinguish those whose diets are deficient from those with minor inadequacies. All nutrients are important for neuronal growth and development, but certain nutrients have greater effects on brain development than others do. Fetal and neonatal malnutrition can have global or circuit-specific effects on the developing brain given that some nutrients influence a specific brain area preferentially. Each of these nutrients has generated a wide range of research literature examining their relation with the brain.

Minerals Iron Iron deficiency is the most prevalent nutritional deficiency in the world. Over 30% of the world’s population is anemic, and iron deficiency is the most common cause of anemia. It is prevalent not only in developing countries but also in industrialized countries, and children and women are the most commonly affected. This raises concern, as both isolated iron deficiency and iron deficiency anemia are thought to adversely influence neurodevelopment and behavior. Some of the consequences of developmental delay associated with iron deficiency are decreased motor development, lower IQ, and difficulties with learning and memory. Furthermore, the adverse effects of iron deficiency occurring in the first 6 to 12 months of life are likely to persist even if iron intake is subsequently normalized. In older children, iron deficiency has been related with poorer social-emotional development and problems of sustained attention, which can be reversed by an adequate supply of iron. Brain tissue is overall rich in iron with concentrations differing according to brain region and stage of development. Some areas—like the cortex, hippocampus, and striatum—are more sensitive to iron deficiency than others. Iron accumulates in the brain during prenatal development. Given the poor bioavailability of iron in human milk, these iron stores in the brain are paramount in the first 6 months of life when infants are unable to regulate iron transport across the blood– brain barrier. Afterward, the brain is able to fully regulate iron entry into the brain even during periods of iron deficiency. The brain’s need for and usage of iron does not end during the perinatal period and infancy; the adult brain still requires an adequate supply of iron (Radlowski and Johnson, 2013). Studies in animals have shown that iron deficiency inhibits neurogenesis in the hippocampus, which provides a basis for behavioral deficits associated with perinatal iron deficiency. Iron homeostasis is critical for the expression of neurotrophic factors that support brain development. These neurotrophic factors influence not only neurogenesis but also neuronal morphology, dendritic outgrowth, and spine density and geometry, which are crucial for cell function. Iron deficiency also affects synaptic plasticity and severely affects myelination (Radlowski and Johnson, 2013). Moreover, iron is essential for neuronal metabolism and the enzymes involved in the

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synthesis of some neurotransmitters, including serotonin, dopamine, and norepinephrine. Dopamine is important for regulating cognition and emotion, reward and pleasure, movement, and hormone release. Serotonin in highly implicated in neurodevelopmental disorders such as autism, anxiety, and depression (Radlowski and Johnson, 2013). Although an unequivocal relationship between iron deficiency and neurologic development has yet to be established, it is important to prevent it. Preterm infants and those born to mothers with anemia, diabetes, hypertension with intrauterine growth restriction, and multiple gestations are at risk of developing iron deficiency, as these circumstances lower fetal iron stores. Dietary recommendations for preterm infants are for an elemental iron intake of 2 to 4 mg/kg/day to a maximum of 15 mg/d by 1 month of age and extending through 12 months of age, with the exception of those who received multiple transfusions in which the need of iron supplementation should be assessed. Iron-fortified formulas provide sufficient iron to meet these requirements, but breastfed preterm infants should be supplemented. Healthy term infants usually have sufficient iron stores until 4 to 6 months of age, and the small amount of iron in human milk is enough for exclusively breastfed infants. Exclusive breastfeeding after the age of 6 months is associated with an increased risk of iron deficiency anemia. Therefore, for exclusively breastfeed term infants, supplementation of 1 mg/kg/day is recommended starting from the fourth month until an appropriate iron intake is achieved with complementary food. Term formula-fed infants do not need any dietary supplementation, as iron requirements can be met for the first 12 months by standard infant formulas containing 12 mg/L iron and the introduction of iron-containing complementary foods at 4 to 6 months. After this age, iron needs can be achieved by consumption of iron-rich foods. Only those children not receiving the recommended iron intake in the diet will require supplementation.

Zinc Zinc is an essential nutrient with multiple roles. It is involved in the activity of more than 200 enzymes and plays a fundamental role in the synthesis of proteins and nucleic acids. It is involved in gene expression, cellular division and development, and in the growth and function of many organs, including the central nervous system. Severe zinc deficiency during pregnancy has been associated with fetal losses and congenital malformations. Animal studies regarding the central nervous system have shown that zinc deficiency during early development results in adverse effects on brain structure and function. Zinc deficiency alters autonomic nervous system regulation and hippocampal and cerebellar development. There are no conclusive data on humans about the effects of zinc deficiency on neurologic development, but some studies have suggested an association with decreased cognitive and motor function as well as behavioral problems (Gogia and Sachdev, 2012). Severe zinc deficiency is rare in humans, but mild to moderate depletion appears to be quite prevalent. In the last half of pregnancy when fetal growth is rapid, there is an additional need for 0.6 mg zinc daily. The United Nations International Children’s Emergency Fund (UNICEF) recommends that all pregnant women in developing countries use multiple micronutrient supplements that include zinc.

Iodine Iodine deficiency is the leading preventable cause of mental retardation worldwide. Iodine is essential for the production of thyroid hormones, for normal growth, and for brain development. In chronic severe iodine deficiency, thyroid hormone

synthesis is reduced. A severe iodine deficiency during critical periods of brain development will result in irreversible brain damage and is associated with both physical and mental impairments. The most serious consequence of iodine deficiency is cretinism, which is characterized by severe, irreversible alterations in brain development resulting in profound mental retardation and neurologic signs including deafness, impaired language development, abnormal eye movements, and motor disorders. Iodine deficiency early in life is associated with a loss of 6.9 to 10.2 IQ points in those who do not develop cretinism, which is estimated to be 5% to 15% of those noncretinous children with severe iodine deficiency (Bougma et al., 2013). Thyroid hormone-dependent neurodevelopment begins in the second half of the first trimester, but it is not until the beginning of the second trimester that the fetal thyroid begins to produce hormones. Even then, the reserves of the fetal gland are low, and it does not fully mature until birth. Thus the fetus is dependent on maternal production of thyroid hormones for brain development until birth. It is therefore important to keep an adequate intake of iodine during pregnancy, when a 50% increase in maternal intake is recommended to produce enough thyroid hormones to meet maternal and fetal requirements. Adequate thyroid hormone for ongoing neurodevelopment remains critical after birth. Newborn intrathyroidal iodine stores are limited to approximately 300 µg, and thyroid hormone requirements for the developing infant are at their highest compared with subsequent growth periods. All this makes newborns and infants particularly vulnerable to iodine deficiency. Prevention of iodine deficiency by iodization of salt has helped to alleviate endemic cretinism, but attention is now turning to the adverse effects of moderate and mild iodine deficiency. In general, it seems that maternal thyroid metabolism can cope with mild iodine deficiency, such that the mother can sufficiently supply the infant with thyroid hormones. Although the developing brain is the most severely affected if iodine is deficient, chronic hypothyroidism also can have effects across all ages. Iodine deficiency has a negative effect on cognitive performance of school-age children, but supplementation of moderately iodine-deficient school children improves cognitive and motor functions, showing that the effects of iodine deficiency later in life are at least partially reversible. Iodine deficiency is still one of the most common micronutrient deficiencies in the world. Iodine is naturally present in seawater and in the soil, and the iodine content of the soil determines its content in vegetables, milk, and eggs. Fish, seafood, and algae are good sources of iodine. Prevention of iodine deficiency is easily managed by iodization of salt, but it is still present in some regions of the world. Recommended dietary iodine intake in pregnant women is 250 µg/day. Whether routine iodine supplementation should be recommended to pregnant women in areas of mild-to-moderate iodine deficiency remains uncertain. Iodine requirements for newborns have been set at 15 µg/kg/day at term and 30 µg/kg/day for preterm infants. An intake of 130 µg/day is recommended during the second half of the first year of life. Exclusively breastfed infants rely entirely on maternal iodine intake to meet their requirements. Commercially prepared formulas contain iodine, but its amount varies worldwide. In addition, iodized salt is discouraged in home-prepared complementary foods for infants. International organizations recommend the universal use of iodized salt to prevent iodine deficiency. In countries with severely iodine-deficient populations, single annual doses of iodized oil may be administered to lactating mothers or weaning infants as a strategy for achieving recommended iodine intakes.



Vitamins Vitamins are organic compounds required by mammals in small amounts to sustain normal metabolism. They must be supplied from exogenous sources because they cannot be synthesized endogenously. Nutritional vitamin deficiency remains a public health problem in developing countries and among the poor worldwide.

Folate Folic acid is a B vitamin that plays and important role in cell proliferation, brain cell repair, and appropriate epigenetic expression of the genome. Folate is believed to be involved in cell division by means of its influence on nucleic acid synthesis, which is necessary for DNA integrity and replication and amino acids synthesis. During pregnancy the rate of cell division increases dramatically, and folate demand increases beyond maternal requirements. It is therefore essential for growth and necessary for normal development of the fetal spine, brain, and skull, in particular during the first 4 weeks of pregnancy. There is widespread evidence that both periconceptional folic acid supplementation and high maternal folate concentrations reduce the risk of neural tube defects, including spina bifida and anencephaly. These congenital malformations of the brain and spinal cord result from failure of normal developmental processes involving failure of the neural tube to close properly during the first trimester of gestation, in particular during the third and fourth week of pregnancy (Benton, 2012). The exact mechanism by which folate supplementation prevents neural tube defects remains unknown. Maternal folate levels have also been related to better performance of their children in tests assessing memory, reasoning, attention, and visual–spatial and verbal abilities. Little attention has been given to folate nutritional deficiency later in the course of pregnancy. Folic acid supplementation may also have beneficial effects on cognitive development and preventive effects on neurodevelopmental disorders such as language delay, autism spectrum disorders, and schizophrenia. The main sources of folate in the diet are vegetables, legumes, and milk. Pregnant women are at risk for folate insufficiency because of the increased need of folate for rapid fetal growth, placental development, and enlargement of the uterus. Generally, reports on average dietary folate intake in pregnant or childbearing women all over the world show low folate intakes compared with the recommendation of 400 µg/day. Neural tube defects occur during the third and fourth week of pregnancy, before a mother becomes aware that she is pregnant. The risk is reduced when women take daily folic acid supplements 3 months before considering pregnancy and continuing up to the sixth week of pregnancy. These recommendations have led some countries to include folic acid food fortification, which has greatly reduced the incidence of spina bifida. Therefore all women of childbearing age are recommended to take a folic acid supplement of 400–800 µg/day, preferably at least a month before conceiving.

Cobalamin (Vitamin B12) Vitamin B12 deficiency during pregnancy has been related to adverse fetal and neonatal outcomes such as neural tube defects and delayed defects, delayed myelination, or demyelination. There is evidence that decreased maternal serum levels of vitamin B12 in humans are associated with an increased risk of neural tube defects, regardless of folic acid supplementation of the diet.

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Most of the data regarding vitamin B12 deficiency in infancy are from case studies of infants born to mothers who were not treated for pernicious anemia or infants who were exclusively breastfeed by mothers on vegan or vegetarian diets. The deficiency results in irritability, anorexia, lethargy, and retarded neurodevelopment. Neuroimaging techniques have also shown severe brain atrophy and retarded myelination in vitamin B12-deprived children. After therapy, recovery has been reported to be variable, with recovery of brain structures but brain function remaining delayed in some children. Later in life, poorer measures of intelligence, memory, and frontal lobe function have been reported in adolescents who as children had received vegan diets and who subsequently ate omnivorous or vegetarian diets (Benton, 2012; Black, 2008). The mechanisms underlying the action of vitamin B12 are unclear. Cobalamin deficiency leads to functional folate deficiency because folate cannot be transformed into its active tetrahydrofolate form. Deficiency of folate and cobalamin results in similar biochemical effects; cobalamin deficiency may contribute this way to the development of neural tube defects. It is also involved in fatty acid metabolism and therefore the maintenance of periaxonal myelination, which occurs from midgestation through the second year of life and continues to and during puberty. It influences the speed of nerve conduction and may in this way influence cognitive development. Some other possible mechanisms include its role in the inflammatory process, altering the balance of neurotrophic and neurotoxic cytokines, affecting the S-adenosylmethionine: S-adenosylhomocysteine ratio, and increasing the accumulation of lactate in brain cells (Benton, 2012; Black, 2008). Provision of vitamin B12 is therefore essential for pregnant and breastfeeding mothers and infants. During pregnancy, serum vitamin B12 concentrations in the mother decline, and they are concentrated in the placenta and transferred to the fetus down a concentration gradient, with newborn vitamin B12 concentrations approximately double those of the mother. The total vitamin B12 requirements of the fetus are estimated to be 50 µg, whereas maternal stores in well-nourished women are estimated at greater than 1000 µg. Thus body stores are adequate to meet fetal needs during gestation. During pregnancy, vitamin B12 is stored in the fetal liver, so that infants whose mothers are well supplied with vitamin B12 are born with a supply sufficient for the first several months. An increased risk of vitamin B12 deficiency is associated with dietary deficiencies with low consumption of animal-source foods, as occurs with strict vegan or vegetarian diets or alternatively with impaired B12 vitamin absorption. The recommended dietary allowance (RDA) for vitamin B12 in pregnancy is 2.6 µg/day, 0.2 µg/day greater than the RDA for nonpregnant women and adolescents.

Vitamin D Vitamin D has recently been considered a neurosteroid and is thought to have a role in brain development and function. The role of vitamin D in the brain is not yet known, but research in recent years has yielded considerable evidence supporting this hypothesis. The major metabolites of vitamin D are present in human cerebrospinal fluid, and the enzymes involved in the conversion of vitamin D are present in the brain. In addition, vitamin D receptors are expressed throughout the human brain. All these findings indicate that vitamin D, like other neurosteroids, may play a role in brain function. Vitamin D receptors appear early in the fetal brain and increase in number during gestation, which may indicate that vitamin D is involved in neurologic development (Benton, 2012). It has been proposed, but not proven, that low levels of vitamin D during pregnancy and infancy could increase the

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risk of neurodevelopmental disorders and psychiatric problems such as schizophrenia and autism. Although it is found in some foods, exposure to sunlight is the greatest source of vitamin D. Changes in lifestyle, including less exposure to the sun and obesity, lead to vitamin D insufficiency in industrialized countries. The vitamin D RDA for women, including during pregnancy, has been recently established at 600 IU per day. Breastfed infants are at high risk of vitamin D deficiency because of the low levels of this vitamin in breast milk. Therefore all breastfed infants should receive a daily vitamin D supplement of 400 IU beginning in the first few days of life.

has been recently reviewed, but there is insufficient evidence at this time to recommend supplementation (Benton, 2012). Choline is the precursor of the neurotransmitter acetylcholine, and it is a precursor for phospholipids that are constituents of cell membranes and the methyl donor betaine. Plasma levels of choline are high in the newborn, which suggests an important functional role. During pregnancy it is critical for brain development as it influences stem cell proliferation and apoptosis, thereby altering brain structure and function (Benton, 2012). Although it is accepted that choline plays a role in brain development, there is to date no evidence that adding choline to the diet improves cognitive development.

Other Vitamins

Long-Chain Polyunsaturated Fatty Acids

Some other vitamins have been related to neurologic development, although evidence is still scarce and the possible mechanisms of action need to be elucidated. Vitamin A is a member of the family of nuclear steroid transcription regulators, and as such, exerts transcriptional control over genes and proteins in different tissues, including genes that control neural differentiation, and plays an important role in neuromodulation. Retinoic acid is a signaling molecule in the brain of growing and adult animals, and retinoid receptors have been found in the hippocampus of rats, which plays a role in memory. Dietary vitamin A deficiency is globally one of the most common forms of malnutrition, with clinical manifestations including ocular disorders, immunosuppression, and impaired growth. It plays a critical role in visual function, and a deficiency continues to be a major cause of infantile blindness in some developing countries. The role of vitamin A on the human brain is poorly understood, but it has been suggested that it influences memory and sleep and plays a role in depression and Parkinson and Alzheimer diseases. The effects of vitamin A deficiency are more likely to be observed in developing than in industrialized countries, where variations in vitamin intake within the normal range may not have functional implications (Benton, 2012). Thiamine (vitamin B1) has an important role in nerve conduction and the synthesis of the neurotransmitter acetylcholine. Studies in animals have noted that thiamine-dependent enzymes play an important role in establishing adult patterns of brain energy metabolism and myelin synthesis. Thiamine requirements are enhanced during pregnancy and lactation, especially in the third trimester when thiamine is preferentially taken up by the fetus. Data from a single study have related thiamine dietary supplementation in children with better intelligence scores, visual acuity, faster reactions times, and better memory. Thiamine deficiency during pregnancy has long-lasting consequences for cognitive development, but this effect has not been demonstrated for subclinical deficiencies (Benton, 2012). Clinical manifestations of dietary thiamine deficiency (beriberi) primarily affect the cardiovascular and nervous systems. Pyridoxine (vitamin B6) is a coenzyme necessary for the production of various amino acid neurotransmitters, including serotonin and noradrenaline. Its deficiency has been associated with irritability, seizures, and peripheral neuropathy in children. Infantile seizures caused by dietary B6 deficiency are rare and may be seen in developing countries. Furthermore, pyridoxine dependency has been recognized in some types of epilepsy and pediatric neurotransmitter diseases. Studies in animals have shown structural and functional impairments in the hippocampus in subjects that are prenatally vitamin B6 deficient. Some other studies have reported an association between vitamin B6 and autism, although recent reviews did not have conclusive results. The influence of vitamin B6 supplementation during pregnancy on neurologic development

The most frequently studied nutrients have been long-chain polyunsaturated fatty acids (LC-PUFA). LC-PUFA have important structural and metabolic functions in the human body. The two major LC-PUFA synthesized in the human body are docosahexaenoic acid (DHA) and arachidonic acid (AA). Mammals are unable to synthesize polyunsaturated fatty acids, thus their precursor essential fatty acids, linoleic acid (LA) and linolenic acid (ALA), must be obtained from the diet. The most abundant fatty acid in cell membranes is DHA. It is present in all organs but it is particularly abundant in neural tissues such as the brain and retina. Lipids constitute approximately 50% to 60% of human brain dry weight; about 35% of the lipids are polyunsaturated fatty acids, and most of them are LC-PUFA. From the beginning of the third trimester of life to 2 years of postnatal age there is enrichment in the relative content of DHA in the brain. Fatty acids in the brain can either be taken up from the blood as preformed DHA or synthesized from ALA inside the brain. Several hypotheses have been proposed to explain the role of DHA in the brain, which in general can be divided into properties conferred by lipid-bound DHA in the membrane bilayer and those related to unesterified DHA. Changes in membrane DHA content can alter membrane physicochemical properties and also affect the signal transduction pathway and neurotransmission. The high proportion of DHA in neural membranes also raises the possibility that n-3 LC-PUFA deficiency may impair membrane biogenesis, influencing neurogenesis, neuronal migration, and outgrowth. Unesterified DHA has a role in regulating gene expression which is influencing stem cell differentiation to neurons and ion channel activity. It can also be further metabolized to neuroprotective metabolites in the brain, and it has been suggested that it has an important role in neurogenesis. Thus n-3 fatty acid deprivation may affect brain development at multiple levels, with the effects and potential for recovery differing depending on when the deficiency occurs. The effects of LC-PUFA on neurodevelopment outcome have been widely studied. In premature births, the umbilical transfer of LC-PUFA is interrupted, thus preterm infants have lower LC-PUFA concentrations than full-term infants. The beneficial effects of adding LC-PUFA to preterm formulas have shown conflicting results with regard to neurodevelopment. Several studies have demonstrated improvements in electroretinogram activity, visual acuity, and short-term global developmental outcome, but recent meta-analysis has shown no clear long-term benefits for preterm infants receiving LC-PUFA supplemented formula on pooling results (Campoy et al., 2012). However, an inappropriate supply of lipids in preterm infants has been reported to lead to biochemical deficiency of essential fatty acids, causing reduced body and brain weight (Hsiao et al., 2014). Meta-analysis of the effects of LC-PUFA in term infants or during pregnancy and early infancy



conclude that there is insufficient evidence to affirm that supplementation exerts a clear and consistent benefit (Campoy et al., 2012). Trials are normally conducted in developed countries with relatively healthy infants, thus they should receive adequate DHA transplacentally and in breast milk. The benefits of supplementation on neurodevelopment might be more pronounced in undernourished children. Furthermore, recent evidence shows that n-3 LC-PUFA supplementation is effective for improving behavioral problems such as attention deficit/hyperactivity disorder (Hsiao et al., 2014). The main natural source of LA and ALA are vegetable oils, particularly safflower and corn oils. AA and DHA are not found in plants, but are synthesized by animals. Only small mammals accumulate a high proportion of them. Meat and eggs are rich sources of AA but not DHA. Marine food is rich in n-3 PUFA as algae are the primary producers of DHA and EPA in the ecosystem. Fish are therefore rich in DHA. Western diets are characterized by low n-3 fatty acids intakes and high amounts of n-6 fatty acids; as a result, EPA and DHA demands are not adequately supplied. The exclusion of fish and meat from the diet can result in very low intakes of DHA. Before birth, DHA is transported to the fetus from the mother across the placenta, and after birth the infant is provided with DHA in breast milk. Therefore pregnant and lactating mothers should receive an average DHA intake of at least 200 mg/day, which means a consumption of two servings of fish weekly. It is unreasonable to expect that micronutrients examined in isolation will be associated with differences in cognitive functioning. Brain function is the result of millions of metabolic processes in which nutrients act in combination. Furthermore, a diet deficient in one component is also likely to be poor in others. A multivitamin and mineral approach is probably more beneficial in terms of cognitive development. It is widely accepted that an insufficient intake of calories, proteins, and micronutrients at critical stages of brain development can produce irreversible changes in brain structure and consequently reduce cognitive capacity for life. There is

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controversy concerning the effects of dietary supplementation in infants who are well fed, however; it is likely that only those children who are poorly nourished respond to nutritional interventions. Further research is necessary to address this question. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Benton, D., 2012. Vitamins and neural and cognitive developmental outcomes in children. Proc. Nutr. Soc. 71, 14–26. Black, M.M., 2008. Effects of vitamin B12 and folate deficiency on brain development in children. Food Nutr. Bull. 29, 126S–131S. Bougma, K., Aboud, F.E., Harding, K.B., et al., 2013. Iodine and mental development of children 5 years old and under: a systematic review and metaanalysis. Nutrients 5, 1384–1416. Campoy, C., Escolano-Margarit, M.V., Anjos, T., et al., 2012. Omega 3 fatty acids on child growth, visual acuity and neurodevelopment. Br. J. Nutr. 107, 85S–106S. Gogia, S., Sachdev, H.S., 2012. Zinc supplementation for mental and motor development in children (Review). Cochrane Database Syst. Rev. 12. Hsiao, C.C., Tsai, M.L., Chen, C.C., et al., 2014. Early optimal nutrition improves neurodevelopmental outcomes for very preterm infants. Nutr. Rev. 72, 532–540. Isaacs, E.B., 2013. Neuroimaging, a new tool for investigating the effects of early diet on cognitive and brain development. Front. Hum. Neurosci. 7, 445. Laus, M.F., Vales, L.D., Costa, T.M., et al., 2011. Early postnatal proteincalorie malnutrition and cognition: a review of human and animal studies. Int. J. Environ. Res. Public Health 8, 590–612. Radlowski, E.C., Johnson, R.W., 2013. Perinatal iron deficiency and neurocognitive development. Front. Hum. Neurosci. 23, 585. Von Beckerath, A.K., Kollmann, M., Rotky-Fast, C., et al., 2013. Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am. J. Obstet. Gynecol. 208, 130 e1–130 e6.

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The Neuronal Ceroid Lipofuscinosis Disorders Joseph Glykys and Katherine B. Sims

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION

Clinical Description and Characterization

The neuronal ceroid lipofuscinosis (NCL) disorders are a group of genetically inherited lysosomal neurodegenerative diseases characterized by the intracellular accumulation of autofluorescent lipopigment storage material that causes progressive neurologic degeneration in all age groups. The clinical course includes progressive dementia, seizures, progressive visual failure (except in the adult-onset forms), and often movement abnormalities. Collectively, these disorders are the most common cause of an inherited childhood neurodegenerative disease and are increasingly recognized in late-onset or adult-onset forms. Prevalence is estimated widely from 1.5 to 9 per million, and incidence, which varies among geographic ethnic regions, has been reported from 1.3 to 7 in 100,000 live births. The clinically relevant pathobiology affects primarily the central nervous system and may include, in variant fashion, cognitive failure (dementia, encephalopathy), seizures that often are myoclonic, movement abnormalities that are often ataxic or extrapyramidal in nature, and visual failure. Retinal degeneration and visual failure are rare in the adult forms of these diseases. This group of genetic disorders has an autosomal recessive inheritance, except the rare autosomal dominant adult-onset disorder. Summaries of NCL disorder mutations and relationship to clinical features have been published.

The first clinical description of NCL was that of the juvenile form in a small Norwegian family. This was soon followed by clinical and pathologic descriptions of familial cases within a larger population of so called “amaurotic family idiocy” by Batten, Vogt, Spielmeyer, and Sjögren. A detailed historical summary of the lives and work of these early and seminal clinician researchers has been published. Significant interfamilial variability in phenotype, in many of the early described NCL cases, gave challenge to a unifying classification. Originally, the NCL disorders were grouped among the sphingolipidosis and the more global clinical characterization as “amaurotic idiocy.” The term “neuronal ceroid lipofuscinosis” was introduced by Zeman and Dyken in 1969, referencing primarily the common pathologic feature of these disorders. Earlier investigators had difficulty distinguishing whether these were single disorders or related ones. But by collection, observation, and report of familial cases, five types of NCLs were eventually clinically characterized: congenital, infantile, late infantile, juvenile, and adult onset. The congenital form was first clinically described by Norman and Wood in 1941 and later associated with cathepsin D deficiency in congenital school-age or adult forms. This NCL has been designated CLN10 (CTSD). The infantile form (INCL; CLN1; Santavuori-Haltia) was clinically described by Hagberg in 1968 and then by Haltia and Santavuori in 1973. Although originally described as infantile in onset, late-infantile, juvenile, and adult forms have been reported. The underlying cause of CLN1, palmitoyl protein thioesterase 1 deficiency, was identified by linkage and fine molecular mapping. The classic late-infantile (LINCL; CLN2; JanskyBielschowsky) form was originally described in patients by Jansky in 1908 and Bielschowsky in 1913. Cases were reported throughout the 1970s with typical clinical presentation and disease course. The underlying cause of CLN2, tripeptidylpeptidase deficiency, was identified by protein study. Clinical correlation with genotype has been reported, although the phenotype continues to be expanded. Other nonclassic lateinfantile clinical disorders have been described, including variant late-infantile and early-juvenile forms due to defects in the CLN5 gene in patients first described clinically in 1991 and in CLN6, CLN7 (MFSD8), and CLN8. A possible CLN9 form has been described that is clinically similar to the juvenile form, although no unique associated genetic locus has been yet identified and the originally reported two sibships have been later shown to have CLN5 disease. The classic juvenile form (JNCL; CLN3; Batten disease) is the most prevalent and characteristic of the NCL disorders. Juvenile, other than CLN3 disease, and early adult-onset forms have been recently characterized by clinical features and molecular gene identification. The adult-onset disorder, later

HISTORICAL CLINICAL CHARACTERIZATION Nomenclature Historically, these disorders were characterized by clinical age of onset and pathologic hallmarks of lysosomal deposition. The individual disorders were initially given names honoring those who first identified the clinical spectrum in narrow ethnic populations and in reference to age of onset. The classic clinical distinction was therefore infantile (INCL), lateinfantile (LINCL), juvenile (JNCL), and late-onset or adult (ANCL; Kufs). The terminology is confusing because it was established before many clinical variants or disorders were defined and before the identification of the etiologic genes. Classification by age of onset is still useful in clinical evaluation. Atypical forms with variable ages of onset are well described. Distinguishing these disorders by genetic etiology is now currently favored and serves the study of disease-specific pathobiology (Table 48-1). The term “Batten disease” was originally used to honor the clinician that first recognized this disease in the juvenile-onset form. Although historically incorrect when applied to all the NCL disorders, this designation is a simple and practical one and has been universally adopted and accepted by family groups, private foundations, and U.S. government agencies.

390

JNCL SpielmeyerSjogren

Kufs [Parry type]

fLINCL (1)

CLN3

CLN4

CLN5

SCAR7

256731

162350

204200

607998

cLINCL 204500 JanskyBielschowsky

CLN2

AR

AD

AR

AR

CLN5

DNAJC5

CLN3

TPP1

PPT1

256730

INCL SantovouriHaltia

CLN1

AR

OMIM # Inherit Gene

Prior Disease Designation

TABLE 48-1  NCL Disorders

CLN5

Cysteine-string protein alpha [CSPα]

CLN3

TPP1 [partial deficiency]

Tripeptidyl peptidase 1 [TPP1]

Palmitoyl protein thioesterase 1 [PPT1]

Protein

Variant late infantile

Juvenile Adult

4–9 yr 17 yr

Juvenile - adult

Classic juvenile

Juvenileadult

Classic late infantile

3–7 yr

teenage– 30 yr +

3–8 yr

childhood– young adult

2–4 yr

18 yr +

4–6 yr

20–40 yr

Adulthood

6–12 yr +

Behavior abnormalities, cognitive decline, seizures, visual faliure, myoclonus, motor abnormalities Visual failure, motor loss, myoclonus, seizures Motor loss, cognitive regression, visual loss, myoclonus, seizures

FP, CL (RL)

Teen– 30 yr +

GROD, FP (CL, RL)

Teenage + FP, CL

10–30 yr

Cerebellar and pons atrophy

Cerebral and cerebellar atrophy

Cerebral and cerebellar atrophy

Microcephaly; increase periventricular white matter signal. Alter thalamic signal. Cerebral atrophy

Imaging

Large-amplitude spike and slow-wave complexes by around 9 years

Characteristic giant occipital polyspike-spike discharges in response to a single flash of light or to low-frequency, repetitive stimulation

Lack of sleep spindles. Absence of attenuation in amplitude when opening eyes by the ages of 16–24 months. Gradual loss of amplitude. EEG isoelectric by around 3 years of age

EEG

‡

‡

Cerebellar atrophy

Continued on following page

Posterior spikes to low-frequency photic stimulation

Cortical atrophy Severely abnormal with is usually generalized or bilateral found. Some independent periodic patients show epileptiform discharges cerebellar atrophy.

Vacuolated Cerebral and lymphs, FP cerebellar (CL, RL) atrophy

Negative

CL

GROD

GROD

GROD

GROD

EM Inclusions

Behavior issues, dementia, 30–40 yr + GROD (CL, seizures, myoclonus, no RL, FP) visual loss

Visual failure, cognitive decline, behavioral and motor difficulties; late seizures

Malignant seizures, myoclonus, developmental regression, visual failure Ataxia, cerebellar signs [pyramidal signs] no visual loss

Late-infantile Developmental regression, 5–12 yr + seizures, visual failure Early Visual failure, seizures, 10–20 yr childhood behavioral, dementia JuvenilePsychiatric, cognitive 50 yr + early adult decline, depression; ataxia, parkisonism, visual loss

2–9 yr

2–4 yr

Developmental failure, seizures, myoclonus, visual failure

Early Symptoms and Signs [in Order of Usual Usual Appearance] Survival

Classic infantile

Clinical Phenotype

6–24 mo

Usual Age of Onset

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EPM3

CLN14

AR

AR

611726

AR

611725

615362

AR

AD

AR

AR

AR

AR

AR

KCTD7

CTSF

ATP13A2

GRN

CTSD

reclassified as CLN5**

CLN8

MFSD8

20–30 yr

8–12 yr

35–65 yr

Adult

Juvenile

Adult

Adult

Juvenileadult

1st decade Early 20s

Congenital

Juvenile

Neonatal

2–7 yr

Northern epilepsy Variant late infantile

Juvenile

11 yr

5–10 yr

Variant late infantile

Adult-onset

Variant late infantile

18 mo– 6 yr

16–50 yr

2–5 yr

Clinical Phenotype

Not reported

40 yr +

EEG

30 yr +

None

RL (GROD)

Cerebral & cerebellar atrophy. Nonspecific white matter lesions

Cerebral & cerebellar atrophy

Diffuse cerebral atrophy

GROD = granular osmophilic deposits CL = curvilinear bodies FP = fingerprint profiles RL = rectilinear inclusions *Kollmann 2013 **Haddad 2012 ‡few cases only

Unknown

Teenage

FP [brain]

FP, Generalized & brainstem atrophy; Basal ganglia vacuolated iron accumulation lymphs

TDP-43

Cerebellar atrophy

Cerebral & cerebellar atrophy

Teenage + GROD FP

Microcephaly, general atrophy

Cerebral & cerebellar atrophy

Cerebral and cerebellar atrophy

Cerebellar atrophy (late)

‡

Cerebral and cerebellar atrophy

Imaging

GROD

< 1 yr

CL, FP, GROD

Teenage + FP (CL, GROD)

?

40 yr +

Tremor, ataxia, pyramidal/ 40–50 yr extrapyramidal, dementia, seizures (rare) 40s–50s

Parkinsonism, ataxia, dementia no visual loss

GROD (FP)

FP, CL, RL

EM Inclusions

Teenage + FP, RL (CL)

Visual failure, myclonic 30 + seizures, ataxia, dementia Myoclonic seizures, ataxia, 50 yr + cognitive decline

Epileptic encephalopathy, microcephaly Ataxia, visual loss, regression

Classic CLN3 phenotype

Seizures, slow dementia without visual loss Myoclonus->myoclonic seizures, ataxia, cognitive decline, visual loss

Developmental delay, visual failure, seizures, dementia, myoclonus Visual failure, motor loss, seizures, ataxia, dementia

Seizures, motor and 20s cognitive decline, visual failure, myoclonus Myoclonic epilepsy, ataxia, 40 yr + dementia, no visual loss

Early Symptoms and Signs [in Order of Usual Usual Appearance] Survival

K+ channel 8–9 mo Infantile Seizures, motor and tetramerization speech regression, domain- 7 visual failure 10 mo–3 yr Late-infantile Without visual loss

Cathepsin F

P-type ATPase

Progranulin

Cathepsin D

CLN8

MFSD8

CLN6

Protein

Usual Age of Onset

1. Variant initially described in Finnish 2. Formally Lake Cavanagh early juvenile NCL variant and Indian-variant late-infantile NCL 3. Formally Turkish variant

Kufs type B

CLN13

607485

FTLD-GRN

606693

614706

Kufs type A

CLN11

Kufor-Rakeb PARK 9

610127

CNCL

CLN10

CLN12

609055

600143

vLINCL

CLN9

610003

EPMR

CLN8

610951

vLINCL(3)

CLN7

204300

Kufs type A

CLN6

601780

vLINCL(2)

CLN6

AR

OMIM # Inherit Gene

Prior Disease Designation

TABLE 48-1  NCL Disorders (Continued)

392 PART VI  Genetic, Metabolic and Neurocutaneous Disorders



termed Kufs disease in honor of the early clinician who recognized this disorder in 1925, is an autosomal recessive form of early-onset dementia with seizures, with or without movement abnormalities, but without vision loss. An autosomal dominant adult-onset form (Kufs, Parry-type) was much later described. Sporadic late-onset cases have since been reported and collectively are grouped as Kufs disease. These include the autosomal dominant form CLN4 associated with DNAJC5, autosomal recessive CLN11 disease, associated with GRN mutations, and with phenotypic overlap with frontotemporal dementia (FTLD-GRN) and CLN12, also termed KuforRakeb or PARK9, associated with mutation in the ATP13A2 gene. Smith and colleagues also described a late-onset form of NCL, termed CLN13 and associated with mutation in CTSF. A late-onset form of CLN6 disease has also been described. Molecular genetic technologies, studies in families, and sporadic cases eventually have led to a NCL disorder classification based on gene mutation (Table 48-1). Although this allows separation into distinct genotypes, there is much evidence that the NCL genes may participate in interrelated pathways and in an overlapping pathobiology. There is increasing recognition of a broad clinical phenotypic scope of each of these genetic forms, with reports of increased intrafamilial variability and of atypical cases. It is presumed that there are important epigenetic modulators to be identified that directly or indirectly affect clinical expression within any one of these genetically defined disorders. In addition to observational clinical case and familial reports, formal assessment tools have been developed and validated. Published and utilized in clinical study are those for infantile and late-infantile forms, Hamburg scale, WeilCornell scale, and for juvenile CLN3 (UBDRS) scale. These are important instruments for the study of the natural history and for clinical trial efficacy measurements. Although the classic clinical features, if all present, (encephalopathy/dementia, seizures, visual loss ± movement disorder) clearly point to a NCL disorder, there is broad and important differential diagnosis which needs consideration. This may, in fact, account for the sometimes long delay in diagnosis. There are many NCL masqueraders particularly in the early stages of disease when only a single clinical feature is evident (Table 48-2).

Molecular Genetics Molecular genetic study of NCL-like patients has allowed for the identification of etiologic genes in clinically identified forms, including congenital, late-infantile, juvenile, and adultonset. Currently 13 genetic loci are identified in association with human NCL disease (Table 48-1). The first NCL genes were identified in 1995 for the infantileonset form (INCL; CLN1), encoding the soluble lysosomal protein palmitoyl protein thioesterase 1 (PPT1) and the CLN3 gene, responsible for the juvenile form (JNCL) reported by a NCL consortium. This was followed by identification of the late-infantile, classic form (cLINCL; CLN2) gene, encoding the soluble lysosomal protein tripeptidyl peptidase 1 (TPP1) in 1997. Variant late-infantile forms have subsequently been identified and include CLN5, CLN6, CLN7, CLN8, and CLN14 (KCTD7). The later has more commonly been described in association with progressive myoclonic epilepsy without documented NCL-like visual failure or pathologic inclusions. A primarily congenital-onset form CLN10 (CTSD) was identified although later onset cases have been described. The genetic etiology of late adult-onset NCL disorders has been identified among the cohort of both sporadic and familial cases by whole exome sequencing. Genetic loci include one autosomal dominant inherited form CLN4 (DNAJC5) reported simulta-

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neously by a number of groups as well as in an autosomal recessive pattern in CLN11, CLN12, and CLN13. As there are cases that, by clinical history and pathologic features, appear to be NCL-like, it is presumed that more genetic loci will be identified in the future. Continued elaboration of a widening phenotypic spectrum, for many of these disorders, is also ongoing. An updated mutation database of all NCL disorders is maintained at the University College of London by Sara Mole (www.ucl.ac.uk/ncl), and publication of mutation spectrum and phenotypic correlations has expanded our understanding of these disorders.

Pathology Early pathologic description of storage material in patient tissues documented an autofluorescent, waxy, dusky lipid accumulation in neuronal endosomes, reminiscent of the aging pigment lipofuscin. This led to the term neuronal ceroid lipofuscinosis being applied to these neurodegenerative disorders. By electron microscopy, these pathologic hallmarks are membrane-bound (lysosomal) inclusions most prominently seen in neurons but recognizable in many cell types. Common sites of biopsy and inclusion identification include the skin, conjunctiva, and/or rectal tissues. Inclusions can appear as granular osmophilic deposits (GRODs), curvilinear (CL), rectilinear (RL), or as more crystalline fingerprint bodies (FP) (Fig. 48-1). Unique to juvenile CLN3 disease are the vacuoles seen by EM in circulating lymphocytes. These ultrastructural crystalline structures have remained an important distinguishing feature of the NCL disorders. Identification of this storage material, by biopsy and EM, strongly suggests an NCL diagnosis. Unfortunately, peripheral tissue biopsy may be negative, as is particularly true in the late-onset forms of NCL. In many of these cases, however, central nervous system storage has been demonstrated. Lipopigment accumulation is presumed to alter lysosomal function, lead to autophagy disruption, and/or cellular oxidative damage. Lysosomal storage of saposins A and D in CLN1 and subunit c of the mitochondrial ATP synthase in CLN2, CLN3, and adult-onset forms are most likely epiphenomenon, or secondary markers, and not disease-specific markers of the primary underlying molecular pathology. Neuronal loss in brain, predominantly in cerebral and cerebellar cortices, and retina, is also characteristic of the NCL disorders, although the underlying biology of this cell loss is not yet clear.

Pathobiology The pathobiologic details are still being elaborated. In the NCL disorders, there is protein deficiency, pathway blockade, and metabolic substrate accumulation, as well as downstream functional deficiencies and potentially detrimental cellular compensatory changes, which may lead to cellular pathobiology and the resultant clinical phenotypes. Active research is ongoing to elucidate the protein functions, the substrates and interacting partners of these proteins, the mechanisms of neuronal death, and the relationships between the various NCL proteins. Affected intracellular pathways involve at least the endosomal-lysosomal autophagy degradation pathways, the synaptic trafficking and function pathways, and the neuroinflammation/immune regulation pathways (Fig. 48-2). CLN1 and CLN2 are caused by deficiency and metabolic block of the classic soluble lysosomal hydrolases PPT1 and TPP1, respectively. Mitochondrial abnormalities in the NCL disorders have also been described, including abnormal mitochondrial ATP synthase regulation, mitochondrial structural changes, and altered respiratory chain function, as well

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TABLE 48-2  NCL Masqueraders Neuronal Ceroid Lipofuscinosis

Clinical Features

Differential Diagnosis

CLN10 (Congenital)

IUGR In utero seizures Spasticity Central apnea Microcephaly

Infant from untreated PKU mother Hypoxic-ischemic encephalopathy Nonketotic hyperglycinemia Untreated aminoaciduria Untreated organic aciduria Sulfite oxidase deficiency Serine synthesis defects GLUT1 deficiency syndrome Cerebral folate deficiency

CLN1 (INCL)

Head circumference deceleration Rapid progressive loss motor skills, speech loss Vision loss—optic atrophy Involution of retinal vessels, no RP Hyperkinesis Myoclonus Seizures

Sialidosis Cerebral folate deficiency Biopterin defects Peroxisomal disorders Rett syndrome GLUT1 deficiency syndrome Niemann-Pick disease type A and B GM2 gangliosidoses Biotinidase deficiency Pyruvate dehydrogenase complex deficiency Lactate dehydrogenase deficiency Mitochondrial cytopathies Alpers disease 3-methylglutaconic aciduria Neuroaxonal dystrophy Pelizaeus-Merzbacher disease

CLN2 (cLINCL)

Motor decline/clumsiness Seizures, often intractable Myoclonus Axial hypotonia/spasticity

Gangliosidosis (GM1, GM2) Mucopolysaccharidoses (without dysmorphism) Leukoencephalopathies; Leukodystrophies Folate receptor defect Neuroaxonal dystrophy Biotin-responsive basal ganglia disease Mucolipidosis IV Krabbe disease Congenital disorders of glycosylation Schindler disease Myoclonic epilepsy with ragged-red fibers Niemann-Pick type C Sialidosis type 1 3-methylglutaconic aciduria L-2 hydroxyglutamic aciduria Smith-Lemli-Opitz syndrome Succinyl-semialdehyde dehydrogenase deficiency Gaucher disease type III Epileptic encephalopathy vLINCL (CLN5, CLN6, CLN7, CLN8)

CLN3 (JNCL)

Visual failure/RP Behavioral problems Progressive cognitive decline

Late-onset CLN1, CLN2, CLN10 Pantothenate kinase-associated neurodegeneration; NBAI Niemann-Pick type C Gaucher disease type III Metachromatic leukodystrophy X-Adrenoleukodystrophy MERRF/ETC abnormalities/mito cytopathies Krabbe disease Late-onset GM2, (GM1) Giant axonal neuropathy Cerebrotendinous Xanthomatosis Sanfilippo type A (SGSH; MPSIIIA) Juvenile Huntington disease Neuroferritinopathy Lafora disease Wilson disease Peroxisomal disorders Gyrate atrophy with hyperornithinemia Refsum disease Congenital disorders of glycosylation Cone-rod dystrophy Bardet-Biedl syndrome Joubert syndrome Juvenile nephronopthisis Alström syndrome Spinocerebellar Ataxia type 7 Alport syndrome

Retinitis pigmentosa

Cone-rod dystrophies



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TABLE 48-2  NCL Masqueraders (Continued) Neuronal Ceroid Lipofuscinosis

Clinical Features

Differential Diagnosis

CLN11, CLN12, CLN13 (ANCL)

Behavioral disturbances Dementia Ataxia/movement disorder [with or without seizures]

Early onset Alzheimer disease, Parkinson disease Frontotemporal dementia Late-onset lysosomal disorders: GM2, Metachromatic leukodystrophy Early onset Alzheimer disease due to PSEN1 mutations Lafora disease Unverricht-Lundborg myoclonic epilepsy Myoclonic epilepsy with ragged-red fibers (MERRF) Dentatorubral-pallidoluysian atrophy Familial Encephalopathy with neuroserpin inclusions bodies Sanfilippo A (SGSH; MPSIIIA) Niemann-Pick type C Krabbe disease

MERRF: Myoclonic epilepsy with ragged-red fibers NBIA: Neurodegeneration with brain iron accumulation ETC: Electron transport chain MPSIII: Mucopolysaccharidosis type IIIA

A

B

C

D

Figure 48-1.  EM photomicrographs of typical inclusion patterns. A, Curvilinear inclusions. B, Fingerprint inclusions. C, Granular osmophilic deposits (GRODS). D, Rectilinear bodies.

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KCTD7 (CLN 14) Ubiquitin-proteasome

DNAJC5 (CLN 4)

Autophagosome

PAS

Autophagolysosome

CLN 3 CLN 5 TPP1 (CLN 2) Nucleus Late Amphisome Transport endosome GRN vesicles (CLN 11) ?

CLN 6 CLN 8

Early endosome

ER

Mutant ATP13A2 Lysosome (CLN 12)

PPT1 (CLN 1) CTSD (CLN 10) MFSD8 (CLN 7) CTSF (CLN 13)

TGN Endocytosis

α-synuclein aggregation

Figure 48-2.  NCL protein localization. Endosomal-lysosomal and autophagy-lysosomal pathway convergence. PAS: pre-autophagosomal structure. ER: endoplasmic reticulum. TGN: trans Golgi network.

as decreased cellular ATP production and neuronal survival in the context of oxidative stress. Mitochondrial dysfunction appears linked to cytoskeleton-mediated presynaptic inhibition in the homozygous CLN3 knockout mouse. Altered mitophagy as a result of NCL-defective autophagy or increased vulnerability to metabolic stress may play a role in the NCL cellular pathobiology associated with the increased oxidative stress and decreased neuronal survival seen in these disorders. Recently human induced pluripotent stem cells (iPSCs) models of CLN2 and CLN3 have been shown to have mitochondrial structural abnormalities, increase mitochondrial ATPase subunit c, in addition to abnormalities in structure and function seen in Golgi, ER, and endosomal-lysosomal compartments. Altered biometal homeostasis and deregulation has also been noted in the NCL disorders. The cellular mechanisms, which may be a secondary phenomenon in the NCL disorders, have yet to be fully elaborated. CLN5 glycosylation defects have been noted and may be further evidence of the widespread and complex secondary cellular pathobiology. Current studies, focusing on the complex endosomal-lysosomal autophagy pathway, continue to highlight potential network disruptions in these disorders. Specific gene mutations may trigger distinct processes that converge on a common cellular pathway as has been shown in CLN6 and CLN3 murine models. Alternatively, there may be direct and specific interactions between these proteins as has been documented between CLN2, CLN3, and CLN5. These studies speak to the nonindependent nature of these pathways and serve to challenge or models of pathobiology and therapeutic intervention.

NCL Models and Clinical Trials Animal models, both naturally occurring and those produced by genetic technologies, have been utilized in the pathobiologic study of many of the NCL disorders. The spontaneous models include many large animals (dogs, sheep, cattle, cats, and goats). Even unicellular and simple animals have yielded NCL models, including those in yeast, C. elegans and Drosophila. The technologies for generating iPSCs lines from human fibroblasts and the techniques being developed that allow for reprogrammed cell-phenotypic differentiation have invaluably changed the ability to make human model systems for these disorders. Recent report of success in generating human iPSCs as models of CLN1 and CLN3 has been reported and allows for study of the endocytic pathway. Therapeutic approaches to the NCL disorders have included enzyme replacement, gene and stem cell delivery, and pharmacologic therapies.

Diagnosis The diagnostic approach has changed through the years and will continue to evolve as panels and whole exome/whole genome technologies and bioinformatics improve. One approach to diagnose NCLs, based on the age of presentation, can be found on Figure 48-3. Skin biopsy is still useful when the initial screen for common CLN disorders is negative or when genetic testing is not as readily available as ultramicroscopic techniques. Sequential evaluation of NCL genes based on age of presentation was the common approach. However,



the introduction of panels, especially epilepsy panels, makes the latter more time and cost efficient. False negative assay results must be taken into consideration given current nextgeneration sequencing efficacy. As a general approach, when a patient presents with refractory epilepsy and/or signs/ symptoms concerning for a NCL disorder, performing an epilepsy panel that has several NCL genes included is a good strategy. Current epilepsy panels in the United States involve more than 70 genes known to cause epilepsy, including almost all the NCL ones. If successful, this allows an expedited diagnosis of an NCL disorder (avoiding expensive sequential gene testing) or the identification of a non-NCL gene that explains and can guide treatment/counseling of the epilepsy of the patient. Whole exome sequencing (WES) will play an increasingly prominent role in NCL patient identification, particularly in atypical cases.

CLN1 (PPT1; OMIM #256730) Clinical Description The typical presentation is of an infantile onset disorder presenting at around 10 to 18 months of age and characterized by profound neurodevelopmental regression with motoric deterioration, seizures, and visual failure. The course of the disease is rapidly progressive and leads to an early vegetative state with prominent spasticity. The children usually die within the first 10 years of life. There is often microcephaly that may have been evident at birth. Visual impairment can be seen at around 1 year of age and there is blindness by 2 years of age. Optic atrophy, thinned retinal vessels, and a discolored, brownish macula are seen funduscopically. Commonly, myoclonic jerks appear after the first year, and many develop generalized seizures. Hand-knitting movements similar to Rett syndrome are observed early but disappear by 2 years of age. At 3 years of age, children are bedridden, hypotonic, irritable, and spastic. At 5 years of age, severe flexion contractures, acne, hirsutism, and rarely, precocious puberty are observed. Children with CLN1 have hypothermia and bradycardia risk especially during anesthesia. Most children die between the ages of 7 and 13 years.

Other Presentations • Later presentation similar to the variant late-infantile onset. Onset is between 1.5 and 3 years. The main features are behavioral disturbances and cognitive decline. Myoclonic jerks are the most prominent paroxysmal phenomenon. Neurologic regression was associated with shrinkage of cortical structures. • Juvenile form is similar to CLN3 but differs as learning problems present initially rather than visual problems and with regression of acquired skills at an earlier age. In a reported case, Behavioral problems followed by vision changes started at 6 years of age and was followed by isolated myoclonic jerks in arms. Seizures appeared at 17 years of age as well as ataxia and intermittent delusions. Another juvenile form presented in an 8-year-old boy with progressive vision loss followed by cognitive and behavior problems. No seizures have been reported. • An adult presentation, starting after 18 years of age, has been described with mood changes and declining academic performance followed by vision changes (including visual hallucinations). Extrapyramidal syndrome (hypokinesia, bradykinesia, rigidity), an unstable flexed posture, and cerebellar ataxia has also been reported in two French

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sisters. Frank seizures have not been reported up to now. Electroencephalography (EEG) showed generalized reduced activity without periodic abnormalities. The progression has been slow.

Genetics and Pathology The genetic defect is in the palmitoyl protein thioesterase 1 (PPT1) gene, which encodes a soluble lysosomal enzyme (PPT1). The function of this lysosomal thioesterase is to remove fatty acids attached in thioester linkages to cysteine residues in proteins. Proteins containing the fatty acylated cysteine residues are usually found at the inner plasma membrane leaflet. PPT1 is located in the lysosome and taken up in a mannose-6 phosphate-dependent manner. PPT1 has also been shown to be localized in synaptic vesicles in neurons. PTT1 deficiency has been implicated in the disruption of the lysosome-endosomal pathway and in other cellular processes, including endocytosis, vesicular trafficking, synaptic function, lipid metabolism, neural specification, and axon connectivity. PPT1 deficiency seems to be involved in cell susceptibility to apoptotic cell death, in abnormalities in the number, intracellular localization, pattern and morphology of mitochondria, as well as defects in the mitochondrial enzyme activities and adaptive energy metabolism. The accumulation of sphingolipid activator proteins A and D (SAPs) in storage cytosomes is probably a secondary phenomenon. Definitive Diagnosis: PPT1 enzyme analysis with identification of confirmatory PPT1 mutations. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN2 (TPP1; OMIM #204500) Clinical Description CLN2 disease, in its classic form, has an onset between 2 and 4 years of age with epilepsy being the initial symptom in most cases. Seizures can be generalized tonic-clonic, focal, absence, and/or myoclonic (most prominent in the face). Thereafter, there is decline in motor skills, often with ataxia and deterioration of speech and language. Sometimes slowing of developmental milestones is evident before the onset of seizures. Visual loss begins often by the fourth year of life and is slowly progressive. Some patients may retain some visual function during the first decade. An early hypotonia is replaced with severe spasticity with flexion contractures. Autoregulation of vascular tone is lost, resulting in mottled, cold hands and feet and hypothalamic involvement leads to temperature instability. Hyperthermia often leads to un­­ necessary fever evaluation for infectious cause. Copious secretions and shallow breathing due to poor chest wall excursions often lead to pneumonias. Most children are nonambulatory and mute by 5 years of age, totally dependent of caregivers and need g-tube support when swallowing becomes problematic. Sepsis and uncontrollable seizures are frequently the cause of death at the end of the first decade or in the early teens.

Other Presentations • An infantile form of CLN2 has been described with onset before the first year of life. In one case, the patient had microcephaly and hypotonia noted at the fourth month of life with impairment of motor and language abilities. By 4 years of life, the patient developed signs and symptoms of progressive myoclonic encephalopathy along with motor and cognitive deterioration.

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• A slowly progressive autosomal recessive spinocerebellar ataxia with childhood onset, referred to as SCAR7 (OMIM #609270) has been described. • A juvenile form of CLN2 disease has been described with disease onset between 6 and 10 years and a protracted phenotype. In one case epilepsy was absent.

Genetics and Pathology CLN2 is caused by defects in a pepstatin-insensitive lysosomal tripeptidyl peptidase (TPP1) that normally removes tripeptides from the amino terminus of proteins. This protein is a soluble lysosomal hydrolase that is transported to the lysosome by a mannose 6-phosphate receptor mediated pathway. The in vivo substrates of this protein are not fully known, but TTP1 has been reported to initiate degradation of subunit c of the mitochondrial ATPase protein. In CLN2 human disease, the gene mutations are primarily missense ones. They are predicted, based on analysis of the CLN2 protein crystal structure, to disrupt folding and to lead to protein instability and degradation. Definitive Diagnosis: TPP1 enzyme analysis with identification of confirmatory TPP1 pathologic mutations. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN3 (CLN3; OMIM #204200) Clinical Description The juvenile form of NCL (JNCL), the most common form of this group of neurodegenerative disorders, is associated with mutations in the CLN3 gene. The first sign of the disease is decreased central vision caused by progressive retinal degeneration (retinitis pigmentosa) usually observed between 4 and 6 years of age. Initial clinical difficulties may be attributed to behavioral issues until the visual loss is recognized. These children are usually followed initially by ophthalmologists as normal children with retinitis pigmentosa who show better use of their peripheral vision. Patients become completely blind between 10 and 14 years of age but sometimes even later. Retinal findings can include macular retinal pigment epithelium atrophy, pigment stippling, bull’s eye maculopathy, retinitis with the appearance of peripheral bone spicules, and variable disk pallor. Complete blindness is accompanied by a disturbed sleep-wake cycle and insomnia. There is slow cognitive regression that occurs during the initial years of this disorder. A subset of affected children may manifest difficult behavior between the ages of 7 and 9 years. There also can be a variety of behavioral symptoms, including anxiety, aggressive behavior, depression, and visual hallucinations. By at least 10 years of age, cognitive decline is noted. Epilepsy can start as early as 12 years of age, but usually seizures do not occur until 14 years of age. Seizures are primarily generalized tonic-clonic, but patients can also have focal and/or myoclonic seizures. Seizures are relatively easily to control until later stages of the disease. Speech is echolalic with perseveration of speech, and there is dysarthria usually after 15 years of age. Cogwheel rigidity is also present in the limbs, and patients walk with a stooped, shuffling gait reminiscent of patients with Parkinson disease. An intention tremor of variable severity is often observed. Patients generally plateau in their middle teens. A large number of patients become depressed and agitated, and a small number become aggressive and psychotic. Growth and physical maturity are not affected. Late-stage symptoms include drooling, difficulty swallowing, and weight loss. Temperature instability, with episodes of extreme hypothermia down to

92°F, alternating with hyperthermia, points to hypothalamic involvement. Some patients develop a cardiomyopathy or sick sinus syndrome with bradycardia. Most patients succumb in their early to mid-20s to seizures and cardiopulmonary arrest. A small number can survive into the fourth decade of life.

Other Presentations • Variant forms of CLN3 disease are associated with a slower disease progression. In some cases, there may be a long silent period after initial visual failure, and patients may remain free of additional neurologic deficits even for decades. • A complex syndrome characterized by autophagic vacuolar myopathy (AVM), hypertrophic cardiomyopathy, pigmentary retinal degeneration, and epilepsy has been described associated with p.Gly165Glu mutation in CLN3. • Cases of retinitis pigmentosa and cone-rod dystrophy have been associated with CLN3 mutations.

Genetics and Pathology A common 1.02-kb deletion accounts for 85% of disease alleles in the United States cohort and more than 93% of CLN3 cases carry at least one common 1.02-kb deletion allele. This suggests a founder effect. Deletion alleles are associated with production of prematurely truncated products. Compound heterozygous point mutation cases are rare. More than 60 mutations have been reported in the CLN3 gene. CLN3 is an endosomal/lysosomal transmembrane protein that seems to play a pivotal role in the late endosomal/ lysosomal membrane transport system. In neuronal cells, a substantial fraction of CLN3 is additionally targeted to neuronal extensions and synaptosomes in which it has been found to reside in early endosomes, presynaptic vesicles, and in so far unidentified vesicles. CLN3 is highly conserved across species. Proposed functions of CLN3 include a possible role in lysosomal acidification, membrane fusion, vesicular transport, autophagy, apoptosis, proteolipid modification, lipid metabolism, mitochondrial abnormalities, and neurotransmission. Furthermore, CLN3 has been shown to interact with CLN5. CLN3 also appears to play a role in the actin/myosin-associated functions and the microtubular system. Definitive Diagnosis: Molecular testing for the common CLN3 deletion and, if necessary, full CLN3 coding region sequence analysis. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN4 (DNAJC5; AUTOSOMAL DOMINANT KUFS; OMIM #162350) DNAJC5 encodes cysteine-string protein alpha (CSFα) and has been recently identified to cause adult-onset NCL disorder in five kindreds. These familial cases were previously well described with autosomal dominant inheritance.

Clinical Description Symptoms usually start during the fourth decade with myoclonic seizures, dementia, and movement abnormalities. Visual function is preserved. In the Czechoslovakian proband, onset was at 30 years of age with myoclonic epilepsy, generalized tonic-clonic seizures, progressive dementia associated with depression, and early death at 37 years of age. Brain pathology documented autofluorescent storage material and



GRODS by electron microscopy. Skin biopsy did not evidence storage by ultrastructural examination. In the reported Parry family, the proband carrying the DNAJC5 mutation (p.L116del) had a clinical history of irritability and obsessive behavior in mid-20s, seizure onset by 32 years of age, followed by gradual loss of memory and an ataxic gait. Normal ophthalmologic examination was noted up to 34 years of age. Other family members were variably affected by a progressive seizure disorder, ataxic gait, and/or progressive dementia, typically starting in the 20 to 30s. Extended clinical characterization in 19 affected patients from three families was reported. Variable features of generalized of tonic-clonic seizures, myoclonus, ataxia, language dysfunction, and generalized dementia, parkinsonism, and early death were reported.

Genetics and Pathology Two human DNAJC5 mutations have been reported to date, p.L115R and p.L116del. These mutations occur in a highly conserved cysteine-string domain of CSFα. By in silico analysis, the identified human DNAJC5 mutation (p.L116del) has been shown to significantly decrease CSFα membrane binding and lead to intracellular missorting. There is also predicted possible effect on palmitoylation and aggregation propensity. Other studies also support this pathobiology, as the mutants are mistargeted and form palmitoylation-induced membranebound aggregates. How these perturbations lead to the neurodegeneration and clinical phenotype seen in CLN4 disease remains unknown. Definitive Diagnosis: Pathologic mutation identified by molecular sequencing of DNAJC5. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN5 (CLN5; OMIM #256731) Clinical Description CLN5 disease can present as a variant late-infantile NCL. The usual age of onset is between 3 and 7 years, but juvenile and adult-onset cases have also been reported (see later in this chapter). Patients usually present with slight motor clumsiness and hypotonia followed by learning problems. Visual failure and blindness may also be an early sign and by the age of 7 to 9 years, there is significant optic atrophy. Seizures usually appear about age 9. Myoclonus is frequently observed and can appear earlier and independent of generalized or focal seizures. Behavioral problems seem to be infrequent. Ataxia and athetosis can occur later. Children lose the ability to ambulate by about 10 years of age, and death occurs between the ages of 14 and 32 years.

Other Presentations • Juvenile onset: visual failure, loss of strength, and tremor in lower limbs starting between 4 and 9 years of age. Disease progression is relatively rapid evidencing behavioral changes, gradual loss of language, myoclonus and seizures, poorly responsive to valproate and clonazepam. There is then rapid progression with blindness and inability to ambulate. Behavioral disturbances and mental deterioration can also be presenting symptoms. • Adult onset: One patient presented after 17 years of age with cognitive regression, followed by visual deterioration, seizures, and motor difficulties. Two Italian siblings presented in their mid-50s with difficulty walking, dysarthria, and progressive cognitive decline. They carried a homozygous mutation in CLN5.

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• A congenital form presenting at 4 months of age has also been described.

Genetics and Pathology The mutation spectrum is wide but at least 50% of the mutations cause a premature termination codon through small deletions, small insertions, or nonsense changes. There are more than 30 mutations described at this time. Although relatively broad in nature, the clinical phenotype is similar in the different mutation and ethnic groups. The CLN5 protein is a soluble lysosomal glycoprotein that is targeted to the lysosome after cleavage from a pro form. The CLN5 gene expression differs between neurons and glia. High expression in microglia and the very early microglial activation in CLN5 deficient mice suggest a role for CLN5 in microglial function. The function of CLN5 is unknown. It appears to interact with many NCL proteins including PPT1, TPP1, CLN3, CLN6, and CLN8. PPT1 and CLN5 bind F1ATPase in vitro, suggesting mitochondrial involvement or defects in lipid transport. A defective sphingolipid transport has also been demonstrated in peritoneal macrophages of the CLN5 knockout mouse. CLN5 is required for the recruitment of Rab7 and subsequently of the retromer complex required for endosome-to-Golgi trafficking. Definitive Diagnosis: Demonstration of pathologic mutations in CLN5. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN6 (CLN6; OMIM #601780) Clinical Description CLN6 disease presents as other late-infantile variant forms of NCL. The clinical features are similar to the classic late infantile form of NCL. However, a significant proportion of patients have a slightly later onset and a more protracted course with seizures, ataxia, and myoclonus as the leading symptoms. The age of clinical onset of disease is broad with usual range between 2 to 5 years of age. Initial clinical features include motor delay and cerebellar findings of dysarthria and ataxia. Seizures (including myoclonic jerks) start in more than 50% of patients before 5 years of age. Visual failure occurred early in 50% of patients. This disease is rapidly progressive to a vegetative state.

Other Presentations • Teenage-onset progressive myoclonus epilepsy: also associated with generalized tonic-clonic seizures and cognitive decline. No report of visual decline, motor weakness, movement disorders. • Juvenile-onset cerebellar ataxia with seizures: Adolescents presented initially with action tremor, walking difficulty, and ataxia between 7 to 9 years of age. Dysarthria and nystagmus is also present. One patient had generalized tonic-clonic seizures. There was no blindness. • Adult form: presenting from 16 to 62 years of age with a semiology consistent with Kufs type A or B. Type A patients usually present with seizures (progressive myoclonic and generalized tonic-clonic seizures) followed by dementia. Type B patients often present with dementia or psychosis with ataxia or other movement abnormalities. These patients have no vision changes.

Genetics and Pathology The CLN6 gene encodes a nonglycosylated membrane protein that is localized to the ER. Although the gene encodes a

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protein conserved among vertebrates, no functional or sequence homologies have been identified with other proteins. Biologic function and the human pathobiologic dysfunction are poorly understood. It has been postulated that CLN6 mediates selective transport of proteins or lipids that are essential for lysosomal function and acidification. The intracellular degradation of endocytosed proteins appear to be reduced which might be related to the finding of increased lysosomal pH in CLN6-defective fibroblasts. CLN6 also impairs both maturation and enzymatic activity of lysosomal hydrolases. In CLN6 disease, there is accumulation of autofluorescent lipopigments, subunit c of mitochondrial ATP synthase, free cholesterol and phosphosphingolipids and glycosphingolipids in lysosome derived storage bodies. CLN6 protein interacts with other proteins. It binds to CLN5 protein, and it interacts with the collapsing response mediator protein 2 (CRMP-2) that is involved in microtubule assembly and cytoskeletal dynamics during axonal outgrowth. CLN6 also appears to regulate genes involved in cholesterol homeostasis, extracellular matrix remodeling, cell signaling, and the immune/inflammatory responses. There have been more than 70 different mutations reported in the CLN6 gene. Definitive Diagnosis: Identification of pathologic mutations in CLN6 gene. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN7 (MFSD8; OMIM #610951) Clinical Description This disorder was initially called the Turkish variant of lateinfantile NCL as it was described in this ethnic group. It is now recognized to be panethnic as disease cases have been subsequently identified in many countries including Italy, Egypt, India, Croatia, Czech Republic, France, and Greece. This disease is hard to distinguish from other late infantile NCL forms (CLN2, CLN5, CLN6, or CLN8). Its onset is usually between 2 to 7 years of age. Initial symptoms are typically aggressive behavior and severe epilepsy in association with developmental regression. The clinical course is rapidly progressive with the appearance of myoclonus/clonic and nocturnal epilepsy, ataxia, dementia, and blindness. Some cases have presented with onset of visual failure and ataxia. There can be significant personality and behavioral changes as well as sleep disturbances. Rett-like onset and a clinical picture that includes midline stereotypic hands movements have been described. Death usually occurs in late childhood, but some patients survive until the second and third decade. Compared with classical CLN2 disease, CLN7 disease shows a somewhat later onset and a more severe seizure phenotype.

Other Presentations: • Pure visual presentation: It has been shown that heterozygous missense variant mutation p.Glu336Gln in the MFSD8 gene is associated with nonsyndromic autosomal recessive macular dystrophy with central cone involvement. Affected individuals showed no other neurologic features typical for variant late-infantile NCL. Age of diagnosis ranged from 27 to 57 years. • Juvenile: One case has been described. The patient presented with visual failure at age 11 and showed a protracted clinical course. Motor impairment and seizures developed at 24 and 25 years of age, respectively, followed by ataxia at 28 years of age. Mental and speech regression were noticed at 30 and 36 years. Patient was still alive at 43 years of age and wheelchair bound.

Genetics and Pathology The CLN7 protein is encoded by the MFSD8 gene, which appears to be evolutionarily conserved. This protein is targeted to the lysosomes. Based on sequence homology analysis, CLN7 belongs to the major facilitator superfamily of transporters proteins and is presumed to function as a lysosomal membrane transporter. Its substrate specificity is not currently known. There have been more than 30 MFSD8 mutations identified to date. Mutation analysis and biologic study seems to show that the primary consequence of the missense mutations is disturbed functional properties rather than altered subcellular localization. Definitive Diagnosis: Genetic demonstration of pathologic mutations in MFSD8. For further details of diagnostic evaluation, see Tables 48-1 and Figure 48-3.

CLN8 (CLN8; OMIM #600143) Clinical Description CLN8 disease was first recognized in the Finnish population in a childhood epilepsy syndrome, designated northern epilepsy (NE) or progressive epilepsy with mental retardation (EPMR), when neuropathologic studies identified cytoplasmic autofluorescent storage typical of a NCL-like disorder. Initial symptoms are short, frequent, and drug resistant generalized tonic-clonic seizures as well as focal seizures, with onset between 5 and 10 years of age, and cognitive decline. Seizures increase until puberty, when epileptic activity starts to decline but does not remit. Cognitive decline starts 2 to 5 years after the onset of seizures. Intellectual decline is most rapid before adulthood leading to mental retardation by the age of 30 at the latest. After 30 years of age, the patients have difficulties with equilibrium, and they walk slowly using broad-based, small steps. The speech becomes dysphasic in some patients. During childhood and puberty almost half of the patients also suffer from behavioral problems such as irritability, restlessness, disobedience, and inattentiveness. Retinal degeneration, a characteristic finding in NCL, has not been reported in EPMR. However, decreased visual acuity has been detected in some EPMR patients without any obvious ocular abnormality. Age at death varies from 17 years to late middle age, but some survive into the fifth decade. CLN8 disease can present as typical late-infantile variant NCL, showing an earlier onset and more rapidly progressive disease course than EPMR. Symptoms usually start around 2 to 7 years of age with developmental delay (motor and language) and then onset of myoclonic seizures and ataxia. There is rapid disease progression after the onset of disease, and by the age of 8 to 10 years there is severe disability and worsening epilepsy. Focal and generalized seizures as well as absence seizures may evolve, and seizures can become very difficult to control. Frequently, there are behavioral problems. Spasticity, tremors, and extrapyramidal movement abnormalities are common. By 10 years of age, most of the children are wheelchair bound.

Genetics and Pathology Currently, there are more than 25 mutations in the CLN8 gene. The CLN8 protein is localized in the ER and the ER/ Golgi intermediate compartment, and its normal function is unknown. An additional location outside of the ER has been suggested in polarized cells, including neurons. It has been postulated that the CLN8 protein may play a role in sensing, biosynthesis, and metabolism of lipids or protection of proteins from proteolysis as CLN8 is a member of the TLC



(TRAM-LAG1-CLN8) protein family. It is also thought that CLN8 protein may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking, in the synthesis and transport of lipids, vesicular/membrane trafficking, autophagy, and apoptosis. Definitive Diagnosis: Identification of pathologic CLN8 mutations. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN10 (CTSD; OMIM #610127) Clinical Description CLN10 disease seems, at this point, to be a rare disease. It has been primarily recognized as a congenital form of NCL, although severe late-infantile cases have been described. Clinically, these patients present at birth with microcephaly, respiratory failure, rigidity, and status epilepticus. Death occurs within hours to weeks after birth.

Other Presentations: • Juvenile presentation: A reported patient first showed neurodegenerative symptoms of ataxia and visual disturbances at early school age. The ocular fundus showed retinitis pigmentosa, and brain MRI revealed cerebral and cerebellar atrophy. The patient developed progressive cognitive decline, loss of speech, retinal atrophy, and loss of motor functions. By 17 years of age, she was wheelchair bound and severely mentally retarded. Another juvenile phenotype (8 to 15 years of age at presentation) was reported in two consanguineous pedigrees. Clinical features included ataxia, retinitis pigmentosa, cognitive decline, and, in one case, cardiomyopathy. All had distinctive muscle pathology (granulovacuolar material in angular atrophic fibers) in addition to GRODs.

Genetics and Pathology CLN10 disease is caused by CTSD mutations. The CTSD gene encodes the major lysosomal aspartic protease cathepsin D (CTSD). CTSD is transported to the lysosomes via a mannose6-phosphate receptor-dependent and independent manner. CTSD is a lysosomal endopeptidase implicated in several specific physiologic functions, including proteolytic processing of selected polypeptides (hormones, growth factors, cytokines, and enzymes), presenting brain antigens, degradation of cytoskeletal proteins, regulation of autophagy, and apoptosis. CTSD has over 50 different interaction partners from various cellular compartments, suggesting involvement in multiple cellular functions. A number of substrates have been recognized in vitro, including prosaposin that can be cleaved into saposins A, B, C, and D. Saposins A and D are essential cofactors for some sphingolipid hydrolysis proteins. Currently there have been seven different CTSD mutations reported. Definitive Diagnosis: CTSD enzyme analysis with identification of confirmatory CTSD pathologic mutations. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN11 (GRN; OMIM #614706) Clinical Description A report of two siblings with an autosomal recessive late-onset neurodegenerative phenotype, lysosomal NCL-like inclusions, and homozygous progranulin (GRN) mutations established CLN11 as a variant phenotype-genotype from the loss-of-

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function heterozygous GRN mutations seen in autosomal dominant frontotemporal lobar dementia (FLTD) with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP/ GRN; OMIM #607485). The identification of NCL cases with GRN homozygous mutations suggests a link between a rare lysosomal disorder and a common late-onset neurodegenerative disease. It also points to potential lysosomal dysfunction in FTLD and highlights the pleiotropic effects of heterozygous/ homozygous mutations in a single gene. The clinical and neurophysiologic features of the CLN11 disorder, as represented by this familial case report and further reported by Canafogliaet and associates include onset in third decade of a retinal dystrophy with optic atrophy, seizures, myoclonus, and ataxia. There was also evidence in some family members in their late 20s of relatively mild cognitive impairment characterized by borderline executive function difficulties and mild depression. Pathologic characteristics of NCL were identified in skin biopsy (vacuoles, fingerprint lysosomal inclusions). Retinal examination showed pigment epithelial dystrophy, vessel attenuation, and optic neuropathy. OCT showed retinal thinning and disruption of retinal pigment epithelium. ERG was absent in one sibling. EEG was abnormal in both siblings with moderate spike and wave discharges predominantly in the posterior regions against a normal background. VEP showed depressed cortical components and distorted waveforms with flash strobe. Brain MRI (age 22 years) showed severe cerebellar atrophy.

Genetics and Pathology Progranulin (PGRN) is a secreted growth factor involved in the regulation of a number of processes and plays an important role in central nervous system neurodegeneration. PGRN biologic activity is mediated through interactions with a number of proteins. Sortilin is a binding partner for PGRN on the cell surface of cortical neurons. PGRN-sortilin interaction regulates PRGN trafficking as sortilin facilitates endocytosis and delivers PRGN to lysosomes. PGRN is localized to lateendosomes and early lysosomes and appears to have a general role as an activator of lysosomal protein transport and, as such, is important in human pathobiology. PGRN is expressed in motor neurons and seems to promote neuronal survival. It has also been shown to protect against mutant TDP43 induced axonopathy. PGRN may even have an immune-regulatory function.

FTLD Biology/Pathology The FTLDs are the second most common cause of presenile dementia and, as a group, exhibit variant clinical phenotypes, variable penetrance, selective atrophy of the frontal and temporal brain regions, and variant pathologic characteristics. There is significant overlap with motor neuron disease/ amyotrophic lateral sclerosis (FTD-ALS), atypical parkinsonian syndromes, progressive supranuclear palsy, and corticobasal syndromes. These diseases can also be classified by the predominant neuropathological protein that is identified, including FTLD-TDP in which TAR DNA-binding protein-43 is stored. It is within the category of tau- and alpha-synucleinnegative and ubiquitin- and TDP-43-positive cases that those with GRN mutations fall. FTLD-TDP associated with GRN mutations make up about 20% of FTLD-TDP disorders and were first described in autosomal dominant kindreds in association with tau-negative and ubiquitin-positive deposition. GRN mutations were identified in two families with primary progressive aphasia. FTLD-TDP/GRN is now considered one of a spectrum of

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TDP-43 proteinopathies, and a summary of mutations indicate that all reported to date are confirmed or predicted to lead to loss-of-function. This suggests haploinsufficiency as pathobiologic mechanism. Clinically GRN-associated FTLD-TDP evidences phenotypic variability with a breadth of features including early behavioral abnormalities and executive function loss, dementia with loss of expressive language, or semantic language comprehension, with or without loss of motoric speech. Clinical features may show an overlap with amyotrophic lateral sclerosis, parkinsonism, or corticobasal syndrome. These cases are grouped into subtypes depending on the associated pathologic protein aggregates.

NCL-FTLD Overlap FTLD-TDP43/GRN may be a partial deficiency state, with risk of lysosomal dysfunction, whereas in the homozygous state, as seen in CLN11, may represent a more severe pathobiology and include, in addition to the executive dysfunction of FTLD, epilepsy and visual failure. This clinical and pathologic overlap raises the intriguing possibility that lysosomal dysfunction, whether primary or secondary, may be a general feature of neurodegeneration. Further study of the more common human disorder FTLD-TDP/GRN may shed light on the pathobiology of CLN11 and the NCL disorders more broadly. Definitive Diagnosis: Identification of pathologic mutations in GRN. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN 12 (ATP13A2; AUTOSOMAL RECESSIVE KUFS DISEASE; OMIM#610513) Clinical Description ATP13A2 mutations were first associated in the very rare autosomal recessive juvenile parkinsonism with dementia phenotype (Kufor-Rakeb syndrome, PARK9, KRS, OMIM #606693) in 2006. After identification of ATP13A2 (neuronal P-type ATPase gene) mutations in a dog model of late-onset NCL, a Belgian family previously reported as juvenile Parkinson disease (PD) and with typical NCL pathology, was studied by whole exome sequencing and a single homozygous mutation in ATP13A2 was found. In this juvenile PD disorder, the clinical features include pyramidal degeneration, supranuclear gaze palsy, and severe dementia. Putaminal and caudate iron have been demonstrated and complex dystonic features noted in some cases. In the reported CLN12 Belgian family, learning difficulties were noted at about age 8 years. By age 11 to 13 years, there was unsteady gait. Over the next years, myoclonus and worsening ataxia, progressive extrapyramidal features with akinesia, and rigidity and speech difficulties were noted. The proband had severe myoclonus and unintelligible speech and was wheelchair bound by the age of 25 years. In addition to the pyramidal and extrapyramidal dysfunction, there were bulbar signs and evidence of gaze palsy with upgaze restriction. CNS pathologic study showed whorled lamellar inclusions typical of NCL in brain tissue, and there was lipopigment deposition in the retina. Other affected family members showed spinocerebellar ataxia, bulbar signs, extrapyramidal and pyramidal abnormalities, as well as dementia. No visual failure was apparent clinically. A sequence study of ATP13A2 in 28 patients with adult-onset NCL, however, failed to identify pathologic variants. Further pathologic study of KRS patients is needed to confirm that KRS and CLN12 are allelic. This work highlights, however, the potential important paral-

lels between NCL and parkinsonian disorders and suggests that lysosomal pathway disruption may lead to a more general neurodegenerative phenotype.

Genetics and Pathology ATP13A2 is thought to be a lysosomal type 5 P-type ATPase with 10 predicted transmembrane domains. Lysosomal dysfunction in ATP13A2 defective cells appears to impair αsynuclein degradation and would presumably predispose to α-synuclein accumulation and toxicity. There is a growing literature documenting lysosomal dysfunction in Parkinson disease (PD). A review of P-type transport ATPases in PD summarizes dysfunctional ATP13A2 retention in the ER or other aberrant intracellular localization and function as well as reported evidence of impaired ATPase activity. ATP13A2 has also been shown to maintain zinc homeostasis and promote α-synuclein export via exosome, possibly by regulation of α-synuclein-specific exosome biogenesis and to affect mitochondrial function. In animal models, a loss of ATP13A2 leads to lipofuscin accumulation as seen in NCL disorders and αsynuclein aggregation as seen in PD. A wide variety of ATP13A2 interactors have been delineated, most of which appear to have roles in ER translocation, ER-Golgi trafficking, or vesicular transport. Further study of this interactome may yield additional understanding of the complex interactions in the endosomal-lysosomal pathway broadly important to both NCL and PD pathobiology. Definitive Diagnosis: Identification of pathologic mutations by sequencing of ATP13A2. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN13 (CTSF, OMIM#615362) Clinical Description This is, as of yet, a rare identified cause of adult-onset NCL. Two Italian siblings were reported after linkage analysis and whole exome sequencing. Mutation in these siblings identified homozygous mutation in CTSF as in one other nonrelated patient. Clinical features were different in the two sisters. Whereas one presented at 20 years of age with cerebellar syndrome characterized by tremor, ataxia and dysarthria, the other patient did not show signs until 32 years of age with onset of a depression and cognitive decline. Seizures were noted in both later, and the younger sister then developed a progressive dementia associated with marked emotional lability and death at 42 years of age. The second sister showed cerebellar signs in later stages as well as pyramidal and extrapyramidal abnormalities and was bedridden by 51 years of age. A recent familial case with apparent “pseudodominant” transmission has been reported in association with a homozygous CTSF splice mutation. Initial apparent autosomal dominant transmission raised question in this Kufs phenotypeexpressing patients of possible DNAJC5 (CLN4) disease or PSEN1-related early onset Alzheimer disease. Careful history taking and family residence in a small village prompted consideration of potential autosomal recessive inheritance and molecular analysis that led to diagnosis. Clinical features in all reported family members documented presentation in third decade with tonic-clonic seizures followed by dementia in the third to fourth decade. CTSF mutations include 4 missense, one splice, and one frame shift mutation. By structural modeling, these CTSF mutations were predicted to cause loss of CTSF enzymatic activity. It is less clear how a CTSF deficiency may lead to neurodegeneration and lysosomal storage.



Genetics and Pathology Human CTSF was cloned in 1998 and shown to be a member of a subgroup of the papain family of lysosomal cysteine proteases. CTSF is synthesized as an inactive preproenzyme and has been postulated to be targeted to the endosomal/ lysosomal compartment via the mannose 6-phosphate receptor pathway, although original work had suggested that it did not contain the usual cathepsin-related signal sequence for lysosomal targeting and that it might be targeted to the lysosome via an N-terminal signal peptide-independent lysosomal targeting pathway. Recent work also suggests that CTSF may participate in an alternative lysosomal LIMP-2 trafficking pathway. Definitive Diagnosis: Identification of pathologic mutation in the CTSF gene. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

CLN14 (KCTD7; OMIM #611725) Clinical Description More than 10 patients have been described to date. Mutations in the KCTD7 gene are associated with an infantile form of NCL and infantile progressive myoclonus epilepsy. The NCL form has been reported in two siblings who presented with seizures at 8 and 9 months of age. Seizures were myoclonic, precipitated or worsened by fevers and refractory to multiple anticonvulsive drugs. Normal development was until 18 months of age, followed by motor and speech regression. By 12 and 10 years of age, the patients had microcephaly, were nonverbal, and had no spontaneous motoric function. There was no response to visual threat and diminished pupillary light reflexes. One patient had mild, bilateral, optic atrophy. Brain imaging showed global cortical and cerebellar atrophy, and some loss of subcortical white matter. There was NCL-type storage in fibroblasts, neurons and eccrine secretory epithelial cells, and fingerprint and GRODs in approximately15% of analyzed lymphocytes. Both patients died from complications of progressive disease in their mid teens. In the infantile progressive myoclonus epilepsy presentation, the disease onset was under 5 years of age (range 10 months to 3 years), presenting with seizures and/or progressive mental and motor impairment with progressive psychomotor regression to severe mental and motor handicap within 2 years (range 1 to 22 months) after onset of seizures. Seizures were myoclonic, atonic, atypical absence, or/and tonic-clonic seizures. Ataxia also developed later and in one case was the presenting symptom. Retinal findings were normal. No lysosomal storage material compatible with NCL was detected in EM analysis of skin biopsies. In the group series of Kousi and colleagues, brain MRI was normal near disease onset in two patients, atrophic changes were seen in one patient, and nonspecific focal lesions were seen in a second patient (only in more advanced disease stages). EEG revealed prominent epileptiform activity with predominance in the posterior region. The patients were still living in 2012.

Other Presentation • Opsoclonus-myoclonus, ataxia-like syndrome: A patient presented with onset of myoclonus and ataxia by 13 months, and associated with abnormal opsoclonus-like eye movements at 16 months of age. Epileptic activity was seen on EEG 2 years later as well as two episodes of myoclonic seizures. At 4.5 years of age, the patient communicated but did not speak, had limited vocalizations, and understood

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simple commands. He also had mild truncal ataxia and continuous myoclonus. Brain MRI and ophthalmologic evaluation were normal. A compound heterozygous missense mutation and large deletion in the KCTD7 gene was reported.

Genetics and Pathology The KCTD7 gene encodes the potassium channel tetramerization domain-containing protein 7. Currently there are at least eight mutations reported in this gene. KCTD7 expression in the murine brain is strong in the mitral cells of the olfactory bulb, the dentate gyrus and CA1–CA3 hippocampal cells, the deep layers of the cerebral cortex, and the Purkinje cells of the mouse cerebellum. The KCTD7 protein is located in the cytoplasm, with the highest expression near the nucleus and a partial localization at the plasma membrane. It has been shown that KCTD7 overexpression in transfected primary cultures of murine neurons hyperpolarizes the cell membrane and reduces the excitability of transfected neurons in patch clamp experiments. Therefore mutations in KCTD7 are consistent with a depolarizing resting membrane potential and increased excitability. It is hypothesized that KCTD7 is required for the proper permeability of a nongated potassium channel that functions in a voltage range around the resting potential. KCTD7 also associates with Cullin-3, suggesting that KCTD7 could be part of an E3 ubiquitin ligase multiprotein complex. Definitive Diagnosis: Diagnosis is made by finding mutations in the KCTD7 gene. For further details of diagnostic evaluation, see Table 48-1 and Figure 48-3.

Management and Treatment of NCL Disorders Unfortunately, there is no cure for the NCL disorders, and management is mainly symptomatic for the range of clinical problems, including seizures, sleep-related problems, malnutrition, gastroesophageal reflux, pneumonia, sialorrhea, hyperactivity, behavior problems, psychosis, anxiety, spasticity, parkinsonian symptoms, and dystonia. A truthful discussion with the caregivers should include goals of care and when the moment is right code status to avoid sometimes unnecessary suffering for the patient and family. There should be surveillance for swallowing problems and microaspirations due to the risk of pneumonia/sepsis as well as x-ray surveillance of hip joints and spine when there is significant immobility or when the patient is wheelchair bound. Seizures. It is one of the hallmark manifestations and can cause the most anxiety in the family. There is no single anticonvulsant medication that will work for all the NCL disorders. An anticonvulsant medication should be selected in discussion with the family and based on the stage of the disease, age of the affected individual, and quality of life assessment. A goal of complete control of seizures may be unrealistic in this disorder. A balance between number of seizures and sedation (which is one of the most common side effects of the anticonvulsant medications) should be discussed with the family and patient (if able to communicate). In a survey of 60 patients with CLN3, one of the largest to date, lamotrigine and valproic acid showed relatively good seizure control in most patients. However, there was no rationale for the choice of these specific anticonvulsive drugs. Importantly, 54% of patients had refractory epilepsy requiring combination therapy by the middle second decade of age. The pathophysiology of epileptogenesis is poorly understood in NCL, and empiric trial of medication is common. Newer anticonvulsive medications may be more beneficial, but there are no studies in this respect for the

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NCLs. Levetiracetam and clobazam should be considered (personal experience). Benzodiazepines may be of benefit for seizures, anxiety, spasticity, and sleep difficulties. However, the main side effect is somnolence; therefore; again, a balance between symptoms and sedation is imperative. Trihexyphenidyl has been used to improve dystonia and sialorrhea. Antidepressants and antipsychotic agents are sometimes indicated for those with severe mood problems and/or aggression. Unfortunately, most of the patients become bedridden and, because of swallowing dysfunction and aspiration, pneumonia is a risk. Patients with swallowing problems may benefit from placement of a gastric feeding tube. Children with NCL disorders benefit from school attendance for socialization and stimulation, even late in the disease. This also affords respite for caregivers. Physical therapy, either at home or at school, is important to avoid painful contractures for the longest period of time possible. The use of augmentative therapies as visual failure occurs and even the teaching of Braille may help in education even for temporary benefit in the context of the progressive dementia. Quality of life assessment in these educational interventions is important. The use of digital tools (tablet, speech-assist devices) may help in communication. Genetic Counseling. (This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with genetics professional). The NCL disorders are autosomal recessive with the exception of one form of adult disease (CLN4) that is autosomal dominant. Once a mutation has been identified in a patient, obtaining parental samples to confirm carrier status is recommended. This will allow family planning for the family as well as discussion with related family members of the risk of inheritance. Siblings of an affected patient have a 25% of being affected, 50% of being an asymptomatic carrier, and 25% of not being a carrier. When the sibling is underage, a discussion with the parents, taking into account current guidelines of national/international genetic associations, is of importance before presymptomatic genetic testing of a minor child. This is particularly controversial and more challenging when the proband has a later onset presentation, and there is a younger sibling. There are genetic guidelines that one should take into account along with the wishes of the family. Patients with infantile NCL, late-infantile NCL, and classic juvenile NCL do not reproduce. Very rarely, individuals with atypical juvenile NCL reproduce, but they are obligate carriers.

An autosomal dominant adult CLN individual has an affected parent. However, an AD adult-onset NCL may have the disorder due to a de novo mutation. Germline mosaicism can also be a cause of not finding a mutation in the parents of an affected individual. Of note, the family history of an affected individual may be negative due to failure to recognize the disorder in a family member, death before onset of symptoms, or late-onset of the disease. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Anderson, G.W., Goebel, H.H., Simonati, A., 2013. Human pathology in NCL. Biochim. Biophys. Acta 1832 (11), 1807–1826. Haltia, M., Goebel, H.H., 2013. The neuronal ceroid-lipofuscinoses: A historical introduction. Biochim. Biophys. Acta 1832 (11), 1795–1800. Jadav, R.H., Sinha, S., Yasha, T.C., et al., 2014. Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes. Pediatr. Neurol. 50 (1), 85–93. Kollmann, K., Uusi-Rauva, K., Scifo, E., et al., 2013. Cell biology and function of neuronal ceroid lipofuscinosis-related proteins. Biochim. Biophys. Acta 1832 (11), 1866–1881. Kousi, M., Lehesjoki, A.E., Mole, S.E., 2012. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum. Mutat. 33 (1), 42–63. Lee, J., Giordano, S., Zhang, J., 2012. Autophagy, mitochondria, and oxidative stress: crosstalk and redox signaling. Biochem. J. 441, 523–540. Mole, S., Williams, R., 2013. Neuronal ceroid-lipofuscinoses. In: Pagon, R.A., Adam, M.P., Ardinger, H.H., et al. (Eds.), GeneReviews. University of Washington, Seattle, Seattle. Mole, S., Williams, R., Goebel, H.H. (Eds.), 2011. The Neuronal Ceroid Lipofusinoses, second ed. Oxford University Press, Oxford.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 48-3 NCL diagnostic workup.

49 

Channelopathies Kelly Knupp and Amy R. Brooks-Kayal

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Channelopathies are a group of genetically and phenotypically heterogeneous neurologic disorders that result from genetically determined defects in ion-channel function. These are considered heterogeneous because mutations in the same gene can cause different diseases and mutations in different genes can result in the same disease phenotype. Mutations of ion channels can alter the activation, ion selectivity, or inactivation of the mutated channel. Neurologic manifestations of channelopathies fall into several clinical phenotypes: epilepsy, pain, migraine, ataxia, movement disorders (all covered in this chapter; see Table 49-1), and muscle disorders (myotonia and weakness; covered in Chapter 151). Ion channels are transmembrane glycoprotein pores that control the excitability of neurons and muscle cells by mediating the flow of charged ions in and out of cells. Channels are typically composed of different protein subunits, each encoded by a different gene. There are two major classes of ion channels: voltage-gated and ligand-gated. Voltage-gated ion channels are activated and inactivated by changes in membrane voltage and are identified according to the principal ion conducted through the channel (e.g., sodium, potassium, calcium, or chloride). Activation and opening of voltage-gated channels have different effects (depolarization, repolarization, or hyperpolarization of the cell membrane), depending on what ion they gate and that ion’s charge, the electrochemical gradient for that ion (which determines in which direction the ion flows when the channel is opened), and where the channels are located on the cell. Sodium channel opening results in the generation of the action potential (i.e., depolarization). Opening of potassium channels repolarizes cell membranes after action potential firing and maintains the resting membrane potential. Calcium channels are important for the generation of muscle contraction, neurotransmitter release, and intracellular signaling via second messengers. Opening of voltage-gated chloride channels results in the hyperpolarization of cells. Ligand-gated channels are heterogeneous complexes composed of multiple protein subunits that are activated by the binding of their respective agonists. Several ligand-gated channels are present in the peripheral and central nervous systems. Gamma-aminobutyric acid (GABA)A receptors mediate most of the fast synaptic inhibition in the brain beyond the fetal and early neonatal periods. They are anion selective and gate primarily chloride, which flows into the cell, causing hyperpolarization upon GABAA receptor activation. Glutamate is the primary excitatory neurotransmitter in the central nervous system and binds to three types of ligandgated, cation-selective receptor channels: N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate. Glutamate receptors gate either sodium only (most AMPA and all kainate receptors) or sodium and calcium (NMDA receptors and some subtypes of AMPA receptors). Nicotinic acetylcholine receptors are nonselective cation channels permeable to Na+ and K+, and Ca2+ in some subtypes; they are located on certain neurons and on the

postsynaptic side of the neuromuscular junction. Opening of nicotinic receptors causes depolarization of the plasma membrane and activation of voltage-gated ion channels that can affect the release of neurotransmitters and activate intracellular signaling cascades.

EPILEPSY SYNDROMES Ion channelopathies, involving sodium, potassium, and calcium channels, have been increasing identified as an etiology of epilepsy. Ligand-gated channels such as GABA receptors and nicotinic receptors have also been implicated. Identifying these syndromes will likely lead to unique treatments for specific syndromes thus entering an era of precision medicine.

Dravet Syndrome Clinical Features Dravet syndrome has a classic presentation in most cases. Children begin to have seizures in the first year of life, typically in the setting of fever and characterized by prolonged sei­ zures with hemiconvulsions. Alternating laterality of seizures can occur with each event, and seizures often evolve into status epilepticus. In the second year of life, other seizure types begin to emerge, including absence, myoclonic, and generalized tonic-clonic seizures, and partial seizures that now occur without fever. Tonic seizures are rare and, if they do occur, tend to be brief and nocturnal. Photo-induced seizures occur in some of these children, and self-induced seizures have been reported. Throughout childhood, elevated body temperature and anticonvulsants that are sodium channel blockers (e.g., carbamazepine, phenytoin, fosphenytoin, oxcarbazepine, and lamotrigine) exacerbate seizures. Seizure control is rarely attained. Episodes of status are com­ mon, including “obtundation status” (Brunklaus and Zuberi, 2014). The phenotype of the clinical seizure and electrographic correlation may not be congruent, making seizure classification difficult (Kim et al., 2014). Development of the affected child is universally normal in the first year of life. As seizure types become more varied and more frequent, there is cessation of developmental progress, which can be misinterpreted as developmental regression. Moderate to severe intellectual impairment is present in many children, and the degree of cognitive impairment is somewhat associated with seizure control (Wolff, Casse-Perrot, and Dravet, 2006). Hyperactivity and autistic traits present in the toddler years. As children enter into adolescence, hyperkinetic behavior tends to improve and is replaced with overall slowed behavior. Not all children with Dravet syndrome present with classic features, as described earlier. Myoclonic seizures need not be present for a diagnosis to be made. These seemingly less affected children continue to be exquisitely sensitive to temperature and sodium channel–blocking anticonvulsants. In some cases these features may suggest the diagnosis. Recently this syndrome was recognized in a large percentage of children

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TABLE 49-1  Channelopathies Associated with Clinical Syndromes in Pediatric Neurology Gene Type

Epilepsy

Headache

Sodium

SCN1a SCN1b SCN2a SCN2A1 SCN9a

SCN1A

Chloride

GABAa CLCN2

Potassium

KCNQ2 KCNQ3 KCNJ11 KCNJ10 KCNMA1

KCNK18

KCNA1 KCNC3 KCND3

Calcium

CACNA1A CACNB4

CACN1A

CACN1A

Ligand-gated channels

GABRG2 GABRB3 GABRD GABRA1 EFHC1 LGI1 CHRNA4 CHRNA7 GRIN2A GPR98 CHRNB2

PRRT2 ATP1A2

ITPR1

(11 of 14) presenting with seizures and encephalopathy after receiving vaccines (vaccine encephalopathy) (Berkovic et al., 2006).

Genetics/Pathophysiology Mutations in the sodium channel gene SCN1A are found in approximately 80% of children with a clinical diagnosis of Dravet syndrome. Most have a de novo mutation, although some of the families have a higher-than-expected history of febrile seizures. There remains equipoise regarding how SCN1A mutations are predicted to cause a loss of sodium channel function, logically a cause of hypoexcitability of individual neurons, could lead to network hyperexcitability and, consequently, seizures. Some research suggests that this seeming contradiction can be explained by the selective loss of SCN1A expression and decreased sodium channel function only in inhibitory interneurons (Yu et al., 2006), causing inhibitory dysfunction and secondary hyperexcitability. Other recent studies suggest that loss of SCN1A occurs more broadly and may result in compensatory increases in other sodium channels that produce a net increase in sodium channel currents leading to hyperexcitability (Liu et al., 2013).

Clinical Laboratory Tests Electroencephalogram (EEG) findings are typically normal in the first year of life, but evolve to demonstrate generalized and multifocal abnormalities. A photoconvulsive response can be seen, and diffuse background slowing can become more prominent as children age. No characteristic pattern is diagnostic of Dravet syndrome, as is seen in Lennox–Gastaut or Doose syndrome; in fact, there can be some overlap between these syndromes and Dravet syndrome, making accurate diagnosis challenging. Magnetic resonance imaging (MRI) in patients with Dravet syndrome is usually without any focal

Ataxia

Pain Syndrome SCN9A SCN11A SCN10A

CLCN2

abnormalities (Striano et al., 2007). Genetic testing is appropriate in patients suspected to have Dravet syndrome. Early diagnosis avoids extensive and expensive metabolic testing and inadvertent exacerbation of seizures by certain medications, and provides prognostic information for the family.

Treatment Seizure control is the primary treatment goal in this disorder. Medications that block the sodium channel exacerbate seizures and should be avoided in most patients (Guerrini et al., 1998). Topiramate, valproic acid, benzodiazepines, and levetiracetam have proven helpful. Combination therapy with stiripentol, clobazam, and either Depakote or topiramate has been reported to be more effective than other combinations of medication (Chiron et al., 2000). Acetazolamide has not been shown to be beneficial. A recent report suggests that verapamil, a calcium channel blocker, may be helpful, but more research is required (Iannetti et al., 2009). Fenfluramine was also successful in a small cohort and requires further study (Ceulemans et al., 2012). Nonpharmacologic treatments, such as vagal nerve stimulation or ketogenic diet, have been useful in some patients. Anecdotal reports in the media suggest that cannabidiol (CBD), a component of marijuana, may reduce seizures in some children, although a retrospective case series found that artisanal CBD oils did not result in a substantial reduction in seizures in most children (Press and Chapman, 2015). Clinical trials of pharmaceutical-grade CBD products are now under way. Avoidance of hot temperatures, both environmental and elevated body temperature, has been used by many families to reduce seizures. Because of the severity of the cognitive impairment, appropriate support must be initiated for the family. Medications for behavioral issues may also be necessary (see Chapters 59 and 60). Cardiac surveillance may also be indicated, given laboratory models of cardiac dysfunction (Auerbach et al., 2013). Because there is a high rate of



sudden unexplained death in this patient population, counseling should be provided.

Generalized Epilepsy with Febrile Seizures Plus Clinical Features Generalized epilepsy with febrile seizures plus (GEFS +) is a familial epilepsy syndrome characterized by febrile seizures in childhood in several generations of family members, often with continuation of febrile seizures into adulthood. In addition, afebrile seizures are often present. Seizure types include generalized tonic-clonic, myoclonic, absence, and atonic seizures. There is variable penetrance of seizures in these familial cohorts. Phenotype also varies among family members. Seizure resolution often occurs by age 12. The majority of these patients have normal development and intelligence.

Genetics/Pathophysiology SCN1B mutations were first reported in a large family cohort (Wallace et al., 1998). Mutations in other sodium channels— SCN1A (Escayg et al., 2000) and SCN2A (Sugawara et al., 2001)—have been found subsequently. The majority of these have been point mutations. In patients with SCN1A mutations, a difference in phenotype from GEFS + and Dravet syndrome can often be predicted, given the location of the mutation (distance from the pore) and alteration in transcription of the gene. Sodium channel mutations do not account for all of the mutations in GEFS +; there also have been reports of mutations identified in two GABAA-receptor subunit genes, GABRG2 and GABRD (gamma 2 and delta subunits) (Harkin et al., 2002).

Treatment There has been little published discussion of the treatment of these syndromes. For patients with sodium channel mutations, avoidance of sodium channel blockers is wise. Treatment when necessary with broad-spectrum anticonvulsants is thought to be useful. Avoidance of temperature changes and routine use of fever control measures may be of some benefit.

Benign Familial Neonatal Seizures Clinical Features Benign familial neonatal seizures are an autosomal-dominant epilepsy presenting with seizures in the first or second week of life, most commonly starting on day of life 2 or 3, resolving within weeks to months. Most seizures have stopped at 4 to 5 months of life. Seizures are usually multifocal clonic seizures or focal seizures. The feature suggesting this entity is the presence of similar seizures in parents and first-degree relatives, occurring at the same age. Development is characteristically normal during this time period, and after seizures stop. Fifteen percent of children will develop epilepsy later in life, usually in childhood or as a young adult. Some children progress to medically refractory epilepsy with encephalopathy (Steinlein, Conrad, and Weidner, 2007).

Genetics/Pathophysiology Mutations in potassium channels KCNQ2 (Singh et al., 1998; Biervert et al., 1998) and KCNQ3 (Charlier et al., 1998) (found on chromosomes 20 and 8, respectively) have been reported in families with benign neonatal seizures. The age specificity of the seizures in this disorder is thought to emanate from brain developmental changes during the neonatal period, when potassium channels play a critical role in

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inhibition that is rapidly replaced by the action of GABA receptors over the first several months of life.

Clinical Laboratory Tests EEG generally demonstrates normal interictal features, although at the time of seizure there is an electrographic correlate. MRI is expected to be normal. Other causes of seizures, such as neonatal infection and metabolic abnormalities, should be excluded.

KCNQ2 Encephalopathy Clinical Features KCNQ2 encephalopathy presents in the first days of life with poorly controlled seizures, which may resolve within the first year of life, but with residual and often profound intellectual impairment. This syndrome has been increasingly recognized as a severe neonatal encephalopathy and can have an overlapping phenotype with Ohtahara syndrome and West syndrome. Seizures are tonic and focal in nature, with some children having myoclonic seizures and infantile spasms. Autonomic changes can be an associated feature with seizures and may include apnea and bradycardia. Most children have EEG findings of a burst-suppression pattern that resolves and is replaced with diffuse slowing and multifocal epileptiform discharges. MRI findings have been reported in several cohorts, and although not universal, many will have thinning of the corpus callosum, frontal lobe atrophy, and nonspecific white-matter findings. Seizures often resolve in the first year of life. Varying degrees of intellectual delay are present, ranging from mild to severe (Weckhuysen et al., 2013).

Genetic/Pathophysiology De novo mutations in KCNQ2 have been reported. Similar mutations rarely have been present in children with benign familial neonatal seizures. Mutations are present in highly conserved areas, leading to loss of function.

Treatment Some children have responded to carbamazepine and other sodium (Na) channel blockers. One child is reported to have had cessation of seizures with retigabine (Barrese et al., 2010). This treatment requires more research, but may be promising.

Developmental Delay, Epilepsy, and   Neonatal Diabetes Developmental delay, epilepsy, and neonatal diabetes (DEND) is a rare syndrome, presenting with neonatal diabetes, developmental delay, seizures, and mild dysmorphic features, and has been associated with a mutation in the KCNJ11 gene that encodes for a subunit of the adenosine triphosphate (ATP)–sensitive potassium channel. This channel is found on pancreatic islet cells and in neurons. Neonates with this disorder usually present with diabetes and subsequently develop seizures and global intellectual impairment. Dysmorphic features, including downturned mouth, bilateral ptosis, prominent metopic suture, and contractures, have also been described (Gloyn et al., 2004). Infantile spasms can present in some children (Bahi-Buisson et al., 2007), in addition to other seizure types, such as tonic-clonic and myoclonic seizures. Seizures have been refractory to traditional antiseizure medications. In contrast, patients are responsive to treatment with sulfonylurea medications, such as glibenclamide, leading to

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improvement in the effects of diabetes, developmental outcomes, and seizure frequency and effects.

Other Genetic Generalized Epilepsies Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Autosomal-dominant nocturnal frontal lobe epilepsy is a familial epilepsy characterized by frontal lobe seizures that typically occur at night and phenotypically present as arousal from sleep with bizarre hypermotor behaviors, such as spinning, thrashing, and rocking. Seizures can be numerous. Nicotinic receptor mutations have been found in many of these familial cohorts (Steinlein et al., 1995), although there are several families for which no gene mutation has been identified. These ligand-gated receptors allow sodium and potassium to cross the cell membrane. Many patients are responsive to carbamazepine and phenytoin.

Benign Familial Infantile–Neonatal Seizures Benign familial infantile–neonatal seizures is an epilepsy syndrome that has been described as being similar to benign neonatal seizures, but it occurs at a slightly older age. Mutations have been found in a sodium channel, SCN2A1, in some cohorts (Herlenius et al., 2007).

Childhood Absence Epilepsy Childhood absence epilepsy has been linked to mutations in GABA receptors (GABRA1 and GABRG2) (Baulac et al., 2001; Wallace et al., 2001) and chloride channels (CLCN2). Mutations have also been described in a calcium channel, CACNA1H. The families with CLCN2 also had members with generalized tonic-clonic seizures on awakening and juvenile myoclonic epilepsy (Baykan et al., 2004).

Juvenile Myoclonic Epilepsy Juvenile myoclonic epilepsy is a seizure disorder that usually presents in adolescents with myoclonic seizures that are more likely to occur in the early morning after awakening, and generalized tonic-clonic seizures that also tend to occur in the morning hours. Several gene mutations have been found in these patients, although the majority of patients have yet to have an underlying etiology determined. It appears that, similar to childhood absence epilepsy, this is likely a polygenic disorder. Channels that have been identified include GABA receptors (GABRA1 and GABRD) (Cossette et al., 2002), calcium channels (CACNB4) (Escayg et al., 2000), and chloride channels (CLCN2) (Baykan et al., 2004). In addition, a gene that is not a direct channel gene but enhances calcium influx into the cell and can stimulate programmed cell death (EFHC1) (Suzuki et al., 2004) has also been identified as being involved in this epilepsy syndrome.

FAMILIAL PAIN SYNDROMES Several pain syndromes have been associated with sodium channel mutations. This is not surprising, as sodium channels are located on spinal sensory neurons in the dorsal root ganglion (Bennett and Woods, 2014).

Clinical Features Inherited Erythromelalgia, Primary Erythermalgia.  Inherited erythromelalgia (IEM), or primary erythermalgia, is a pain syndrome characterized by episodes of redness and swelling of the hands and feet, associated with burning pain. These episodes can be triggered by mild warmth or exercise.

Erythema can become constant, and edema may be associated (Drenth and Waxman, 2007; Cook-Norris et al., 2012). Age of onset can vary from childhood to adulthood, and can be familial or sporadic (Drenth et al., 2008; Han et al., 2009), with about 15% being familial and having autosomaldominant inheritance. Paroxysmal Extreme Pain Disorder.  Paroxysmal extreme pain disorder (PEPD), formerly called familial rectal pain, is characterized by episodic severe pain, which commonly occurs in the perirectal region but can also involve the genitals, limbs, and face, especially the periorbital region. Stimulation of the region by bowel movements, contact in the perianal region, eating, or sudden changes in temperature can induce pain episodes. Flushing, harlequin skin changes, pupillary abnormalities, and cardiac abnormalities can occur at the time of the pain episode. Tonic episodes that are nonepileptic in nature can occur with the pain episodes and are secondary to the intense severity of the pain. Weakness has been present with pain in the limbs, lasting up to 24 hours after the pain has resolved. Constipation is a common problem because the episodes are induced by passing stool. Symptoms have been reported as early as at the time of delivery, and occurrence in utero is suspected (Fertleman et al., 2007). Congenital Indifference to Pain.  Congenital indifference to pain (CIP) is a syndrome characterized by insensitivity to pain and, in some cases, loss of smell. A more severe form has been reported that is associated with anhydrosis; intellectual delay and hypotonia may be present in these children. Individuals with anhidrosis can experience episodes of hyperthermia that can be life-threatening if not recognized. Awareness of a stimulus is present, but pain is not experienced in relation to the stimulus. Because of this altered response to pain, fractures, burns, and other significant injuries can go unnoticed. Fractures, foot injuries, and injuries to the fingertips may be present for several days without awareness of injury. Individuals can differentiate between hot and cold, but lack the ability to determine whether a temperature is extreme enough to cause injury. Signs of peripheral neuropathy on clinical examination or neurophysiological testing and autonomic nervous system abnormalities are lacking (Golshani et al., 2014).

Genetics/Pathophysiology Mutations in SCN9A, a sodium channel, have been associated with IEM, PEPD, and CIP. Mutations thought to lead to hyperexcitability of the sodium channel have been identified in IEM and PEPD. Mutations in IEM allow the channel to be activated by smaller-than-normal depolarizations, and the channel remains open longer after activation (Drenth et al., 2005). Mutations in PEPD lead to prolonged action potentials and repetitive neuronal firing when stimulated (Jarecki et al., 2008). Mutations in this same channel that lead to loss of function are associated with CIP (Goldberg et al., 2007; Nilsen et al., 2009). The alteration of function created by the mutation leads to different phenotypes and different pain syndromes.

Treatment Treatment for IEM, including use of sodium channel blockers, has not been very effective, although there have been reports of some relief with lidocaine, mexiletine (Choi et al., 2009), and carbamazepine (Fischer et al., 2009). Recently a pilot study of an Na channel antagonist demonstrated some benefit, although further studies are needed (Goldberg et al., 2012). Response to medications may vary with different mutations. Carbamazepine has been helpful in treating PEPD, but topiramate and gabapentin have not.



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Congenital indifference to pain does not have a specific treatment, but patients need to be observed carefully for occult injuries, including fractures, joint injuries, and burns, in addition to mouth and hand injuries. Establishing a daily routine to monitor for injuries is important.

sants, beta blockers). Limited correlation exists between drug response and hemiplegic migraine type. There have been reports of the use of valproic acid and lamotrigine in FHM2 with good response, (Pelzer et al., 2014), and corticosteroids (Sanchez-Albisua et al., 2013); further study is needed.

MIGRAINE AND ATAXIA SYNDROMES Familial Hemiplegic Migraines Clinical Features

Episodic Ataxia Clinical Features

Familial hemiplegic migraine often presents in the first or second decade of life with severe headache, often unilateral, and is associated with unilateral weakness typically lasting 24 hours or, rarely, several days. Extreme symptoms of prolonged duration (30 days) and coma are rare, as are seizures during hemiplegia. The clinical presentation can be less impressive with unilateral paresthesia and hemianopsia (Roth et al., 2014). Ataxia and dysarthria have been reported between attacks, or for a short duration while recovering from an attack. Family members also have occasionally had a prior diagnosis of benign paroxysmal torticollis of infancy (Giffin et al., 2002), although this is rare, and it is unclear whether this is or is not related to the gene mutation. Diagnostic criteria established by the International Headache Society include migraine with aura with motor weakness and at least one firstor second-degree relative with similar symptoms. Genetic information allows for further subtyping. Headaches can have features of basilar migraine, including vertigo, visual symptoms, tinnitus, dysarthria, and ataxia. Some patients have been reported to have progressive ataxia later in life (Terwindt et al., 1998). In addition, cognitive impairment has been noted in affected patients (Marchioni et al., 1995).

Genetics/Pathophysiology Genetic etiology has been linked to a calcium channel mutation (CACNA1A) (Stam et al., 2008); people with mutations of this gene are more likely to have ataxia and coma, and to be more prone to delayed cerebral edema after minor head injury (Terwindt et al., 1998; Kors et al., 2001; Stam et al., 2009). Mutations in CACNA1A (FHM1) also have been reported in patients with alternating hemiplegia of childhood, which phenotypically has some overlap with hemiplegic migraine (de Vries et al., 2008), and in patients with episodic ataxia type 2 (see following discussion) and spinocerebellar ataxia type 6. Mutations in ATP1A2 (FHM2), SCN1A (FHM3), and PRRT2 (Riant et al., 2012) also have been found in some patients with this clinical syndrome (De Fusco et al., 2003; Dichgans and Markus, 2005).

Clinical Laboratory Tests MRI findings are not pathognomonic, but cerebellar atrophy (Terwindt et al., 1998), particularly in the superior cerebellar vermis, has been reported. Magnetic resonance (MR) spectroscopy of this region has demonstrated metabolic abnormalities consistent with neuron loss (Dichgans and Markus, 2005). EEGs during events can demonstrate slowing in the affected hemisphere, and mild asymmetries with minimal unilateral slowing have been noted on EEGs performed between episodes (Marchioni et al., 1995).

Treatment Most commonly, patients are treated with acetazolamide, calcium channel blockers such as verapamil, or a trial of other standard migraine prophylactic drugs (tricyclic antidepres-

This disorder is characterized by intermittent periods of ataxia (see also Chapter 91). There are two commonly described disorders: episodic ataxia type 1 and type 2. Phenotypic presentation differs slightly in each case, allowing clinical separation. Episodic ataxia type 1 is characterized by frequent, brief episodes of ataxia, involving ataxic gait and slurred speech, precipitated by strong emotional outbursts, sudden movements, and exercise. Episodes can last several seconds to minutes in duration and can occur several times a day. In addition, there usually is evidence of muscle hyperexcitability manifested by the presence of myokymia, both clinically and electrographically. Some family members have reported seizures and isolated myotonia (Graves et al., 2014). Episodic ataxia type 2 primarily involves truncal ataxia, with more prolonged periods of ataxia lasting hours to days. Eye movement abnormalities are sometimes present. Episodes can be induced by stress or exercise. Myokymia is rare. Some patients can have subtle, slowly progressive cerebellar features. Cerebellar atrophy has been reported. Migraine symptoms can be present in both types of episodic ataxia, but are more common in type 2; migraine symptoms may have many features consistent with basilar migraine, including vertigo, nausea, and occipital pain (Nachbauer et al., 2014).

Genetics/Pathophysiology Both disorders are inherited in an autosomal-dominant fashion, with incomplete penetrance. Type 1 has been associated with point mutations in KCNA1 (Lassche et al., 2014; Browne et al., 1994). This is a potassium channel that has no intervening introns. Episodic ataxia type 2 has been linked to mutations in CACNA1A (a calcium channel). Mutations that interfere with splicing or lead to a premature stop have been linked to the episodic ataxia type 2 phenotype (van den Maagdenberg et al., 2002).

Clinical Laboratory Tests Electromyography (EMG) is helpful with episodic ataxia type 1 in identifying and/or confirming myokymia. MRI also may be useful, especially in episodic ataxia type 2, and should be performed to rule out other underlying etiologies of ataxia. Cerebellar vermis atrophy has been reported in episodic ataxia type 2.

Treatment Acetazolamide and carbamazepine have both been reported to lead to reduction in the frequency and severity of events.

Spinocerebellar Ataxia Clinical Features Several progressive ataxias have been described and reported as resulting from a variety of etiologies (see Chapter 92). Channelopathies are responsible for one subtype, now called spinocerebellar ataxia type 6. This type presents as a slowly progressive cerebellar degeneration, with ataxia, dysmetria,

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and other cerebellar signs as prominent clinical features. Spasticity and cranial neuropathies are not prominent. There can be some overlap with episodic ataxia type 2, with episodes of truncal ataxia lasting for several hours to days and often precipitated by stress or exertion. There also may be some features associated with basilar migraine or familial hemiplegic migraine.

Genetics/Pathophysiology Spinocerebellar ataxia type 6 has been reported to be associated with triplet repeats in the CACNA1A gene (Zhuchenko et al., 1997). Unlike the gene changes associated with other triplet-repeat disorders, mutations in SCA6 seem to be relatively stable, and the expansion is smaller than that typically seen in association with an abnormal phenotype. It is unclear if symptoms are related to channel dysfunction or the cytotoxic effects of the repeat, as is seen in other diseases. The overlap between these phenotypes suggests that there is a pathologic role in the abnormal function of the calcium channel. Mutations in this gene also have been reported in cohorts with familial hemiplegic migraine, which usually have point mutations. Cohorts with episodic ataxia type 2 also have been reported to have mutations in this gene that often lead to splicing errors or premature stops.

Clinical Laboratory Tests MRI is helpful because many patients with symptomatic episodic ataxia will have cerebellar atrophy.

Treatment Supportive treatment is recommended. Patients with episodes of headaches may be helped by the treatments outlined for the episodic ataxias and familial migraine syndromes. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Auerbach, D.S., Jones, J., Clawson, B.C., et al., 2013. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS ONE 8 (10), e77843. Bahi-Buisson, N., Eisermann, M., Nivot, S., et al., 2007. Infantile spasms as an epileptic feature of DEND syndrome associated with an activating mutation in the potassium adenosine triphosphate (ATP) channel, Kir6.2. J. Child Neurol. 22 (9), 1147–1150. Barrese, V., Miceli, F., Soldovieri, M.V., et al., 2010. Neuronal potassium channel openers in the management of epilepsy: role and potential of retigabine. Clin. Pharmacol. 2, 225–236. Baulac, S., Huberfeld, G., Gourfinkel-An, I., et al., 2001. First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene. Nat. Genet. 28 (1), 46–48. Baykan, B., Madia, F., Bebek, N., et al., 2004. Autosomal recessive idiopathic epilepsy in an inbred family from Turkey: identification of a putative locus on chromosome 9q32-33. Epilepsia 45 (5), 479–487. Bennett, D.L., Woods, C.G., 2014. Painful and painless channelopathies. Lancet Neurol. 13, 587–599. Berkovic, S.F., Harkin, L., McMahon, J.M., et al., 2006. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol. 5 (6), 488– 492. Biervert, C., Schroeder, B.C., Kubisch, C., et al., 1998. A potassium channel mutation in neonatal human epilepsy. Science 279 (5349), 403–406. Browne, D.L., Gancher, S.T., Nutt, J.G., et al., 1994. Episodic ataxia/ myokymia syndrome is associated with point mutations in the

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Graves, T.D., Cha, Y.H., Hahn, A.F., et al., 2014. Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation. Brain 137 (Pt 4), 1009–1018. Guerrini, R., Dravet, C., Genton, P., et al., 1998. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 39 (5), 508–512. Han, C., Dib-Hajj, S.D., Lin, Z., et al., 2009. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain 132 (Pt 7), 1711–1722. Harkin, L.A., Bowser, D.N., Dibbens, L.M., et al., 2002. Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus. Am. J. Hum. Genet. 70 (2), 530–536. Herlenius, E., Heron, S.E., Grinton, B.E., et al., 2007. SCN2A mutations and benign familial neonatal-infantile seizures: the phenotypic spectrum. Epilepsia 48 (6), 1138–1142. Iannetti, P., Parisi, P., Spalice, A., et al., 2009. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Res. 85 (1), 89–95. Jarecki, B.W., Sheets, P.L., Jackson, J.O., et al., 2008. Paroxysmal extreme pain disorder mutations within the D3/S4-S5 linker of Nav1.7 cause moderate destabilization of fast inactivation. J. Physiol. 586 (Pt 17), 4137–4153. Kim, S.H., Nordli, D.R. Jr., Berg, A.T., et al., 2014. Ictal ontogeny in Dravet syndrome. Clin. Neurophysiol. Kors, E.E., Terwindt, G.M., Vermeulen, F.L., et al., 2001. Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann. Neurol. 49 (6), 753–760. Lassche, S., Lainez, S., Bloem, B.R., et al., 2014. A novel KCNA1 mutation causing episodic ataxia type I. Muscle Nerve 50 (2), 289–291. Liu, Y., Lopez-Santiago, L.F., Yuan, Y., et al., 2013. Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann. Neurol. 74 (1), 128–139. Marchioni, E., Galimberti, C.A., Soragna, D., et al., 1995. Familial hemiplegic migraine versus migraine with prolonged aura: an uncertain diagnosis in a family report. Neurology 45 (1), 33–37. Nachbauer, W., Nocker, M., Karner, E., et al., 2014. Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. J. Neurol. 261 (5), 983–991. Nilsen, K.B., Nicholas, A.K., Woods, C.G., et al., 2009. Two novel SCN9A mutations causing insensitivity to pain. Pain 143 (1–2), 155–158. Pelzer, N., Stam, A.H., Carpay, J.A., et al., 2014. Familial hemiplegic migraine treated by sodium valproate and lamotrigine. Cephalalgia 34 (9), 708–711. Press, C.K.K., Chapman, K., 2015. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. Riant, F., Roze, E., Barbance, C., et al., 2012. PRRT2 mutations cause hemiplegic migraine. Neurology 79 (21), 2122–2124. Roth, C., Freilinger, T., Kirovski, G., et al., 2014. Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene. Cephalalgia 34 (3), 183–190. Sanchez-Albisua, I., Schoning, M., Jurkat-Rott, K., et al., 2013. Possible effect of corticoids on hemiplegic attacks in severe hemiplegic migraine. Pediatr. Neurol. 49 (4), 286–288. Singh, N.A., Charlier, C., Stauffer, D., et al., 1998. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat. Genet. 18 (1), 25–29. Stam, A.H., Vanmolkot, K.R., Kremer, H.P., et al., 2008. CACNA1A R1347Q: a frequent recurrent mutation in hemiplegic migraine. Clin. Genet. 74 (5), 481–485.

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Stam, A.H., Luijckx, G.J., Poll-The, B.T., et al., 2009. Early seizures and cerebral oedema after trivial head trauma associated with the CACNA1A S218L mutation. J. Neurol. Neurosurg. Psychiatry 80 (10), 1125–1129. Steinlein, O.K., Conrad, C., Weidner, B., 2007. Benign familial neonatal convulsions: always benign? Epilepsy Res. 73 (3), 245– 249. Steinlein, O.K., Mulley, J.C., Propping, P., et al., 1995. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 11 (2), 201–203. Striano, P., Mancardi, M.M., Biancheri, R., et al., 2007. Brain MRI findings in severe myoclonic epilepsy in infancy and genotypephenotype correlations. Epilepsia 48 (6), 1092–1096. Sugawara, T., Tsurubuchi, Y., Agarwala, K.L., et al., 2001. A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc. Natl. Acad. Sci. U.S.A. 98 (11), 6384–6389. Suzuki, T., Delgado-Escueta, A.V., Aguan, K., et al., 2004. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat. Genet. 36 (8), 842–849. Terwindt, G.M., Ophoff, R.A., Haan, J., et al., 1998. Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Dutch Migraine Genetics Research Group. Neurology 50 (4), 1105–1110. van den Maagdenberg, A.M., Kors, E.E., Brunt, E.R., et al., 2002. Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene. J. Neurol. 249 (11), 1515–1519. Wallace, R.H., Marini, C., Petrou, S., et al., 2001. Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat. Genet. 28 (1), 49–52. Wallace, R.H., Wang, D.W., Singh, R., et al., 1998. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat. Genet. 19 (4), 366–370. Weckhuysen, S., Ivanovic, V., Hendrickx, R., et al., 2013. Extending the KCNQ2 encephalopathy spectrum: clinical and neuroimaging findings in 17 patients. Neurology 81 (19), 1697–1703. Wolff, M., Casse-Perrot, C., Dravet, C., 2006. Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Epilepsia 47 (Suppl. 2), 45–48. Yu, F.H., Mantegazza, M., Westenbroek, R.E., et al., 2006. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat. Neurosci. 9 (9), 1142–1149. Zhuchenko, O., Bailey, J., Bonnen, P., et al., 1997. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat. Genet. 15 (1), 62.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 49-1 Distribution of mutations in the SCN1A gene.

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Neurodevelopmental Disorders

Neurodevelopmental Disabilities: Conceptual Framework Iris Etzion, Sinan O. Turnacioglu, Karen A. Spencer, and Andrea L. Gropman

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

GENERAL CONCEPTIONS AND CONSIDERATIONS WHEN APPROACHING A CHILD WITH SUSPECTED DEVELOPMENTAL DISABILITIES Child development, a general term relating to neurologic and psychological growth and development of a human being from birth to adulthood, is a continuum starting in the prenatal period and extending throughout life, with close and inevitable interaction with the environment. Perceiving development as a series of milestones gained in a stepwise fashion in various categories—though practical in the clinical setting— belies the complex concept of its very essence: an integrative process, in which each aspect interacts with all others, leading the individual from utter helplessness to independence, adaptive social skills, and emotional integrity. The traditional concept of development relates to six domains: gross motor, fine motor, receptive language, expressive language, problem-solving, and social-adaptive skills. Neuromuscular assessment can be performed as early as 20 weeks of gestation (Ballard et al., 1991). Term newborns already exhibit relation to the environment, and maladaptive patterns of behavior can be identified. Several assessment tools exist (i.e., Brazelton Neonatal Behavioral Assessment Scale) for birth up to 2 months of age. The scale relates to four aspects of early development: regulation of the autonomic system, of the motor system, of the state of alertness in response to various stimuli, and primary communicative skills. The first 2 years of life are the most striking developmentally. Hence, the various estimation tools used (mentioned in section on approach to the evaluation of a child with NDD) regard development in 3-month intervals. Toddlers are commonly assessed in 6-month intervals and by school age, a yearly evaluation of a neurotypically developing child is customary. By then, focus shifts from the “classical” developmental benchmarks to academic skills as reflected by the child’s achievements at school. Delay refers to a lag in one or more—and occasionally all—aspects of development. Global developmental delay (GDD) is a common term used at an early age to describe what might later turn out to be intellectual disability (ID). Dissociation regards a discrepancy between different developmental domains. This is typically seen in children with cerebral palsy, who struggle to gain gross motor milestones but do not necessarily display difficulties with language acquisition. Dissociation might be used to describe a difference in the extent of delay in two or more fields, for example, significant language delay along with mild motor delay, as is often seen in children diagnosed with autism spectrum disorder (ASD). Deviance is a term used to describe an abnormal sequence of development, usually “skipping” milestones that might indicate a

hidden pathology (Accardo et al., 2008). For instance, pushing to stand without crawling might indicate hypertonicity of the lower limbs. The “cocktail-party chatter” typical of William syndrome represents another deviance pattern, in which expressive language appears more elaborate then receptive abilities. The developmental trajectory observed over time serves as yet another clue to the underlying pathology leading to developmental disabilities. Early delay with later catch-up is typical of preterm infants, with catch-up occasionally continuing into adolescence. On the contrary, normal gain of early milestones with difficulties emerging later on up to possible loss of already acquired skills denotes investigation of a possible metabolic or neurodegenerative disorder. A continuous GDD with a stable yet below age-average learning curve suggests a future ID and might warrant a genetic workup (Moeschler et al., 2014).

Spectrum of Neurodevelopmental Disabilities In its broadest sense, the term neurodevelopmental disabilities can include a wide range of disorders with significant overlap and varying causes (Box 50-1). These include conditions that affect motor, sensory, cognitive, language, and executive functions, and social and behavioral disorders. Typical conditions included within this designation include cerebral palsy, GDD, ID, attention-deficit/hyperactivity disorder (ADHD), ASD, and learning disorders. Neurodevelopmental disabilities are related to abnormalities in central nervous system (CNS) development and may lead to lifelong functional impairment. They are a heterogeneous group of disorders. They can be defined quantitatively based on results of developmental or neuropsychological assessments, or qualitatively by comparing an individual’s developmental profile to that of same-age peers (Shevell, 2010). Socioeconomic, racial, and ethnic factors may affect the timing of diagnosis. In ASD, for example, lower socioeconomic status and Hispanic ethnicity have been associated with a later age at first diagnosis. The functional implications of neurodevelopmental disabilities are addressed in the World Health Organization’s International Classification of Functioning, Disability, and Health, which uses three components—body function and structure, activity, and participation—that help delineate the nature of an individual’s disability. A key aspect of the evaluation of a child suspected of having a neurodevelopmental disability is the approach to establishing diagnoses. Accurate diagnoses help guide further investigation into causality, implementation of necessary services, family counseling, and anticipation of long-term

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BOX 50-1  Frequently Encountered Neurodevelopmental Disabilities Attention-deficit/hyperactivity disorder Autism spectrum disorder Cerebral palsy Communication disorders Global developmental delay Epilepsy Hearing impairment Intellectual disability Learning disorders Leukoencephalopathies Neurogenetic disorders and inborn errors of metabolism Neuromuscular disorders Visual impairment

prognosis. Certain genetic disorders predispose children to neurodevelopmental disorders, as do other predisposing factors, including prematurity, neonatal encephalopathy, and socioeconomic status. It is now well recognized that individual patients can be affected by more than one neurodevelopmental disability.

Overview and Scope of the Problem These conditions exist at the intersection of the disciplines of neurology, psychiatry, developmental pediatrics, neurodevelopmental disabilities, and psychology, and may be evaluated by specialists in any or all of these fields. Features of neuro­ developmental disabilities highlight the overlap and interaction between the fields of neurology and psychiatry. With growing understanding of the genetics and neurophysiology underlying these conditions, neurologists in the future may be expected to manage conditions previously designated as psychiatric disorders. For example, Rett syndrome was listed as one of the pervasive developmental disorders in American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders—IV (DSM-IV), but with the identification of MeCP2 as the cause of this syndrome, it has subsequently been considered a neurogenetic disorder and removed from the current edition of the DSM (American Psychiatric Association, 2013). Neurodevelopmental disabilities can be diagnosed on the basis of practice parameters such as those released by the American Academy of Neurology/Child Neurology Society for Global Developmental Delay (Chapter 51) and ASD (Chapter 57) , or by applying diagnostic criteria as detailed in the DSM-5 (American Psychiatric Association, 2013). In DSM-5, neurodevelopmental disorders are described as “disorders with onset in the developmental period, often before starting school, and that are characterized by a range of developmental deficits that impair normal functioning.” They include ID (intellectual developmental disorder), communication disorders (language disorder, speech sound disorder, and childhood-onset fluency disorder), ASD, ADHD, specific learning disorder, and motor disorders (developmental coordination disorder, stereotypic movement disorder, and tic disorders). A formal classification system can be used, for example, with characterization of cerebral palsy by neurologic subtype or by gross motor skills (Chapter 97). There is a need to consider children’s diagnoses in a longitudinal manner. Children with diagnoses of GDD have a high likelihood of experiencing persistent developmental and func-

tional impairments at school age but not necessarily cognitive impairment. These conditions often persist throughout life, and affect adults’ health issues as well as have an impact on employment status, social relationships, and activities of daily living. One way to establish a diagnosis or diagnoses is to refer a child for developmental or neuropsychological evaluation (Chapter 10), which will quantitatively determine the child’s level of function related to age expectations or qualitatively establish appropriate DSM diagnoses. Another, not mutually exclusive, approach is a diagnostic workup that may include neuroimaging, metabolic and genetic testing, and neurophysiology studies. Chromosomal microarray has been recommended as a first-line investigation for the etiology of ID and ASD, and ongoing research has explored the yield of more advanced genetic testing, including whole exome sequencing and whole genome sequencing. Identification of a genetic diagnosis for a child with ID or ASD can have a significant impact for a family on the care of the child and may lead to more refined treatments, in the case of dietary treatment and enzyme replacement for metabolic disorders or optimal anticonvulsant treatment in the cases of SCN1A or GLUT1. Recent investigations using animal models now imply that ID can be reversible through pharmacology interventions (Chapter 59) or appropriate learning or retraining paradigms. The concept that epilepsy itself or the presence of an epilepsy syndrome can contribute to a child’s cognitive and behavioral impairments has been explored extensively, and epileptic encephalopathy is addressed in the current classification system for epilepsy. In the absence of clinical evidence that raises concern for epilepsy, current practice parameters advise caution in carrying out electroencephalography in patients with GDD or ASD. Population-based studies have indicated that 15% of children aged 3 to 17 years have a developmental disability on the basis of parent report. A recently published survey noted that there has been a 21% increase in disabilities related to neurodevelopmental or mental health conditions in the United States in the 2000s. The breakdown among individual disabilities varies. GDD is estimated to affect 1% to 3% of children, whereas a prevalence rate of 7.66% was found for ID. The Centers for Disease Control (CDC)’s Autism and Developmental Disabilities Monitoring Network noted that the prevalence of cerebral palsy has ranged from 0.31% to 0.36% since 1996. ASD prevalence rates in the most recent CDC surveillance findings were at 1.4% among 8-year-olds. Among learning disorders, reading was reported to have 5.3% to 11.8% cumulative incidence rates, math incidence rates of 5.9% to 13.8%, and writing 6.9% to 14.7% cumulative incidence rates in a populationbased birth cohort.

Determinants and Risk Factors The prime determinants of neurodevelopmental disabilities involve genetic and metabolic abnormalities and aberrant CNS development, prematurity, low birth weight, perinatal complications, chronic physical health conditions, exposure to environmental hazardous substances, compromised family functioning, and low-socioeconomic family background. Families of children with ADHD have been found to have higher rates of alcoholism, other drug abuse, depression, delinquency, and learning disabilities than controls. The concept of the broader autism phenotype addresses the higher incidence of social and communication symptoms and stereotypical behaviors in family members of children with ASD.



Commonalities Although diagnostic criteria and recommendations for workup and treatment of individual disabilities have been established, a number of common elements are shared among neurodevelopmental disability diagnoses. Individual children can have multiple neurodevelopmental diagnoses, and diagnoses may evolve over time, with the child initially diagnosed with GDD later identified as having a learning disorder. For conditions that are diagnosed primarily by behavioral manifestations and through application of DSM-5 criteria, there is a notorious lack of biomarkers. Neuroimaging and electroencephalography tend to be unrevealing or nonspecific. The American Academy of Neurology/Child Neurology Society (AAN/CNS) practice parameter recommends neuroimaging as part of the diagnostic evaluation, but indicates that data are insufficient for a recommendation regarding the role of EEG in child with GDD in whom there is no clinical evidence of epilepsy. In ASD, nonspecific EEG abnormalities have been found in most children and there is a lack of evidence to support universal screening EEG without a clinical indication. Children with neurodevelopmental disabilities are often found to have evidence of neurologic soft or subtle signs, such as mirror movements, synkinesis, clumsy finger movements, difficulties with balance, and motor persistence. These soft signs have been noted in patients with ADHD and ASD and have been followed longitudinally in cohorts of patients. Beyond treatments for inborn errors of metabolism, medications are typically prescribed to treat specific behaviors in children with neurodevelopmental disabilities, including stimulants and nonstimulants for inattention, hyperactivity, and impulsivity; antipsychotics and nonstimulants for aggression and irritability; and selective serotonin reuptake inhibitors and related medications for anxiety and mood symptomatology. Physical, occupational, language, and educational therapies are prescribed to these children.

Overlap in Neurodevelopment Disorders Neurodevelopmental conditions are frequently seen in combination in particular patients. Gillberg has proposed the acronym ESSENCE (early symptomatic syndromes eliciting neurodevelopmental clinical examinations), to describe the coexistence of impairing symptoms that can be initially identified in the first few years of life. In his classification, the ESSENCE conditions affect general development, communication and language, social interrelatedness, motor coordination, attention, activity, behavior, mood, and sleep. Children who are diagnosed with a particular neurodevelopmental diagnosis at an early age may no longer meet criteria for the specific diagnosis as they age, but may ultimately receive another neurodevelopmental disorder diagnosis (Gillberg, 2010). Children with ASD often have coexisting problems that include ADHD, epilepsy, ID, learning disorder, oppositional defiant disorder, anxiety disorder, mood disorder, and obsessive compulsive disorder. Recent genetic research has called into question the current categorical diagnostic algorithm used for neurodevelopmental disorders (NDDs) as delineated in DSM-5. Similar genetic findings have been identified in individuals with different neurodevelopmental diagnoses. For example, genetic changes at 16p11.2 that were initially associated with ASD have been found to be associated with developmental delay, ID, communication problems, abnormal head circumference, and psychiatric conditions, including schizophrenia and bipolar disease, and SCN2A mutations have been associated with ASD and epilepsy.

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The National Institutes of Mental Health has addressed the difficulty of diagnostic classification by introducing the Research Domain Criteria project as a framework for ongoing research that characterizes psychiatric disorders as neurophysiological disorders with a basis in genetics, electrophysiology, and functional imaging.

Approach to the Evaluation of a Child with Suspected Neurodevelopmental or Intellectual Disability Many of the principles of evaluating children with a neurodevelopmental disorder are similar to evaluating any child with a neurologic disorder. These principles are covered extensively in Part I: Clinical Evaluation. However, there are few aspects of these that merit special attention for children with neurodevelopmental disorders.

The Developmental History Ascertaining a child’s current developmental milestones is an important part of the evaluation of a child with a neurodevelopmental disorder. Given the limited amount of time during an office visit, it may sometimes be helpful to obtain reports of previous testing that has been performed in other settings, such as school or early intervention. Another dimension of the developmental assessment is adaptive measures, which refer to the ability to perform activities of daily living. This is an important part of understanding the level of functional disability of a child and is a requirement for the diagnosis of ID in the DSM-5. The Vineland Adaptive Behavior Scale, Second Edition (Vineland-II) is the most commonly used measurement, and can be a helpful tool to identify a child’s strengths, as well as areas that require more attention. Assessing the pattern of a child’s development is important in generating a differential diagnosis. Is there a concern for a developmental regression or a loss of developmental milestones? Is one area more affected than another? Children with isolated motor delays raise concern for neuromuscular disorders or cerebral palsy. Children with language delays may have difficulty with hearing or comprehension, or may have autism. Children with abnormal socialization may have autism or Rett syndrome, or may be suffering from the effects of trauma or neglect. Developmental problems that began during the school years can raise concern for ADHD, learning disabilities, or psychiatric issues, including anxiety or depression.

Birth History Medication and drug exposure during pregnancy may influence the child’s development. Information about the child’s delivery should include the need for perinatal resuscitation, postnatal respiratory support, or low Apgar scores which may all be indicators of neonatal hypoxic ischemic encephalopathy. Providers should be aware of the newborn hearing screen results and if there was any follow-up.

Social History Because there is a complex interplay between the family milieu and children with neurodevelopmental disorders, taking a social history is important. Children with neurodevelopmental disorders often require significant financial and emotional support, which places stress on the child as well as the family. Assessing the needs of these families is an important aspect of their care.

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PART VII  Neurodevelopmental Disorders

Psychosocial stressors in the home can manifest themselves in the child and appear to be consistent with a neurodevelopmental disorder. For example, a child who has suffered from trauma or neglect has abnormal socialization and can present with developmental delay. Exposure to adverse events can make a child more likely to have emotional dysregulation, heightened responses to perceived negative stimuli, and executive dysfunction. These children are at increased risk for developing disorders such as ADHD, anxiety, and depression. Children with neurodevelopmental disorders require a close assessment of their home environment to understand concomitant stressors and adverse exposures so that the child’s well-being is preserved. History should include assessment of the school environment. Children with neurodevelopmental disorders are more likely to have a significant number of missed days at school, have fewer friends than their peers, be bullied at school, and, in the case of children with special healthcare needs who required behavioral services, to bully other children. They participate less in extracurricular activities and are at risk for social isolation. Their happiness and level of inclusion at school should be an important aspect of the social history.

Family History The family history can give important clues to the etiology of the developmental disorders. ADHD and dyslexia have strong genetic aspects. Children suspected of having fragile X syndrome may have maternal relatives with anxiety or depression, autistic-like features, or ADHD.

Physical Examination One of the most important aspects of the evaluation of the child is observing his or her behavior in as unstructured an environment as possible, such as providing toys and opportunities for the child to play while the practitioner obtains the medical history from the caregiver. Through this, there are many aspects of a child that may not be apparent through history alone. For example, how does the child interact with the toys? Does the child mouth or lick the toys, or does he or she use them functionally? Does the child share his or her enjoyment with you or the examiner, or does the child prefer to keep to herself? How does the child interact with toys that he or she needs help with? Does the child look to his or her caregivers, or to you, for help, or does the child simply put the toy aside? Or does he or she become inconsolable? Is the child limited in any way by difficulties with coordination or motor functioning? As the examination proceeds, important things to note include the ability of the child to make eye contact and respond to his or her name, to follow directions with and without demonstration, and the level of engagement he or she has with you as the examiner. For the older child, engaging him or her in conversation during the examination may be more revealing. Is the child able to hold a conversation with you, or does he or she have difficulty? Asking about social life and interests can be an important way to help engage. Adolescents, if developmentally appropriate, may be more easily examined alone, so that they may feel more comfortable sharing information with you. For a child with neurodevelopmental disorders, special attention is made to the child’s appearance to rule out any dysmorphic features, the skin examination to evaluate for neurocutaneous disorders (i.e., neurofibromatosis type I can be associated with learning disabilities and autism), and the eye examination to evaluate for evidence for genetic or metabolic abnormalities.

Testing Testing children with suspected neurodevelopmental disorder should take a highly individualized approach based on the concern. The initial evaluation will provide clues to the nature of what testing should be pursued. Children with an abnormal neurologic examination finding revealing focal deficits require neuroimaging. Neuroimaging is recommended for children with GDD, per the American Academy of Neurology guidelines. For many children with neurodevelopmental disorders, the most important testing is a neuropsychological evaluation. For school-aged children, this can occur in the school setting. For children younger than 3 years, they are entitled to a developmental assessment through an early intervention program. Office-based screening tools may be helpful to guide the testing that needs to be done. For example, a Vanderbilt assessment is helpful not only for symptoms of ADHD, but also to screen for any comorbid behavioral difficulties, such as conduct disorder, oppositional defiant disorder, anxiety, and depression. Difficulties in school and activities of daily living are assessed. Identified problems can help guide the provider to refer the child for further testing to address academic performance or for behavioral therapy. Many children with neurodevelopmental disorders are at risk for having comorbid emotional or behavioral disorders. There are many in-office tools that can be helpful to assess these children’s risks. Children who have positive screens for behavioral or emotional disorders should be referred to other providers for further management.

Multidisciplinary Approach to the Care of the Child with a Neurodevelopmental Disorder Caring for children with neurodevelopmental disorders is often complex and requires a multidisciplinary approach to their care. Families of these children have significant financial stressors and difficulties with coordinating medical care. These patients often have numerous medical providers as well as a team of therapists and educators who are all working to care for them. An attentive medical provider can be instrumental in helping to assure that these children are able to access the care they need to support their disabilities. This section discusses the challenges facing these families. Children with chronic emotional, behavioral, or developmental problems are more likely to have health conditions that affect their daily activities, as well as be uninsured or underinsured; have unmet healthcare needs; have difficulty obtaining referrals; have more missed days of school; and have at least $1000 per year in out-of-pocket health-related expenses. These families have high levels of financial stress, including decreased levels of employment and high out-of-pocket costs (Kuo et al., 2013). High out-of-pocket costs are associated with the medical severity of the disorder as well as the need for mental health services in addition to medical services. Families of children with autism have the highest reported out-of-pocket costs. Children with special healthcare needs who have functional limitations have more difficulties accessing needed services and getting needed referrals. Compared with healthy peers, children with neurodevelopmental disorders have significant challenges that can affect their quality of life. Children with ADHD, learning disabilities, and intellectual disabilities are all more likely to have a comorbid psychiatric disorder than their typically developing peers. A study by Klassen et al. reveals that children with ADHD have poorer measures on health-related quality of life than controls, including measures of mental health and



self-esteem. Children with ADHD and comorbid psychiatric disorders tend to fare worse on quality-of-life measures (Stein et al., 2011). Children with learning disabilities have an increased risk of comorbid psychiatric disorders and increased social difficulties with peers. Children with intellectual disabilities have a much higher likelihood of having an emotional disorder or psychiatric disorders than typically developing children. Children with autism face social isolation from peers and, as young adults, have a higher likelihood of social isolation than peers with another developmental disorder, including intellectual disabilities. Children with special healthcare needs who have emotional problems or functional limitations have worse school outcomes than children with special healthcare needs who don’t have those problems. Families of children with a neurodevelopmental disorder and a comorbid emotional or behavioral disorder tend to fare poorly. A study of children with neurologic con­ditions and behavioral disorders indicated that families of children with both a neurologic disorder and a behavioral disorder had more unmet needs and reported greater dissat­isfaction with care, care coordination, ability to obtain a referral, and to use other services. A study by Nageswaran et al. of children with developmental disabilities with comorbid mental health diagnoses found similar findings (American Academy of Pediatrics, 2005). REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Accardo, P.J., Accardo, J.A., Capute, A.J., 2008. A neurodevelopmental perspective on the continuum of developmental disabilities. In: Accardo, P., Accardo, J., Capute, A.J., (Eds.), Capute & Accardo’s Neurodevelopmental Disabilities in Infancy and Childhood, third ed. Paul H. Brookes Publishing Co., New York, pp. 3–7. American Academy of Pediatrics, 2005. Care coordination in the medical home: integrating health and related systems of care for children with special health care needs. Pediatrics 116, 1238– 1244. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders, fifth ed. APA, Washington, DC.

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Ballard, J.L., Khoury, J.C., Wedig, K., et al., 1991. New Ballard Score, expanded to include extremely premature infants. J. Pediatr. 119, 417–423. Gillberg, C., 2010. The ESSENCE in child psychiatry: early symptomatic syndromes eliciting neurodevelopmental clinical examinations. Res. Dev. Disabil. 31, 1543–1551. Klassen, A.F., Miller, A., Fine, S., 2004. Health-related quality of life in children and adolescents who have a diagnosis of attention-deficit/ hyperactivity disorder. Pediatrics 114 (5), e541–e547. doi:10. 1542/peds.2004-0844. Kuo, D.Z., Goudie, A., Cohe, E., et al., 2013. Inequities in health care needs for children with medical complexity. Health Aff. 33, 2190–2198. Moeschler, J.B., Shevell, M., Committee on Genetics, 2014. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 134, e903–e918. Shevell, M.I., 2010. Present conceptualization of early childhood neurodevelopmental disabilities. J. Child Neurol. 25, 120–126. Stein, D., Blum, N.J., Barbaresi, W.J., 2011. Developmental and behavioral disorders through the life span. Pediatrics 128, 364–373.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 50-1 Formation of the neural tube from folding of the epiblast layer to near-closure of the anterior neuropore. Fig. 50-2 Schematic outline of human brain development from the embryonic stage to the adult mature brain, including major substructures. Fig. 50-3 Development of the cortical six-layer structure. Fig. 50-4 Schematic timeline of synaptogenesis and myelination during human brain development. Fig. 50-5 Brain magnetic resonance imaging scans demonstrating the development of human brain with postgestational age. Box 50-2 The Medical Home Table 50-1 Behavioral Assessment Screening Tools for Children

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Global Developmental Delay and Intellectual Disability Elliott H. Sherr and Michael I. Shevell

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

DEFINITIONS Global developmental delay (GDD) and intellectual disability (ID) are related, nonsynonymous terms with common and distinctive characteristics. They can be defined as early onset, chronic disorders with disturbance in the acquisition of cognitive, motor, language, or social skills, which has a significant and continuing impact on the developmental progress of an individual (Michelson et al., 2011). The 2002 consensus definition of the American Association on Mental Retardation (AAMR; now known as the American Association on Intellectual and Developmental Disabilities [AAIDD]) defined ID as “characterized by a significant limitation both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, practical, and adaptive skills.” This disability originates before the age of 18 and manifests with severe problems in the capacity to perform (i.e., impairment), ability to perform (i.e., activity limitations), and opportunity to function (i.e., participation restrictions). For the young child, the term “global developmental delay” has emerged to describe a disturbance across a variety of developmental domains. The latest consensus definition used by the American Academy of Neurology (AAN) and the Child Neurology Society practice parameter statement defines GDD operationally as a significant delay in two or more developmental domains (e.g., gross/fine motor, cognitive, speech/ language, personal/social, activities of daily living) (Michelson et al., 2011). Typically, if there is delay in two domains, this often implies delay across all domains. Thus the definitions of ID and GDD reflect an approach to disability that emphasizes adaptive behaviors and contextual factors as opposed to a single objective measure.

Epidemiology Assuming a normal distribution of IQ scores (and that adaptive skills correlate closely with these more conventional metrics of intellectual ability), approximately 2.25% of individuals will have an IQ below 70 and a diagnosis of ID. Early population-based studies confirmed this theoretical estimate, documenting an overall rate of ID of 2%, with 1.5% having mild ID (IQ of 50–70) and 0.5% having moderate or severe ID (IQ of less than 50). Although the population studied and the instruments used can influence the rate of mild ID, they seem to have little effect on the rate of severe ID. Thus the prevalence rates for mild ID in 15 subsequent studies varied broadly from 5 to 80 cases per 1000 people, whereas the prevalence of severe ID varied only between 2.5 and 7 per 1000 (Leonard and Wen, 2002). Many changes that affect the rate of mild ID can affect the overall numbers of persons with ID in the population (e.g., poor education, nutrition, tobacco or alcohol use, environmental toxins such as lead). Additional risk has been associated with low birth weight and maternal age. Paternal smoking also increases the risk of having children with ID. In addition, race and gender disparities have also been reported, with ID overrepresented by as much as 50% among African Americans

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relative to the Caucasian population (thought to be influenced heavily by social context), and the male-to-female ratio was 1.4 : 1.0. ID cases are often grouped by prenatal, perinatal, and postnatal causes. Prenatal causes include genetic syndromes and chromosomal disorders, central nervous system malformations, and maternal toxic or infectious causes. Perinatal conditions include birth asphyxia, stroke, and infection. Postnatal conditions include infection, toxins (e.g., lead), and injury, such as nonaccidental trauma. Simple public health measures (e.g., iodized salt, community-wide rubella vaccination, newborn screening) have prevented an estimated 15% of cases of ID in the industrial world. Currently the most common potentially preventable cause of ID in high-resource settings is fetal alcohol syndrome, whereas congenital hypothyroidism caused by maternal dietary iodine deficiency remains the most common preventable cause world-wide. Using the above framework, over 60% of children with ID do not have identified causes. Among the causes identified, chromosomal defects are common, and Down syndrome is the single most common known chromosomal cause. The increasing widespread availability and application of chromosomal microarray (CMA; also referred to as array comparative genomic hybridization [CGH]) and whole-exome sequencing in the clinical setting will increase the percentage of attributable causes to these subtler genetic disruptions (Sherr et al., 2013). Many individuals with ID are unable to become productive members of society and require institutionalized or grouphome care. The economic costs are substantial, with one study showing the financial burden on society equal to the economic impact of stroke, heart disease, and cancer combined (Meerding et al., 1998). Another analysis estimates lifetime costs of more than $1 million dollars per person with ID, which is more than that for cerebral palsy, hearing loss, or vision impairment.

DIAGNOSIS Definitions and Testing Accurate diagnosis of GDD or ID is an essential precondition to proper management and service provision. Accurate diagnosis helps understand the specific medical and psychiatric complications, determine eligibility for service and support provision, aid in family counseling, and confirm legal recognition of disability. Multiple standardized, age-appropriate measures have been normed and validated on typically developing populations to assess intellectual function and adaptive behavioral skills.

Advances in Diagnostic Testing An approach to the diagnosis of ID/GDD can begin with the AAN practice parameter and evidence report for GDD (Figure 51-1) (Michelson et al., 2011). The recommendations incorporate a combination of broad screening tools and



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Unexplained Global Developmental Delay / Intellectual Disability

A) B) C) D) E) F)

51

Detailed medical and developmental history, including prior diagnostic testing, especially newborn screening labs Three-generation family history Complete physical and neurological examination with attention to dysmorphism Consider EEG testing if history concerning for epileptic seizures or encephalopathy Consider psychoeducational testing, vision testing, and hearing testing Consider referral to a clinician with relevant expertise if child appears to have an unrecognized genetic syndrome

Specific Etiology Suspected?

A) B) C) D)

Yes

No A) All severities and genders: Microarray if possible Otherwise: karyotype and StFISH B) Moderate to severe and female: MeCP2 testing C) Mild and either gender: FMR1 testing

Abnormal

Genetic syndrome: single gene tests XLID: XLID gene testing Structural abnormality: MRI Metabolic disorder: screening tests

Test parents and siblings as appropriate Refer for genetic counseling

Normal Neuroimaging: Head MRI If available, consider MRS

Diagnostic

Specific testing as appropriate

Non-diagnostic Metabolic testing, based on clinical judgment: A) Plasma amino acids, ammonia, acylcarnitines B) Serum uric acid C) Urine organic acids D) Urine and plasma creatine, creatinine, and guanidinoacetic acid E) Appropriate testing for CGDs F) Plasma VLCFA, pipecolic acid, phytanic acid, and RBC plasmalogens G) Serum 7-dehydrocholesterol H) Urine mucopolysaccharides and sialic acid I) Blood or fibroblast screening for lysosomal enzyme deficiencies J) CSF glucose, lactate, pyruvate, glycine, organic acids, folate, and neurotransmitter metabolites

Abnormal

Specific testing as appropriate

Normal Ongoing follow-up Consider further evaluation as warranted Consider referral to a medical geneticist

Figure 51-1.  Algorithm for the evaluation of the child with unexplained global developmental delay or intellectual disability. A detailed history, a complete physical examination, psychoeducational testing, and screening tests for visual and hearing deficits are recommended for all children with GDD/ID. EEG is recommended when there is concern about seizures or an epileptic encephalopathy. In children with features suggesting a specific etiology, genetic testing, neuroimaging, and metabolic testing may be useful for confirmation. For children without features suggesting a specific etiology, testing can be done in a stepwise or parallel manner for genetic abnormalities, structural brain abnormalities, and metabolic abnormalities. Although an extensive list of metabolic tests is provided in this algorithm, there is insufficient evidence to make specific recommendations as to which testing sequence would have the greatest diagnostic yield. The algorithm is explained in greater detail in the Clinical Context section of this guideline. This algorithm is based on data contained in an evidence-based review on this topic (Michelson et al., 2011). CGD, congenital disorder of glycosylation; CSF, cerebrospinal fluid; EEG, electroencephalogram; GDD, global developmental delay; ID, intellectual disability; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; RBC, red blood cell; VLCFA, very long chain fatty acids; XLID, X-linked intellectual disability. (Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011.)

disease-specific testing based on a heightened pretest probability, given identifying clinical features. Correctly applied, each individual disease-specific test has a reasonable pretest probability (>1%) of diagnosis, whereas the more recently introduced broad-based genomic screening tools have a high pretest

probability (5% to 25%). The current algorithm begins with a complete clinical assessment. For patients in whom a specific diagnosis is considered, targeted testing is recommended. For the remaining patients a step-wise approach is recommended that begins with CMA followed by chromosomal karyotype

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if that is negative. This recommendation reflects the capacity of CMA to detect clinically relevant chromosomal changes, and is also recommended by a consortium of clinical genetics laboratories (Miller et al., 2010; Michelson et al., 2011). Fragile X and meCP2 testing are examples of specific gene/ syndrome approaches. However, if these tests are unrevealing, the algorithm recommends conducting brain magnetic resonance imaging (MRI; with single-proton spectroscopy, where available). If this approach is not diagnostic, comprehensive metabolic testing is then recommended (see Figure 51-1). As the yield of these diagnostic tools advances (a discussion of some recent advances, such as whole-exome sequencing, are expanded upon below), these algorithms will continue to change to reflect these technical improvements. Regardless, clinical judgment will always be tantamount.

Genomic Microarray Genomic microarray technology detects copy number changes in the genome, usually with a resolution of 30 kb or less. These platforms identify interstitial copy number variants (CNV). Studies done thus far confirm the importance of CNVs as a cause of neurodevelopmental disabilities, detecting many chromosomal changes not visible with high-resolution karyotyping. Many studies in autism, mental retardation, and cohorts with multiple congenital anomalies (who also have neurodevelopmental disabilities) show that many CNVs occur repetitively with the same chromosomal breakpoints and at a much higher frequency in affected individuals than in controls. Although in some cases the link between CNV and ID is well established, this determination is challenging or not possible when that genetic variation has never been reported previously, or its incidence in cases and controls is not well documented. To address etiology in these variants of unknown significance, the first step is to establish whether a documented copy number change is de novo or familial: determining the size of the CNV, knowing whether it is a deletion or duplication, and knowing the genes (and gene density) in the CNV. The establishment of publicly available and actively updated genotype–phenotype databases aids in the process of establishing pathogenicity of these less common CNV. Whole-Exome Sequencing: As outlined previously, advances in genetic testing have driven much of the progress in understanding the causes of ID. For example, CMA give positive diagnostic yields of approximately 7% to 8%, above that seen via karyotypes (Sherr et al., 2013). Recent data highlight the diagnostic potential of whole-exome sequencing. Two recent studies from a combined 3000 families demonstrate a diagnostic rate of approximately 25%. When patients with developmental delay were specifically examined, the rate of identification increased to 36% to 40%, exceeding that seen for CMA or karyotypes. Most of these diagnoses resulted from de novo mutations in known genes, and in some cases either homozygous recessive (for consanguineous families) or compound heterozygous inherited mutations were causative. The rate of de novo mutations has been shown to correlate to paternal age and suggests that some of the increased incidence in neurodevelopmental disorders in developed countries can be explained by this societal change in parental age.

Advances in Imaging High-quality MRI has significantly advanced the ability to detect many brain malformations. Certain studies suggest that structural MRI is useful for detecting abnormalities in up to 50% of children with developmental delay, including the identification of polymicrogyria, pachygyria, lissencephaly, callosal agenesis, and periventricular nodular heterotopia, for

which genes are known to cause these syndromes. Proton MR spectroscopy measures the resonance of molecules in the brain, allowing the measurement of metabolism intermediates and helping in the diagnosis of mitochondrial disorders (lactate and pyruvate) or measuring creatine in disorders of creatine deficiency, potentially treatable forms of ID and GDD.

ETIOLOGY General Considerations The known specific causes of ID are too numerous to be listed here. The term “intellectual disability” returns more than 3000 entries in the Online Mendelian Inheritance in Man site alone, and this catalogs only identifiable genetic causes. As mentioned previously, ID usually is classified by prenatal, perinatal, postnatal, and undetermined causes. In most U.S.-based studies, the largest category of known primary causes is genetic or chromosomal (Leonard and Wen, 2002), with up to 75% of the known cases attributable to chromosomal aberrations. In contrast, in some regions of the world, cretinism (stunted physical growth and ID) from severe iodine deficiency occurs in up to 2% to 10% of the population of isolated communities. Mild mental impairment from iodine deficiency occurs five times more frequently than cretinism, making iodine deficiency the most common preventable cause of mental retardation. Treatment during the first trimester has a significant effect on the frequency of cretinism. In regions of mainland China with iodine deficiency, children score on average 10 IQ points less than cohorts in iodine-rich regions. This link between iodine deficiency and mental retardation has a strong genetic component, because alleles of the deiodinase type II gene and the ApoE4 allele confer a significantly greater risk of ID when the pregnant mother is iodine deficient. Despite the tremendous wealth of information about the causes of ID, the cause remains unknown in most individuals. Genetic and epidemiologic approaches likely will continue to make progress toward unraveling and treating these currently unelucidated causes.

Genetic Causes Both inherited and de novo mutations have been shown to be causative for ID and GDD, and the advances in clinical application of genetic tools have accelerated the rate of discovery of new causes.

Fragile X Syndrome Fragile X syndrome, caused by inactivation of the FMR1 gene, has an estimated prevalence of 1 in 3000 males and is the most common inherited causes of ID. Expansion of the trinucleotide sequence CGG to more than 200 copies results in CpG methylation and inactivation of transcription of the FMR1 gene. Patients have narrow and elongated faces, large protruding ears, macroorchidism in males, and joint hyperlaxity. Up to 50% of patients have ASD and 20% have epilepsy, and most have complex partial seizures. Carrier females and males with somatic mutations have a range of levels of intellectual impairment; studies demonstrate that the amount of the residual FMR protein detected in hair roots correlates well with IQ. Although previous studies suggested that premutation male carriers (55 to 200 repeats) were asymptomatic, later work has demonstrated that a range of symptoms are present in premutation carriers, including migraines, seizures, autism, and ID. Moreover, investigators have identified a progressive neurologic disorder, the fragile X–associated



Global Developmental Delay and Intellectual Disability

tremor/ataxia syndrome (FXTAS) in premutation carriers. After the age of 50, primarily male patients present with intention tremor and cerebellar ataxia, and cognitive decline. This syndrome, which is unique to these premutation carriers, may result from an increase in expanded repeat FMR1 mRNA that is consistent with a toxic “gain of function” mechanism. Although treatment still remains symptomatically based, investigators have shown that fragile X syndrome leads to an exaggerated activation through metabotropic glutamate receptors, and early clinical studies have tested compounds that inhibit this signaling. Although the initial results did not demonstrate enhanced outcomes, it is possible that a greater understanding of these mechanisms may lead to targeted therapies.

Other X-Linked ID Conditions The increased prevalence of ID in males and the relative ease of detecting familial transmission of X-chromosome mutations have led to the discovery of novel ID genes on the X chromosome. Since the early 1990s, more than 120 genes have been identified as causes of X-chromosome-linked syndromic and nonsyndromic ID (Table 51-4). Mechanistically some of these genes work directly at the level of the synapse. For example, the protein family neuroligin on the postsynaptic membrane (with two X-linked neuroligin genes [NLGN3 and NLGN4]), and its binding partner neurexin on the presynaptic side have been shown to promote synapse formation in vitro. Similarly, multiple genes that participate in signaling at the synapse through the small G protein RHO are mutated in many cases of X-linked ID: GDI1, PAK3, OPHN1, and ARHGEF6. There are also many genes without synaptic function that are well-established causes of ID, such as the genes ARX and MECP2. These genes can cause syndromic ID (as in patients with X-linked lissencephaly with ambiguous genitalia [XLAG] and Rett’s syndrome) and nonsyndromic ID, depending on the severity of the mutation. These observations demonstrate the complexity of understanding how genetic alteration causes mental retardation, what form it takes, and how genotype may correlate with phenotype.

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DE NOVO DOMINANT GDD AND ID In addition to inherited cases of ID, there has also been significant strides in identifying genes that cause de novo dominant ID. The recent papers to detail the results of clinical exome sequencing report that, of the designated causative genes, nearly 1/3 of these were discovered in the last 18 months. At some point, the community of clinicians and investigators will begin to see a “saturation” for gene discovery, but that is still likely quite a ways off. Thus a specific listing of genes would be unproductive; however, there are many important themes that emerge: 1. The genetics of ID overlaps significantly with other neurodevelopmental disorders. This has been observed clinically, and was recently confirmed in cohorts of patients with de novo mutations demonstrating overlap between ID, ASD, epileptic encephalopathies, and schizophrenia causes. 2. Many genes have both syndromic and nonsyndromic presentations, depending on the severity and penetrance of the mutations. 3. Approximately 5% of patients will actually have two causative genes, suggesting that more complex disorders may be caused by these unexpected combinations. 4. Increasing the risk for de novo mutations by an older population contributes to this disease burden. 5. Postzygotic mutations play a significant role in these disorders in addition to germline mutations.

Other Etiologic Considerations Several questions arise when considering the causes of mental retardation that guide the clinician in evaluating patients and help the researcher focus on the underlying pathophysiology. What is the prevalence of any genetic cause for ID and how many genes can cause this disorder? Will cases of mild ID be caused by less severe mutations in these same, alreadydiscovered genes or in a completely different subset? How many cases of ID will be found to be caused by genetic factors alone, environmental factors alone, or the interplay between the two, as has been demonstrated for iodine deficiency?

TABLE 51-4  Genes Implicated in X-Linked Intellectual Disability Gene

Function

Locus

Study

Xq23 Xq28 Xp21.3 Xq26.3 Xq28 Xq23 Xq23 Xp11.23 Xq13.1 Xq13.1 Xp22.32 Xp11.23 Xp22.12 Xp11.3

Schulze (2003) Ethofer et al. (2004) Eichler et al. (2002) Barnea-Goraly et al. (2004) Baribeau and Anagnostou (2013) Fillano et al. (2002) Marin-Garcia et al. (1999) Lib et al. (2003) Schulenberg et al. (2004) Hou et al. (1998) Delange et al. (2001) Cao et al. (1994) Guo et al. (2004) Wang et al. (2000)

Xq12 Xp22.11

Crawford et al. (2001) Willemsen et al. (2004)

Xq28

Willemsen et al. (2003)

Genes Primarily Implicated in Nonsyndromic Intellectual Disability P21 (CDKN1A)-activated kinase 3 PAK3 Guanosine triphosphate (GTP) dissociation inhibitor 1 GDI1 Interleukin 1 receptor accessory protein-like 1 IL1RAPL1 Rac/Cdc42 guanine nucleotide exchange factor 6 ARHGEF6 Creatine transporter 8 SLC6A8 Long-chain fatty acid-coenzyme A ligase 4 FACL4 Angiotensin II receptor, type 2 AGTR2 FTSJ1 S-adenosylmethionine-binding protein Synapse-associated protein 102 (anchoring protein) DLG3 Neuroligin 3 (postsynaptic receptor) NLGN3 Neuroligin 4 (binds neurexin) NLGN4 Polyglutamine binding protein 1 PQBP1 Serine/threonine kinase RPS6KA3 Zinc-finger protein involved in chromatin activation ZNF41 Genes Implicated in Syndromic and Nonsyndromic Intellectual Disability OPHN ARX MECP2

Rho-GTPase activating protein (cerebellar hypoplasia) Aristaless-related homeobox (X-linked lissencephaly with ambiguous genitalia [XLAG]) Methyl-CpG binding protein 2 (Rett’s syndrome)

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PART VII  Neurodevelopmental Disorders

EVALUATION OF THE PATIENT History The assessment of a child with suspected GDD or ID begins with a detailed history, including family history, mother’s gestational history, perinatal history, birth, and early neonatal history. The next component of history, history of present illness, includes the age at which the developmental concern became manifested to the caregiver and the timing of developmental milestones determined. The possibility of regression of previously acquired developmental skills should be specifically questioned, as this would mandate a different and more urgent approach to etiologic evaluation and follow-up. Current skill level in developmental domains and the degree of independence in activities of daily living must be documented. For the school-aged child, important points include scholastic history, with special reference to actual school and classroom placement, and the identification of the provision of any supplemental educational resources. Coexisting medical problems, with particular reference to possible seizure disorders or feeding difficulties, should be questioned. Sleeping and problematic behaviors (e.g., aggressive, inappropriate, or self-injurious) may be particular concerns of the parents and are often underappreciated by health professionals. The medical history, including possible chronic medical conditions, prior hospital admissions, or surgical procedures, should be documented. Past and current medications prescribed, their indications, and their effects (beneficial or deleterious) must be assessed. The current social situation of the child and family must be carefully probed and the examiner must determine whether the patient has access to appropriate rehabilitation services. This approach should provide clear ideas regarding evidence of a static or progressive encephalopathy; the developmental and functional level; the timing of an underlying cause; a prioritized list of etiologic causes; the social or rehabilitation status of the affected child; and the possibility of associated medical or behavioral conditions meriting intervention.

Physical Examination The physical examination begins with careful observation of the child. The availability of a play area with appropriate toys, including paper, crayons, dolls, and representational toys, may allow for a nonintrusive assessment of developmental skills, behavior, and interaction with the surroundings and others. Much of the neurodevelopmental examination can take place during extended history-taking by observation alone. In the older child, language skills, both spontaneous and responsive, expressive and receptive, should be established, together with an understanding of simple cognitive concepts (i.e., size, shape, analogies, action, commonalities, numbers). The general physical examination should specifically ascertain possible dysmorphology, hepatosplenomegaly, and markers of neurocutaneous disorders. The spine should be carefully inspected, including the sacral region, to look for dermal sinuses, hair tufts, or other subtle signs of spinal dysraphism. Height, weight, and occipitofrontal circumference should be obtained and plotted. In cases of microcephaly or macrocephaly, the parental occipitofrontal circumferences also should be obtained and plotted. The head shape and status of the anterior and posterior fontanels in the infant, together with the sutures, should be observed. Determination of the presence of any focal or asymmetric neurologic findings is the primary objective of the formal neurologic examination. Careful evaluation of vision, in addition to aiding in a definitive diagnostic process, is indicated to minimize the contribu-

tion of potentially correctable visual impairments to the burden of disability. Similarly, this approach applies to evaluating for possible gross auditory impairments in the office setting. Within the clinical office setting, several test instruments exist for use as objective screening assessments of development during the first years of life (i.e., Denver Developmental Screening Test). These may be supplemented or complemented by the use of parent-based questionnaires (e.g., Child Developmental Inventory and Ages and Stages Questionnaire) that provide an aspect of objective developmental screening.

Laboratory and Other Diagnostic Testing Laboratory testing is directed at establishing the possible cause of the individual’s delay or ID. Laboratory testing is undertaken in the spirit that the potential value of a definitive etiologic diagnosis from individual and familial perspectives may be substantial. Recent work has emphasized the delineation and diagnosis of nearly 90 treatable metabolic diseases associated with GDD or ID. Technologic advances, especially in the domains of genetic testing and neuroimaging, have improved diagnostic yield and precision, and will continue to improve with newer diagnostic tools. Aiding the formulation of a rational approach to laboratory investigations in this clinical population is the AAN practice parameter and updated evidence report (see Figure 51-1) (Michelson et al., 2011). For the globally or intellectually delayed child without an apparent cause after history and physical examination, current recommendations would include CMA testing, followed, if clinically indicated, by high-resolution MRI. How and with what frequency whole-exome and whole-genome sequencing will be part of the standard clinical evaluation is not completely clear, but given the early success of this tool to aid in diagnosis, it is likely to be quickly incorporated into upcoming practice parameter revisions. Electrophysiologic studies, such as electroencephalography, should be undertaken only in the situation of a suspected coexisting paroxysmal disorder or evidence of language regression or behavioral abnormalities suggestive of an epilepsy syndrome, such as Landau–Kleffner or electrical status epilepticus during slow-wave sleep. Visual- and auditory-evoked potentials are of use in assessing the integrity of the visual and auditory systems in the young, uncooperative child.

Consultation Concerns about the developmental and functional patterns highlighted at the time of specialty evaluation should prompt referrals to other health professionals with different but complementary expertise, permitting a multidisciplinary, comprehensive evaluation of the affected child. These health professionals represent genetics, occupational therapy, physical therapy, speech and language pathology, and psychology. Specific care needs, such as tube feeding, respite care, or financial difficulties, may prompt nursing or social service intervention. Vision and hearing screening is important because of the high frequency of potentially correctable primary sensory impairments in this population.

MEDICAL MANAGEMENT OF   COEXISTING CONDITIONS With a greater drive to incorporate intellectually disabled individuals into the community comes a better awareness of the unique and challenging profile of their psychiatric and medical issues, and of how best to optimize their treatment to improve



quality of life and outcome for both the individual and family. These disorders, both psychiatric and medical, uniformly occur at a greater frequency in developmentally delayed and intellectually disabled children and youth compared with typically developing or cognitively able children. Psychiatric disorders encountered include anxiety, mood disorders, disruptive behaviors, inattention, and aggression. Medical issues include epilepsy, sleep disorders, sensory impairments, and feeding problems.

OUTCOME AND PROGNOSIS The vast majority of developmentally delayed or intellectually disabled children presently remain at home with the best caregivers possible—a loving, supportive, and nurturing family. Longitudinal studies suggest continued intellectual development in those with mild or moderate delay, and the absence of such improvement in those with severe or profound ID. Functional attainment for the child with severe neurodevelopmental disability by age 6 typically represents the functional attainment with respect to ambulation, feeding, toileting, and self-hygiene achieved for the life span. As such, the pragmatic aims for education should be on short-term achievable goals that assist in improving functional capacity. The transition to adult life can be challenging with issues related to living situations, limited access to entitlements, termination of educational options, sexuality, and employment (sheltered or supported), and the locus of medical care provision (i.e., pediatric to adult). Family involvement in transition planning is essential for the successful adjustment to adult life. Individuals with ID have had higher unemployment rates than the general population and a tendency for placement in segregated (i.e., sheltered) environments. Periodic, ongoing support often has been found to be a necessary precondition for continued employment. The life expectancy of a child with mild to moderate ID who is in good general health without evidence of cardiorespiratory disease or severe epilepsy can be considered similar to that of the general pediatric population. Significant mobility limitations, lack of functional hand use, and feeding dependency (especially placement of a gastrostomy tube) limit life expectancy. However, a positive trend is evident, with life expectancy improving overall for those with ID, even for the most severely affected individuals. Acknowledgments The authors wish to thank Brieana Fregeau for her help with references and Alba Rinaldi for her original secretarial assistance. M.I.S. was supported by the MCH Foundation (Guyda Chair in Pediatrics) during the writing of this chapter.

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REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Leonard, H., Wen, X., 2002. The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment. Retard. Dev. Disabil. Res. Rev. 8, 117–134. Meerding, W.J., Bonneux, L., Polder, J.J., et al., 1998. Demographic and epidemiological determinants of healthcare costs in Netherlands: cost of illness study. BMJ 317, 111–115. Michelson, D.J., Shevell, M.I., Sherr, E.H., et al., 2011. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 77, 1629–1635. Miller, D.T., Adam, M.P., Aradhya, S., et al., 2010. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764. Sherr, E.H., Michelson, D.J., Shevell, M.I., et al., 2013. Neurodevelopmental disorders and genetic testing: current approaches and future advances. Ann. Neurol. 74, 164–170.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Table 51-1 Measures for evaluation of intellectual, neurodevelopmental, and behavioral progress Table 51-2 Qualitative description of IQ and index scores on Wechsler tests Table 51-3 Categories and causes of intellectual disability Box 51-1 Factors that increase the risk of neonatal mortality and intellectual disability Box 51-2 Eye abnormalities Box 51-3 Seizures Box 51-4 Skin abnormalities Box 51-5 Hearing abnormalities Box 51-6 Vomiting Box 51-7 Hair abnormalities Box 51-8 Hepatosplenomegaly Box 51-9 Metabolic acidosis Box 51-10 Other abnormalities

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Cognitive and Motor Regression Stanford K. Shu, David J. Michelson, and Stephen Ashwal

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Progressive encephalopathies (PE) are diseases that cause a gradual decline in cognitive and motor function over time. Toxic, infectious, inflammatory, and neoplastic disorders that can present in a subacute to chronic fashion must be considered in the evaluation of patients presenting with PE. This chapter will focus on the wide array of genetic and metabolic diseases that typically present with PE and pose several diagnostic challenges for clinicians. One such challenge relates to the etiologies being individually rare and thus generally unfamiliar to clinicians. A second challenge relates to the phenotypic variability of genetic disorders. Many inborn errors of metabolism (IEM) caused by mutations in genes for critical enzymes, for example, have a “classic” and severe presentation related to complete enzyme deficiency (i.e., neonatal encephalopathy with multiorgan failure) but can be milder and even subtle with later presentation (i.e., psychiatric changes in adulthood) owing to increasing degrees of residual enzymatic function.

DEFINITION There is no accepted definition of the term “progressive encephalopathy,” and it has been used interchangeably with such terms as “neurodegenerative disorder,” “neurodegenerative encephalopathy,” and “progressive intellectual and neurologic deterioration.” We use the term PE in this chapter to refer to disorders that cause progressive central nervous system (CNS) injury and loss of function, affecting multiple domains (i.e., cognitive, affective, psychomotor, social, perceptual, and linguistic).

EPIDEMIOLOGY A few surveillance studies have informed our sense of the overall incidence of PE in various regions of the world. Two studies from Norway reported incidence rates of 0.6 per 1000 person years. Etiologies were most often metabolic (66%) or neurodegenerative (32%), but 20% of cases remained unclassified. A decreasing incidence was seen with age, with cases distributed among neonates (0 to 4 weeks, 32.1%); infants (1 to 12 months, 39.3%); and juveniles (6 to 12 years, 4.8%), with none seen in late juveniles (6 to 12 years, 4.8%) and late juveniles (older than 12 years, 0%). Far more neonatal onset cases were metabolic (46%) than neurodegenerative (7%) in nature. A related study from the same investigators examined survival rates and prognostic factors for survival among these patients. Overall, 37% of the patients suffered early death, and the cumulative probabilities for survival were 81% at 1 year and 66% at 10 years. Neonatal onset of symptoms and a metabolic versus neurodegenerative etiology were risk factors for mortality. The 10 year survival rate for children with metabolic diseases (58%) was significantly poorer than that of children with neurodegenerative diseases (87.5%). Much of what has been published regarding these disorders has been retrospec-

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tive and focuses on individual conditions, providing little basis for a discussion of their collective epidemiology.

ETIOLOGY Most genetic causes of PE are due to either an IEM or a neurodegenerative disorder (ND). Chapters 23, 26, 32, 48, 50, and 99 provide overviews of many of the conditions that can present with PE. Chapters 23, 26, 48, 50, and 99 provide overviews of many of the conditions that can present with a progressive encephalopathy. The IEMs are themselves frequently divided into three groups, based on pathophysiology. In the first group are those disorders in which symptoms of acute or chronic intoxication are caused by the intracellular and extracellular (and thus measurable in blood, urine, and/ or cerebrospinal fluid) accumulation of the compounds proximal to the defective enzyme. Examples include errors of amino acid metabolism (e.g., phenylketonuria and maple syrup urine disease), organic acidemias (e.g., methylmalonic aciduria and propionic acidemia), urea cycle disorders (e.g., ornithine transcarbamylase deficiency and argininemia), disorders of carbohydrate metabolism (e.g., galactosemia and hereditary fructose intolerance), disorders of metal transport (e.g., Wilson disease and Menkes disease), and disorders of porphyrin metabolism. Because the placenta acts to maintain homeostasis of small molecules that can cross its capillaries, these disorders are, overall, less likely to cause embryonic toxicity and more likely to present in infancy and childhood after a symptom-free period whose length depends in part on the degree of enzyme deficiency. Other circumstances such as fever, illness, and dietary changes can also influence the timing and severity of symptoms. The second group of IEMs is comprised of those disorders in which symptoms are due, at least in part, to the inability of the brain and other organs to produce or utilize sufficient energy for normal function. Energy deficiency can result from defective function of the mitochondria, including defects of pyruvate transport and modification, the Krebs cycle enzymes, the fatty acid oxidation enzymes, and the respiratory chain enzymes that allow for aerobic metabolism. Energy deficiency can also result from defects in cytoplasmic enzymes such as those responsible for glycogen synthesis, glycolysis and gluconeogenesis; insulin secretion and responsiveness; creatine synthesis and transport; and the pentose phosphate pathway. It is not uncommon for children with IEMs causing energy defects to present with congenital dysmorphism or cerebral dysgenesis. Disorders in the third group of IEMs are typically thought of as storage disorders, in which incompletely catabolized complex molecules accumulate within neuronal and extraneuronal tissues and cause progressive neurologic symptoms and somatic changes. Examples include mucopolysaccharidoses, oligosaccharidoses, and lysosomal storage disorders. Some authors expand this third group to include disorders of complex molecule synthesis and breakdown that result in a loss of function without measurably abnormal storage such as



Cognitive and Motor Regression

peroxisomal disorders, congenital disorders of glycosylation, and disorders of cholesterol biosynthesis. Nonmetabolic genetic causes of PE associated with progressive neuronal loss, usually demonstrable as atrophy on neuroimaging, are classified as neurodegenerative disorders (ND). The description and recognition of NDs were previously based purely on clinical features. However, the past decades have seen the elucidation of a genetic basis for most and a pathophysiologic basis for many. NDs of as yet unclear pathophysiology are sometimes categorized based on whether they affect the brain homogenously (diffuse encephalopathies) or preferentially affecting the cerebral cortex (poliodystrophies), the cerebral white matter (leukodystrophies), the basal ganglia (corencephalopathies), or the cerebellum, brainstem, and spinal cord (spinocerebellar diseases). An early study of the incidence of PE at two large academic centers in the United States found 341 pediatric cases with one of more than 50 different CNS disorders among 1218 hospital admissions over the course of 10 years (Table 52-1). Although

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72% of the cases were found to have genetic or metabolic disorders, the study also included a significant number of cases with isolated lower motor neuron syndromes and cases attributable to acquired injuries from infections, immunologic disorders, refractory epilepsy, chronic environmental insults, nutritional deficiencies, and iatrogenic factors. Data from another study are summarized in Table 52-2. After the initial description in 1996 of 10 cases of new variant Creutzfeldt-Jakob disease (nvCJD) affecting young adults in the United Kingdom, several countries instituted prospective surveillance programs to collect data on patients with PE to better identify additional cases of nvCJD. Although these studies have relied on reports from pediatricians and have been unable to describe absolute incidence or prevalence figures, they have reported relative prevalences within their areas. The first report from the surveillance done in the United Kingdom collected and analyzed pediatric cases of progressive intellectual and neurologic deterioration over a 5-year span. Of the 798 cases collected, 577 (72%) had a confirmed

TABLE 52-1  Diagnoses in 341 Cases of PE Diagnosis CORTICAL DISORDERS

Number (%) 129 (38%)

Diagnosis

Number (%)

Organic acidurias

2

Lysosomal storage disorders

39

Letterer-Siwe disease

2

Hypoxic poliodystrophy

29

Sturge-Weber syndrome

2

Idiopathic poliodystrophy

24

Zellweger syndrome

2

West syndrome

17

Homocystinuria

1

Lennox-Gastaut syndrome

9

Incontinentia pigmenti

1

Metabolic poliodystrophy

4

Sjögren-Larsson syndrome

Toxoplasmosis

3

SPINOCEREBELLAR DISORDERS

51 (15%)

Postvaccine poliodystrophy

3

Spinal muscular atrophy

19

Lowe syndrome

1

Hereditary spastic paraplegia

12

1

WHITE MATTER DISORDERS

71 (21%)

Acute cerebellar ataxia

8

SSPE

26

Infantile polymyoclonus

4

ADEM and MS

17

Charcot-Marie-Tooth disease

2

Adrenoleukodystrophy

8

Friedreich ataxia

2

Metachromatic leukodystrophy

5

Marinesco-Sjögren syndrome

1

Pelizaeus-Merzbacher disease

4

OPCA

1

Krabbe disease

4

Spinocerebellar degeneration

1

Phenylketonuria

2

Refsum disease

Cockayne syndrome

2

BASAL GANGLIA DISORDERS

Canavan disease

1

Idiopathic corencephalopathy

8

Alexander disease

1

Huntington disease

5

1

Maple syrup urine disease

1 26 (8%)

Mitochondrial disorders

4

DIFFUSE ENCEPHALOPATHIES

63 (19%)

Dystonia musculorum deformans

2

Tuberous sclerosis

19

Pantothenate kinase-associated neurodegeneration

2

Idiopathic encephalopathy

17

Ataxia-telangiectasia

1

Hyperammonemic disorders

6

Congenital indifference to pain

1

Mitochondrial disorders

4

Infantile neuroaxonal dystrophy

1

Neurofibromatosis

4

Familial dysautonomia

1

Achondroplasia

2

Wilson disease

1

ADEM, acute disseminated encephalomyelitis; MS, multiple sclerosis; OPCA, olivopontocerebellar atrophy; SSPE, subacute sclerosing panencephalitis. (Adapted from Dyken, P., Krawiecki, N., 1983. Neurodegenerative diseases of infancy and childhood. Ann Neurol 13, 351–364.)

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TABLE 52-2  Diagnoses in 66 Cases of PE Disease

N (%)

Metachromatic leukodystrophy

14 (21%)

Adrenoleukodystrophy

11 (16%)

Subacute sclerosing panencephalitis (SSPE)

8 (12%)

Wilson disease

6 (9.8%)

Friedreich ataxia

5 (7.5%)

Lipidosis

4 (6%)

Gaucher disease

3 (4.5%)

Alexander disease

2 (3%)

Pantothenate kinase associated neurodegeneration

2 (3%)

Multiple sclerosis

1 (1.5%)

Ataxia telangiectasia

1 (1.5%)

Unknown etiology

6 (9.8%)

(Adapted from Pierre, G., 2013. Neurodegenerative disorders and metabolic disease. Arch Dis Child 98(8), 618–624.)

diagnosis. Higher prevalence rates were seen in populations with higher rates of consanguineous marriage. Updates of the study reported 147 different confirmed diagnoses in 1114 (42%) of the 2636 patients. In total, six of the children were found to have confirmed or probable nvCJD. A survey-based study conducted in Australia identified 230 cases of childhood PE in a 2-year period, with 134 patients having Rett syndrome, 20 having a lysosomal storage disorder, 16 having a leukodystrophy, and 15 having a mitochondrial disease. The previously described Norwegian study gathered cases of pediatric PE over an 18-year period from the area’s single children’s hospital and from the national diagnostic laboratory for metabolic diseases. The authors excluded patients with diseases in which cognitive impairment was either atypical (e.g., spinocerebellar ataxia and spinal muscular atrophy) or typically seen only late in the course (multiple sclerosis). In addition, unlike the studies already discussed, this study excluded disorders such as regressive autism and Rett syndrome, in which intellectual deterioration may be seen early in the course but typically stabilizes. As mentioned, the authors reported a total of 84 cases of PE, of which they classified two-thirds as metabolic, one-third as neurodegenerative, and two cases, both due to HIV/AIDS, as infectious. The authors found an increased (seven-fold) risk of PE in children born within communities with higher rates of consanguineous unions. They further estimated that avoidance of consanguineous marriage would decrease the incidence of PE by 30 to 50%.

DIAGNOSTIC EVALUATION When PE is suspected, a timely evaluation that results in a specific diagnosis can be of great value. It is not uncommon for the child neurologist to uncover clinical features of a progressive process in a patient who is referred for developmental delay or autism. In this regard, a key element in the evaluation of global developmental delay (GDD) or intellectual disability (ID) is a second visit to ensure that the child’s condition is nonprogressive. The diagnostic yield for evaluating children with PE is far less well studied than the yield of evaluations of children with GDD or ID. Nevertheless, it is even more urgent that children with PE undergo a comprehensive diagnostic evaluation.

Although specific treatments are available for only a minority of the diseases responsible for PE, an etiologic diagnosis has many other direct benefits (Chapter 59), including the ability to: 1. Relieve caregivers of anxiety and uncertainty when specific information about inheritance and prognosis can be given 2. Empower caregivers to become involved in support groups, advocacy, and research networks 3. Limit further diagnostic testing, which may be costly (in time and money) or invasive 4. Prevent recurrences in family members through carrier screening and prenatal testing, when available 5. Improve understanding of a. Available treatments b. Long-term prognosis c. Associated coexistent conditions d. Recurrence risk and mode of inheritance In all cases, the diagnostic tests employed should be tailored to the presentation of the child and, in most cases, testing should proceed from least to most invasive. Consideration should be given to the early identification or exclusion of all potentially treatable causes of the patient’s symptoms.

HISTORY Developmental History Every child suspected of having a neurodevelopmental disorder should undergo a thorough clinical evaluation that includes a detailed medical and developmental history, family history, and review of systems and detailed physical and neurologic examinations. The clinical features most suggestive of a PE—the gradual loss of previously acquired skills and the gradual emergence of neurologic signs and symptoms after a period of normal development—are more readily observed when they are of later onset and when they progress more rapidly. In this regard, a key element in the evaluation of GDD or ID is a second visit to ensure that the child’s condition is nonprogressive. A combination of late but rapid deterioration is not common to most disorders but can occur. The features of PE are more difficult to recognize when the progression is very slow or when the onset is so early that even initial development is clearly abnormal. A number of children initially given a diagnosis of cerebral palsy (CP) due to a presumed remote brain injury were later found to have an IEM or ND. This experience suggests that children with a diagnosis of CP should undergo further evaluation when there is no definite history of a preceding injury, when there is a family history of neurologic symptoms or of parental consanguinity, or if there is an inadequately explained oculomotor deficit, movement disorder, ataxia, muscle atrophy, or sensory deficit. Unexplained episodes of altered mental status, dietary aversions, vomiting, or abnormal movements should arouse strong suspicion that a child is suffering from an IEM. Conversely, children whose underlying neurologic disease is not itself progressive can nevertheless present with gradual loss of skills and emergence of new neurologic signs and symptoms for a variety of reasons, including medication side effects, intercurrent medical and psychiatric illnesses, and worsening of preexisting hydrocephalus, spasticity, dystonia, or epilepsy. Some epileptic syndromes (e.g., epileptic encephalopathies) and neurodevelopmental disorders (e.g., regressive autism) are associated with a gradual loss of function or developmental arrest during their course but are unlikely to show relentless clinical deterioration, global involvement, or evidence of CNS damage.



The critical elements of the clinical evaluation are the same as have been outlined in detail for children presenting with nonprogressive neurodevelopmental disorders (Chapter 51). To establish the progressive nature of a child’s symptoms or clinical findings, however, it can be particularly helpful to review any records of the child’s prior appearance and abilities to which caregivers can provide access, including photographs, videos, and examples of the child’s writing and drawing. Repeated examinations over months, even years, may be necessary to uncover very subtle regression.

Family History A family history of developmental delay, intellectual disability, learning disability, early deaths, and seizures can be quite helpful in elucidating the etiology of a child’s neurologic issues. A three-generation pedigree should be obtained. Consanguinity varies significantly from one culture to the next. Practitioners should be tactful when asking if the child is the product of a consanguineous union, one in which the parents are second cousins or more closely related.

Maternal History Chromosomal abnormalities account for 50% to 70% of miscarriages of less than 10 weeks gestation and are found in about 50% of couples with a history of recurrent miscarriages. Previous stillbirths, neonatal deaths, or infant deaths attributed to sudden infant death syndrome (SIDS) may be due to an IEM (Chapter 90). Exposure in utero to teratogens have been associated with developmental delay and intellectual disability but not with PE.

Neonatal History Delivery complications such as hypoxia and early postnatal complications such as hypoglycemia, CNS infection, and seizures may have profound effects on development. Patients with severe perinatal injuries, neuromuscular disorders, and epileptic encephalopathies may be difficult to distinguish from cases of early onset and severe PE given that both groups can show difficulty in reaching even the earliest developmental milestones.

Environmental History Lead encephalopathy and pica of other toxic substances such as mothballs (paradichlorobenzene) may cause PE. Acute and chronic hydrocarbon exposure has been associated with anxiety, mood disorders, and progressive neuropsychologic changes.

General Medical History The medical history can be obtained in a systematic fashion by organ systems. A history of complex congenital heart disease (CHD) may cause a progressive encephalopathy due to systemic and cerebral hypoperfusion may can cause permanent cerebrovascular injury and visible hypoplasia or atrophy. Endocrine disorders such as hypothyroidism and hyperthyroidism have been associated with developmental regression and movement disorders. Hashimoto encephalopathy has presented as a progressive myoclonic epilepsy syndrome. Both Addison disease and Cushing Syndrome are associated with a progressive encephalopathy. Infections such as Creutzfeldt-Jakob disease (CJD) and subacute sclerosing panencephalitis (SSPE) cause progressive

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neurologic deterioration that can be drawn out over many years. HIV infection may also be the cause of PE. Current criteria divide patients with HIV-encephalopathy into three groups: those who are asymptomatic, those with a mild neurocognitive disorder, and those with dementia. HIV encephalopathy was previously reported to occur in up to 30% of children with HIV. The use of highly active antiretroviral therapy (HAART) has decreased the incidence to 12%. Additional information on SSPE and HIV are provided in Chapter 115. Nutritional disorders or vitamin deficiencies (e.g., thiamine, niacin, biotin, folate, and vitamin E) have been associated with PE. Neurologic symptoms due to these conditions are reviewed in Chapters 46 and 47. Autoimmune encephalopathies with autoantibodies directed against proteins on the neuronal membrane (e.g., NMDA receptors) are increasingly well described and recognized in clinical practice. Symptoms may develop very acutely over the course of days, mimicking infectious meningoencephalitis, or may develop very slowly over the course of weeks to months, with early behavioral and psychiatric changes followed by seizures, dyskinesia, dysautonomia, sleep dysfunction, and an altered level of consciousness. These conditions are discussed in Chapters 118 and 119.

EXAMINATION The clinicians’ ability to recognize clinical patterns and features suggestive of a specific etiology can significantly narrow the diagnostic evaluation of a child with PE (Chapters 1–9). Primary motor and sensory functions are readily assessed by the screening neurologic examination, even in uncooperative children, but higher cortical functions are far more difficult to evaluate. The collective observations of clinicians, parents, and teachers who suspect subtle cognitive decline should be supplemented by those of a neuropsychologist. Chapter 10 reviews the approach to neuropsychological testing in children. Abnormalities of head size, stature, and facial morphology can suggest specific diagnoses such as Angelman syndrome. Neurocutaneous stigmata may suggest one of the phakomatoses, as with café-au-lait spots (neurofibromatosis); hypomelanotic macules and angiofibromas (tuberous sclerosis); blistering of the skin, swirling macular hyperpigmentation and linear hypopigmentation (incontinentia pigmenti); or a port wine stain on the face and glaucoma (Sturge-Weber syndrome). Hepatosplenomegaly and corneal clouding may suggest one of the mucopolysaccharidoses. Cardiomyopathy may be caused by a mitochondrial disorder. Progressive retinal degeneration has been associated with the neuronal ceroid lipofuscinoses and a cherry red spot is associated with sphingolipid storage disorders, in addition to central retinal artery occlusion, drug toxicity (quinine, dapsone), and toxic exposures (carbon monoxide, methanol).

LABORATORY TESTING Screening studies that might be done on a regular basis in the evaluation of a child with unexplained PE include those that look for evidence of involvement of non-CNS organ systems and narrow the differential diagnosis. These commonly include a complete blood count (CBC) and comprehensive metabolic profile (CMP). Other tests, often chosen because they can identify treatable causes of PE, include thyroid function tests, serum lead level, and tests of vitamin B12 and folate levels. In patients with progressive weakness or hypotonia, a serum creatine kinase level is often done to screen for muscular dystrophies. Other tests are difficult to interpret in

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cases of PE without highly suggestive and specific clinical and neuroimaging findings and so are rarely included as screening tests. When it is difficult to decide if a patient has a static or progressive encephalopathy, the diagnostic approach may be the same as for children with global developmental delay or intellectual disability (ID), as is discussed in Chapter 51. Increasingly microarray studies are being used for initial genetic diagnostic testing. Microarray studies can be used to screen the entire genome for copy number variants (CNVs) that are smaller (0.3 Mb) than can typically be detected by even a high-resolution karyotype (5 Mb). Array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays are both clinically available and, with reported yields of up to 15% to 20%, are typically used as first-line genetic tests for most children with unexplained ID. Microarrays will not detect mutations other than CNVs such as single nucleotide substitutions within an individual gene or large chromosome rearrangements. A karyotype is still recommended when the child appears dysmorphic or when there is a family history of multiple miscarriages or of similarly affected children. CNVs may be recognizably pathogenic, known to be benign, or may be variants of uncertain significance (VUS). Parental testing may be needed to guide the interpretation of a VUS. If a parent tests positive for the same CNV, it is considered more likely to be benign. However, if neither parent tests positive for the CNV and it appears to be a de novo mutation in the child, it is considered more likely to be pathologic. Although less frequently ordered now, routine cytogenetic testing (G-banded karyotype) has a yield of 3.7% to 10% in patients with mild to moderate developmental delay and is helpful for diagnosing aneuploidy and rearrangements such as translocations and inversions. Fluorescent in situ hybridization (FISH) or multiplex ligation-dependent probe amplification (MLPA) for specific disorders such as velocardiofacial syndrome (22q11 deletion) are done on patients with suggestive clinical features. Subtelomeric FISH studies were previously recommended but such testing for copy number variants (CNV) has been supplanted by the microarray studies with broader genome-wide coverage. Fragile X is the most commonly inherited cause of ID; however, the family history may be negative, and the dysmorphic features, usually recognizable in older children and adults, may not yet be apparent in young children. Other X-linked disorders such as Rett syndrome are found predominantly in girls. Testing for Rett syndrome (MeCP2 gene sequencing and MLPA) has been recommended for all girls with unexplained severe ID, particularly those with developmental regression, stereotypic hand movements, deceleration of head growth, and seizures. More than one hundred other genes have been associated with X-linked ID. Whole exome sequencing (WES), which sequences the protein encoding regions of all genes, has additional diagnostic utility and is increasingly becoming clinically available. The ability to test both parents (forming, along with the child, a trio) is crucial for WES interpretation as this technique regularly identifies hundreds or thousands of benign, inherited mutations. A 2012 study showed a diagnostic yield of 16% for WES in 100 severe ID trios. In the future, sequencing of the entire genome, including noncoding regions, is likely to become available on a clinical basis. Please refer to Chapters 34 and 35 for a more detailed discussion of genetic testing. The yield from metabolic evaluations of children with global developmental delay and PE is 0.2% to 5%. Some of these disorders are treatable or have symptoms that can be ameliorated with no more than a change in diet. Intrauterine or early diagnosis of some of these disorders may allow affected siblings to be treated at a milder or even asymptom-

atic stage of the illness. Please see Chapters 36, 50, and 51 as well as the section later in this chapter on the diagnostic approach for additional discussion. Electroencephalography is a valuable diagnostic tool in the evaluation of children with suspected PE. Epileptic encephalopathies describe a group of disorders in which abnormal CNS electrical activity persistently disturbs neuronal networks involved in cognition. Although the value of EEG is recognized in children with a suspected epileptic encephalopathy, the diagnostic yield in children with cognitive decline without obvious clinical seizures has not been clearly determined. However, it is common practice to acquire an EEG in this subset of patients because clinical seizures may be very subtle and because it is hoped that anticonvulsant use may, in some patients with epileptic encephalopathies, improve cognitive function. Neuroimaging studies are also an important part of the evaluation of children with PE. Magnetic resonance imaging (MRI) is the investigation of choice for structural abnormalities, neuronal migrational disorders, white matter diseases and posterior fossa structures. Computed tomography (CT) can more readily show intracranial calcifications and cranial bone abnormalities such as craniosynostosis. Specialized applications of MRI as spectroscopy, susceptibility weighted imaging, diffusion weighted imaging, and diffusion tensor imaging can provide additional information about brain structure and function. Up to 40% of patients undergoing evaluation for developmental disability show a structural or biochemical abnormality on neuroimaging. Although the abnormalities are often nonspecific, such as mild global atrophy, there are times when the findings are highly suggestive of a specific disorder (Chapter 12). A lumbar puncture to quantify cerebrospinal fluid (CSF) amino acids, lactate, and neurotransmitter levels may be considered in patients being evaluated for PE. A recent study reported diagnostic CSF results in 25.8% of 62 patients suspected of having a pediatric neurotransmitter diseases based on their clinical symptoms. See Chapter 44 for further details.

BRAIN BIOPSY The necessity for brain biopsy for nonneoplastic conditions has substantially diminished over the years as advances in neuroimaging, biochemical, and genetic tests have provided safer and easier means by which to make a diagnosis. However, biopsy may still play an important role in the evaluation of patients with PE that remains unexplained despite extensive noninvasive testing. In some cases, biopsy is the only method by which a particular diagnosis can be confirmed and in others, the biopsy results provide crucial information about therapeutic options and prognosis. See online chapter.

DIAGNOSTIC APPROACH Professional societies and governmental agencies have produced systematic reviews and evidence-based clinical practice guidelines regarding the evaluation of children with neurodevelopmental disabilities (Miclea et al., 2015; Srour and Shevell, 2014; Dunfield et al., 2014; Michelson et al., 2011; Miller et al, 2010; Moeschler and Shevell, 2006; Curry et al., 1997; Shevell et al., 2003; Valle website). However, these reports were focused on children with nonprogressive symptoms. Studies specifically reviewing the diagnostic workup of children with PE have a variable yield for an etiologic diagnosis depending on the inclusion criteria and which neuroimaging studies, metabolic and genetic testing is done. Three alternative methods to approach the diagnostic evaluation of children with PE have been described. The first



approach, similar to that used to evaluate children with nonprogressive developmental disorders, begins with general screening tests that are performed for all such children and then adds additional screening tests for infectious, toxic, endocrinologic, genetic, neoplastic, metabolic, autoimmune, and nutritional disorders based on the child’s individual history or initial screening test results (See Table 52-8). This approach is based more on frequency of likely diseases rather than on treatability. Abnormal screening tests will often suggest the need for further neuroimaging with magnetic resonance spectroscopy or diffusion tensor imaging; further electrophysiologic testing with electroretinography or electromyography; or further metabolic or targeted genetic screening tests or tissue biopsies for microscopy or enzyme analysis. A second approach to the evaluation of PE is to use an interactive database to generate a broad differential diagnosis. SimulConsult (www.simulconsult.com) is a web-based pro­ gram that is freely available to clinicians and students. As clinical information is entered, the program orders its differential based on likelihood and makes suggestions regarding what additional findings and laboratory tests would most help clarify the diagnosis. A broad differential can help clinicians to avoid cognitive pitfalls that commonly contribute to diagnostic error and delay including the biases of availability and representativeness (favoring familiar diagnoses over less wellknown diagnoses or disease variants) and those of framing and premature closure (favoring findings that confirm rather than question a preexisting diagnosis). DiagnosisPro (en.diagnosispro.com) is another web-based database that is not specific to neurology. A third approach, as proposed by the British Columbia Children’s Hospital group, is referred to as the Treatable Intellectual Disability Endeavor (TIDE) algorithm (www.tidebc.org) (Van Karnebeek and Sockler-Ipsiroglu, 2014). The TIDE algorithm emphasizes testing patients for treatable disorders, even when rare, before testing them for more common but untreatable disorders. This protocol is reviewed in Chapter 59. The first tier of testing, to be applied to all children presenting with PE, calls for blood and urine studies that are available at most commercial laboratories at a reasonable price and which are likely to detect up to 60% of the currently known treatable disorders (Table 52-9). Second tier tests are generally more expensive and invasive and are recommended on a more selective basis, based on clinical judgment and suggestions from textbooks, online resources, and other specialists such as metabolic geneticists. Use of the TIDE protocol has the potential to reduce the cost and diagnostic delay involved in identifying patients with treatable IEMs. The individual disorders causing PE in childhood are too numerous to discuss in detail in this chapter, but they are presented in the online version of the book in tables based on age and symptomatology (i.e., Tables 52-10 to 52-24). Up-to-date information about the sensitivity and availability of tests for specific genetic disorders is available through the Gene Tests website (www.genetests.org). Some genetic tests can be performed on a research basis through direct communication and cooperation between the clinician and research laboratory.

MANAGEMENT The specific cause of childhood PE cannot be determined in at least half of the cases (as reported in large epidemiologic surveys). However, because a small number of disorders can be at least ameliorated by medical therapies, pursuit of a diagnostic workup is warranted. Caregivers can be expected to have a great number of questions and concerns that will require a large amount of time, patience, and sensitivity on the part of

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TABLE 52-9  Treatable Intellectual Disability Endeavor (TIDE) Diagnostic Protocol TIER 1: NONTARGETED METABOLIC SCREENING TO IDENTIFY 54 (60%) TREATABLE IEM: Urine Blood Plasma amino acids Organic acids Plasma total homocysteine Purines and pyrimidines Acylcarnitine profile Creatine metabolites Copper, ceruloplasmin Oligosaccharides Glycosaminoglycans Amino acids (when indicated) TIER 2: CURRENT PRACTICE ADHERING TO INTERNATIONAL GUIDELINES (1 OR MORE OF): Low yhreshold for ordering Audiology tests Ophthalmology Cytogenetic testing (array CGH) Thyroid studies CBC Lead Metabolic testing Brain MRI and 1H spectroscopy (where available) Fragile X Targeted gene sequencing/ molecular panel Other TIER 3: TARGETED WORKUP TO IDENTIFY 35 (40%) TREATABLE IEM REQUIRING SPECIFIC TESTING: According to patient’s aymptomatology and clinician’s expertise Utilization of digital tools (www.treatable-id.org) Specific biochemical/gene test Whole blood manganese Plasma cholestanol Plasma 7-dehydroxy-cholesterol : cholesterol ratio Plasma pipecolic acid and urine α-amino adipic semialdehyde (AASA) Plasma very long chain fatty acids Plasma vitamin B12 and folate Serum and CSF lactate : pyruvate ratio Enzyme activities (leukocytes): arylsulfatase A, biotinidase, glucocerebrosidase, fatty aldehyde dehydrogenase Urine deoxypyridonoline CSF amino acids CSF neurotransmitters CSF:plasma glucose ratio CoQ measurement fibroblasts Molecular analysis: CA5A, NPC1, NPC2, SC4MOL, SLC18A2, SLC19A3, SLC30A10, SLC52A2, SLC52A3, PDHA1, DLAT, PDHX, SPR, TH genes (Adapted from Van Karnebeek, C.D., Stockler-Ipsiroglu, S., 2014. Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia. Paediat Child Health 19(9), 469–471.)

the clinician. Even when disease-specific treatments are not available, the clinician can be of great assistance in maintaining the child’s quality of life. Efforts should be made early in the course to direct the child to other sources of supportive care, including rehabilitation specialists, nutritionists, special education instructors, and speech, occupational, and physical therapists. When possible, the child’s caregivers should be referred to a social worker who can help them obtain financial support, nursing care, and social support networks and a genetic counselor who can explain the inheritance patterns and aspects of family planning and antenatal diagnostic possibilities, provide talking points to communicate with family members, and help identify support groups and opportunities for advocacy.

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FUTURE DIRECTIONS Earlier diagnosis of conditions causing PE, particularly before devastating neurologic symptoms develop, will improve patient treatment and family planning. Prenatal diagnosis has several advantages but is currently difficult even in families with known risks. Noninvasive prenatal testing (NIPT) can examine a pregnant mother’s blood for fetal DNA abnormalities and is currently being offered to mothers at high risk for aneuploidies such as Trisomy 21. This method is likely to expand to screening for CNVs and point mutations as technical and ethical issues are worked out. Single nucleotide polymorphisms (SNPs) are the most abundant sequence variations in the human genome, with approximately 150 million discovered thus far (www.ncbi .nlm.nih.gov/snp). Current arrays simultaneously genotype thousands of SNPs, providing information about CNVs but also about uniparental disomy and regional homozygosity (which can reflect parental consanguinity). Next generation sequencing (NGS) techniques are faster and less expensive than older sequencing methods and are already providing a greater number of patients with access to large gene panels. It is certain that the future will bring us testing methods for metabolic and genetic disorders that is increasingly personalized, sensitive and specific, cost-efficient, and better able to provide patients with a clear diagnosis with minimal delay. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Curry, C.J., Stevenson, R.E., Aughton, D., et al., 1997. Evaluation of mental retardation: recommendations of a consensus conference. Am. J. Med. Genet. 72, 468–477. Dunfield, L., Mitra, D., Tonelli, M., et al., 2014. Protocol: screening and treatment for developmental delay in early childhood. Accessed at: . Michelson, D.J., Shevell, M.I., Sherr, E.H., et al., 2011. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 77 (17), 1629–1635. Miclea, D., Peca, L., Cuzmici, Z., et al., 2015. Genetic testing in patients with global developmental delay / intellectual disabilities. A review. Clujul Med 88 (3), 288–292. Miller, D.T., Adam, M.P., Aradya, S., et al., 2010. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am. J. Hum. Genet. 86, 749–764. Moeschler, J.B., Shevell, M., 2006. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 117, 2304–2316. Shevell, M., Ashwal, S., Donley, D., et al., 2003. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 60, 367–380. Srour, M., Shevell, M., 2014. Genetics and the investigation of developmental delay/intellectual disability. Arch. Dis. Child. 99, 386– 389.

Valle, D., Vogelstein, B., Kinzler, K.W., et al. The Online Metabolic and Molecular Bases of Inherited Disease. . Van Karnebeek, C.D., Stockler-Ipsiroglu, S., 2014. Early identification of treatable inborn errors of metabolism in children with intellectual disability: The Treatable Intellectual Disability Endeavor protocol in British Columbia. Paediatr Child Health 19 (9), 469–471.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Table 52-3 Diagnoses in 1114 Cases of PE Table 52-4 Diagnoses in 84 Cases of PE Table 52-5 Patients Initially Misdiagnosed as Having Cerebral Palsy Table 52-6 Cortical Localization of Cognitive Impairments Table 52-7 Pediatric Neurotransmitter Disorders Diagnosed by Lumbar Puncture in 62 Patients Table 52-8 Screening Diagnostic Tests for Nonspecific Progressive Encephalopathy Table 52-10 Classification of Inborn Errors Presenting in the Neonatal Period (0–3 Months) Table 52-11 Progressive Encephalopathy in Infancy (1–12 Months) with Obvious Somatic Symptoms Table 52-12 Progressive Encephalopathy in Infancy (1–12 Months) with Specific or Suggestive Neurologic Signs Table 52-13 Progressive Encephalopathy in Infancy (1–12 Months) without Suggestive Neurologic Signs Table 52-14 Progressive Encephalopathy in Early Childhood (1–5 Years) with Somatic Signs Table 52-15 Progressive Encephalopathy in Early Childhood (1–5 Years) with Paraparesis Table 52-16 Progressive Encephalopathy in Middle to Late Childhood (1–5 Years) with Ataxia and Incoordination Table 52-17 Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) with Seizures and Ataxia Table 52-18 Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) with Predominant Extrapyramidal Signs Table 52-19 Severe, Diffuse, Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) Table 52-20 Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) with Polymyoclonus Table 52-21 Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) with Predominant Cerebellar Ataxia Table 52-22 Progressive Encephalopathy in Middle to Late Childhood (5–15 Yrs) with Predominant Polyneuropathy Table 52-23 Progressive Encephalopathy in Middle to Late Childhood (5–15 Years) with Predominantly Psychiatric Symptoms Table 52-24 Progressive Encephalopathy in Adulthood (15–70 Years)

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Developmental Language Disorders Doris A. Trauner and Ruth D. Nass

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Developmental language disorders (DLDs) include a number of conditions that adversely affect language development. The most common DLD is specific language impairment (SLI), a neurodevelopmental disorder (NDD) that affects 2% to 11% of the population, making it one of the most common NDDs. The hallmark of SLI is that a child with normal intelligence and hearing fails to develop language in an age-appropriate fashion. SLI is a clinical diagnosis, based on the presence of a normal nonverbal IQ, evidence of expressive and/or receptive language significantly below expected for age and intelligence (SLI is often defined by scoring at least 1.5 standard deviations below the mean for age on standardized, age-appropriate tests of language), and absence of other specific conditions such as autism, global intellectual disability, metabolic or genetic disorders, or severe environmental deprivation. Although this condition is commonly called “specific” language impairment, there is controversy as to how specific the condition is and whether the terminology should be changed to a more generic term, such as language impairment. Despite this controversy, however, at present the terminology remains the same. Other forms of DLD include stuttering, selective mutism, verbal apraxia, and epileptic aphasia. Box 53-1 lists normal language milestones as a baseline for assessing a child’s developing language competence.

NEURAL SUBSTRATES OF LANGUAGE In adults, specific brain regions, primarily in the left hemisphere, are believed to mediate language, based primarily on studies of adults with strokes and more recently on neurophysiological and functional imaging studies. The neural substrates of language during early development are not as clearly defined, and in fact may differ markedly from those that mediate language once it has developed. Children who had a left-hemisphere stroke in early life do not typically demonstrate aphasia, or even a functional language impairment. A classic study by Bates et al. (2001) demonstrated the differences between children with perinatal stroke and adults with late-acquired stroke in the left hemisphere, showing that children performed equally well as their typically developing counterparts on multiple aspects of language, unrelated to the hemispheric side of the lesion, whereas adults who had a later-onset left-hemisphere stroke showed significant impairments on the same tasks. Such findings suggest that language is not “hardwired” into specific brain regions, but that the process of language acquisition requires more widely distributed neural networks. Studies of very early language awareness in the first few months of life indicate that infants learn very early to attend to the linguistic traits that are relevant to the language to which they are exposed. Typically developing children attend more to speech sounds when their attention is directed to auditory rather than visual stimuli, whereas children with SLI are unable to sufficiently attend to speech sounds in the same setting, suggesting that there may be a

deficit in auditory attention or in general attentional resources at the basis of SLI. Rapid processing of sensory information, particularly in the auditory modality, may also be a contributing factor to impaired language development. Efficient processing of auditory stimuli has been shown to be impaired in many children with SLI. It is as yet unclear whether the primary deficit is in the ability to focus attention to process auditory information or whether the processing deficit is the principal causal factor. In either event, basic sensory processes are disrupted in SLI, leading to impaired language development.

NEUROANATOMY OF SPECIFIC   LANGUAGE IMPAIRMENT Although SLI has been an important area of research and clinical focus for many years, there have been relatively few studies of brain structure in this condition, and those reported have not been consistent. Clinical neuroimaging scans (magnetic resonance imaging [MRI]) generally yield normal results, although a higher-than-expected incidence of abnormal findings, including ventriculomegaly, central volume loss, and white-matter hyperintensities, has been described, suggestive of possible disruption of normal white-matter structure. Quantitative neuroimaging techniques have focused primarily on the frontal and temporal regions thought to be important for language and have demonstrated abnormal gyrification in the inferior frontal gyrus, the absence of the normal left-right asymmetry of the planum temporale, or atypical right-greaterthan-left asymmetry of both anterior and posterior temporal lobes. Arguments for atypical lateralization of the developing brain for language as a cause for SLI have been made based on the differences in brain symmetry observed in some of the imaging studies (Badcock et al., 2012). Functional neuroimaging studies have also demonstrated lack of the expected left lateralization of activation on linguistic tasks. Diffusion-tensor imaging techniques have demonstrated white-matter structural changes in the superior longitudinal fasciculus (SLF) of adolescents with SLI. The SLF is a major white-matter tract that is thought to be crucial for language processing because it connects the anterior areas of the cortex to the posterior areas and, among other areas, the Broca’s area to the Wernicke’s area. Differences in SLF structure provide a possible structural explanation for the language-processing problems found in SLI. Other types of imaging studies have demonstrated functional changes in the brains of children and adults with SLI. Single-photon emission-computed tomography (SPECT) studies have shown reduced cerebral blood flow in the left hemisphere of children with SLI compared with controls. With the use of transcranial ultrasound to examine blood flow to each hemisphere during a word-generation task, aberrant hemispheric blood-flow responses have been demonstrated in adults with SLI. Magnetoencephalography was used to track the spatiotemporal course of brain response to real words and pseudowords in children with SLI compared with typically developing children. Bilateral superior temporal cortex regions

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BOX 53-1  Normal Language Milestones RECEPTIVE • Some words understood by 9 months • Follows one-step commands by 12 months without being cued by a gesture EXPRESSIVE • Cooing—2 months • Babbling—6 months • Variable babble—8 months • One word other than dada and mama—12 months • 10 to 50 words used meaningfully—16–20 months • Two-word phrases—20–24 months • Points to at least one body part and to named objects and people on command—20 months • Vocabulary greater than 200 words—2 years • Two-word combinations—2 years • Follows two-part commands—2 years • Sentences of three to four words—3 years • Compound and complex sentences—4 years • Passive voice—6 years

were activated to word and pseudoword presentations, but in contrast to controls, children with SLI showed equally strong activation to both words and pseudowords. Further, children with SLI did not show the typical attenuation of activation the second time the same word was presented, indicating that the linguistic activation that underlies word recognition may be defective in SLI.

FACTORS ASSOCIATED WITH DEVELOPMENTAL LANGUAGE DISORDERS As with many neurodevelopmental disorders, there is a higher incidence of SLI in males (1.6 : 1 males : females). The cause for the gender differences is not known. Numerous biological and environmental risk factors for SLI have been identified. Low birth weight, prematurity, and prenatal exposure to drugs (e.g., cocaine) and to cigarettes have been reported to adversely affect language development, although no single perinatal complication has been definitively associated with SLI; rather, an aggregate of perinatal complications could contribute to later language impairment. Although frequent episodes of otitis media have been suggested as causing language impairment, there is little evidence from controlled studies to indicate a causal relationship. Intermittent hearing loss may interfere with language development in at-risk children, but is not likely to cause long-term language issues in otherwise normally developing children. Language impairment is seen in association with specific neurologic and genetic disorders. For example, perisylvian polymicrogyria (or congenital bilateral perisylvian syndrome) is a disorder of defective neuronal migration that has a spectrum of neurologic impairments that include severe epilepsy and cognitive impairment. In some children with this condition, language impairment is the most prominent feature. Language impairment is also prominent in a number of chromosomal disorders, including Down, Klinefelter, and fragile X syndromes. Epileptic encephalopathies, particularly Landau– Kleffner syndrome (LKS), may have language impairment (often receptive greater than expressive impairment) as an isolated or primary symptom. Rolandic epilepsy, often considered to be “benign,” may be complicated by language impairment and learning disabilities.

GENETICS Heritability rates for SLI run as high as 0.5, but they are variable and are affected by the criteria used to diagnose the disorder (SLI vs. more general DLDs that may be associated with known genetic syndromes) (Bishop and Hayiou-Thomas, 2008). The median incidence rate for language difficulties in the families of children with language impairment is up to 35%, compared with a median incidence rate of 11% in control families. Increased concordance rates in monozygotic versus dizygotic twins indicate that heredity, not just shared environment, is responsible for familial clustering. Studies using genome-wide scanning have implicated a number of gene loci, but the same loci have not been found in a reproducible fashion (Vernes et al., 2008). Isolated families with specific mutations have been studied. In the threegeneration KE family, half the members are affected with a severe speech and language disorder that is transmitted as an autosomal-dominant monogenic trait involving the FOXP2 forkhead-domain gene. Notably, however, a screening of 270 4-year-olds with SLI was negative for the FOXP2 mutation. Recently HLA alleles have been associated with SLI. Maternally but not paternally inherited HLA-B B8 and HLADQA1*0501 were associated with impaired receptive language. HLA-A A2 was associated with expressive language ability. HLA-DRB1 was found with greater frequency in individuals with SLI than in controls. In other studies, the calciumtransporting ATPase 2C2 (ATP2C2) gene on chromosome 16 has been considered as a candidate gene for SLI. It is unlikely that there will be one specific gene whose function would be restricted to forming the genetic basis for language acquisition. It is more likely that there are many genes that contribute to a variety of functions, and that these genes form networks that are recruited in the process of language acquisition. The issue of pleiotropy, or the influence of the same genes on multiple phenotypes, has also been discussed in the literature on SLI, given the substantive overlap in regions of linkage for a variety of developmental disorders, such as speech and sound disorders (SSD) and developmental dyslexia, and SLI and autism. Whether these are true examples of pleiotropy or outcomes of the imprecision of phenotype definitions is yet to be determined.

DIAGNOSIS SLI is a clinical diagnosis based on a delay in language development for expected age, in the absence of intellectual disability, autism, hearing impairment, or environmental deprivation. In children for whom formal language assessments are conducted, a score of 1.5 or more standard deviations from the normative mean on a standardized test of language is considered diagnostic for SLI. Box 53-3 lists warning signs that suggest a DLD during the first 3 years. Language delay can be diagnosed very early. The developmental history provides strong evidence for language delay when the child does not meet expressive language milestones, does not seem to understand directions without associated gestures (e.g., “get your ball” without pointing to the ball), or does not point on command. During the examination, similar instructions can be given to the young child, and the child can be asked to point to various body parts or to point to pictures of common objects in a book. If there is a suspicion of language delay, the young child can undergo more formal language testing, such as with the MacArthurBates Communicative Development Inventory (normed for 8–30 months) or the Preschool Language Scale–4 (normed for birth to 6 years 11 months), both of which assess receptive and expressive language at young ages.



Developmental Language Disorders

BOX 53-3  Warning Signs of a Developmental Language Disorder

BOX 53-4  Glossary of Terms Used in Describing Linguistic Functions

LIMITATIONS IN EXPRESSIVE LANGUAGE • Early problems with sucking, swallowing, and chewing • Excessive drooling • Failure to vocalize to social stimuli • Failure to vocalize two syllables at 8 months • Few or no creative utterances of three words or more by age 3

Functors

LIMITATIONS IN VOCABULARY • Limited repertoire of words understood or used • Slow or difficult new-word acquisition

Lexicon Mean length of utterance (MLU) Morpheme

LIMITATIONS IN COMPREHENDING LANGUAGE • Excessive reliance on contextual cues to understand language LIMITATIONS IN SOCIAL INTERACTION • Reduced social interaction, except to have needs met LIMITATIONS IN PLAY • No symbolic, imaginative play by age 3 • No interactive play with peers LIMITATIONS IN LEARNING SPEECH • Numerous articulation errors in expressive speech • Unintelligible to unfamiliar listeners LIMITATIONS IN USING STRATEGIES FOR LANGUAGE LEARNING • Use of unusual or inappropriate strategies for age level, e.g., overuses imitation (echolalia), does not imitate verbalizations of others (dyspraxia), does not use wh- questions for learning (why, what, where, etc.) LIMITATIONS IN ATTENTION FOR LANGUAGE ACTIVITIES • Little interest in book reading, talking, or communicating with peers (Modified with permission from Nelson NW. Childhood Language Disorders in Context: Infancy through Adolescence. New York: Macmillan, 1993; Hall N. Semin Pediatr Neurol 1997;4:77–85.)

Before the age of 2 years, delay may not always equal disorder. Research on late-talking toddlers suggests that about 40% of children retained the diagnosis of SLI at ages 3 and 4 years. This is particularly true if the early language delay is primarily expressive. However, many children with early language delay who appear to “catch up” go on to have languagebased learning disabilities (e.g., dyslexia). It is therefore important to recommend periodic reassessment of a child’s language and academic functioning after an early language delay has been diagnosed. Children with receptive language impairments are more likely to have a persistent SLI. These children are more likely to have academic and social problems as a result of poor comprehension of language, and in some cases slowed processing of auditory information, which makes it difficult for them to follow a conversation or to follow a spoken lecture. Thus concern for poor language prognosis should be heightened when receptive language deficits are identified. Speech articulation disorders may be found in isolation or in association with language disorders. Early articulation errors are common and usually mild. However, if there are other features (e.g., excessive drooling or inability to chew food properly) or if a child is not able to be understood virtually 100% of the time by age 4 years, this should raise concern about a more serious condition, such as oral-motor apraxia. A thorough oral-motor examination by the physician will

Phoneme

Phonology Pragmatics

Prosody

Semantics Syntax

433

The small words of the language, such as prepositions, conjunctions, and articles; also called closed-class words because they are limited in number The words in a language; the dictionary of word meanings The number of morphemes per utterance The smallest meaningful unit in a language, occurring either in a word or as a word. (For example, the compound word compounding is made up of three morphemes: com-pound-ing.) Prefixes, suffixes, and inflected endings such as -ed, -s, and -ly are also morphemes A distinct sound unit in a language (In English, there are 46: 9 vowels and 37 consonants.) The rules a speaker follows when combining speech sounds The communicative intent of speech rather than its content (e.g., asking a question at the right time and in the right way) The melody of language; the tone of voice used to ask questions, for example, or to show emotion The meaning of words; their definition The grammar of a language; the acceptable relationship between words in a sentence

identify apraxia in severe cases. Milder forms may require a more extensive oral-motor assessment by a speech pathologist or pediatric occupational therapist.

NOSOLOGY OF DEVELOPMENTAL   LANGUAGE DISORDERS There is not uniform agreement on the proper nosology of the DLDs. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) of the American Psychiatric Association (2013) includes DLD under Communication Disorders, and specifies subcategories of language disorder (“language disorder” combines expressive and mixed receptive– expressive language disorders—this is synonymous with SLI in common usage), speech-sound disorder (i.e., phonological disorder), childhood-onset fluency disorder (i.e., stuttering), and social (pragmatic) communication disorder (in the absence of autistic features). These constitute general subtypes of DLDs. A more specific nosology has been proposed by Rapin (1996) based on psycholinguistic features. The subtypes are named for the linguistic areas that are most problematic (see Table 53-1 and the glossary of terms in Box 53-4).

Articulation and Expressive Fluency Disorders Pure Articulation Disorders Articulatory skills improve with age, and as with language development, the normal range is considerable. Most children speak intelligibly by age 2 years. Unintelligible speech is the

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TABLE 53-1  Subtypes of Developmental Language Disorders Receptive Expressive Verbal Auditory Agnosia

Expressive

Phonological Syntactic

Verbal Dyspraxia

Higher Order

Phonological Programming

Semantic Pragmatic

Lexical Syntactic

↓↓

↓ ↓

Comprehension—Receptive Phonology Syntax Semantics Production—Expressive Semantics (lexical) Syntax Phonology Repetition Fluency Pragmatics

↓↓ ↓↓ ↓↓

↓ ↓ ?

↓↓ ↓↓ ↓↓ ↓↓ ↓↓ N1 or ↓

↓↓ ↓↓ ↓ ↓ N1 or ↓

? ↓↓ ↓ N1 or ↓

? ↓ N1 or ↓

↓↓

↓ ↓

↑ N1 or ↑ ↓↓

↓ ↓ ↓

Nl = normal; ↓ = impaired; ↓↓ = very impaired; ↑ = atypically enhanced; ? = unknown (Modified from Nass R, Ross G. Disorders of higher cortical function in the preschooler. In: David R, ed. Child and Adolescent Neurology. St. Louis, MO: Mosby, 1997; Rapin I. Preschool Children with Inadequate Communication. London: Mackeith, 1996.)

exception at age 3 years. However, almost 50% of children at age 4 years still have mild articulation difficulties, primarily defective use of th or r sounds. At kindergarten entry, one third of children still have minor to mild articulation defects, but speech is unintelligible in less than 5%.

mediation paired-associate learning task may help select the best remediation method for each child because some are better with symbols and some with signs.

Stuttering and Cluttering

Children with verbal dyspraxia, also called dilapidated speech, are extremely dysfluent. These children are unable to convert an abstract phonological representation into a set of motor commands to the articulators (i.e., there is a deficit in phonology–motor conversion). Utterances are short and laboriously produced. Phonology is impaired and includes inconsistent omissions, substitutions, and distortions of speech sounds. Children with dysarthria make voicing errors that distort, whereas children with dyspraxia make place substitution errors. In conversation, they make phrasal errors. Syntactic skills are difficult to assess in the face of dysfluency. Language comprehension is relatively preserved, but many children have receptive language problems. Children with verbal dyspraxia who do not develop intelligible speech by age 6 years are unlikely to acquire it later. The frequency with which nonverbal praxis deficits—buccal-lingual dyspraxia (e.g., positioning muscles of articulation) and generalized dyspraxia—coexist with verbal dyspraxia is unknown. The presence of a more diffuse disorder of praxis has significant therapeutic implications because children with verbal dyspraxia may depend on signing and writing skills for communication. Developmental coordination disorder (DCD) is commonly comorbid with speech/language learning disabilities. Young children who are in early intervention programs for speech/language delays may have significant coordination difficulties that will become more evident at kindergarten age, when motor deficits begin to affect self-care and academic tasks.

Stuttering is a disorder in the rhythm of speech. The speaker knows what to say but is unable to say it because of an involuntary repetitive prolongation or cessation of a sound. Some degree of dysfluency is common as language skills evolve during the preschool years, particularly as the mean length of utterance (MLU) reaches 6 to 8 words between ages 3 and 4 years. However, stuttering, in contrast to developmental dysfluency, is probably a linguistic disorder (errors occur at grammatically important points in the sentence) and a motor planning problem. Typically, onset of stuttering is between the ages of 3 and 6 years, and reports indicate unassisted recovery rates of 75%. Thus the prevalence of stuttering as a lifetime disorder is much lower than its incidence (0.5%–1% vs. 4%–5%). However, persistence of stuttering may be associated with other aspects of language impairment, such as difficulty with processing of syntactic information. Stuttering is often a genetic trait. Although the cause of developmental stuttering is unknown, the main theories are anomalous dominance and abnormalities of interhemispheric connections. Cluttering, by contrast, as seen in fragile X syndrome, is characterized by incomplete sentences and short outbursts of two- to three-word phrases, along with echolalia, palilalia (compulsive repetition reiterated with increasing rapidity and decreasing volume), perseveration, poor articulation, and stuttering.

Phonological Programming Disorder Children with the phonological programming disorder have fluent speech, and their MLU approaches normal. Despite initially poor intelligibility, serviceable speech is expected. Language comprehension is relatively preserved. Most such children show delayed rather than deviant phonology and improve during school years. It is debatable whether this disorder is a severe articulation problem or a mild form of verbal dyspraxia. The fact that patients with phonological programming disorder have more difficulty learning manual signs than do controls supports an association with dyspraxia. A prere-

Verbal Dyspraxia

Disorders of Receptive and   Expressive Language Phonological Syntactic Syndrome Phonological syntactic syndrome (also called mixed receptive expressive disorder, expressive disorder, and nonspecific formulation-repetition deficit) is probably the most common DLD. The phonological disturbances consist of omissions, substitutions, and distortions of consonants and consonant clusters in all word positions. The production of unpredictable



and unrecognizable sounds makes speech impossible to understand. The syntactic impairment consists of a lack of functors and an absence of appropriate inflected endings. Plurals, third-person singulars, past tense, the auxiliary verb be, the and a, infinitives (to), and case markings on pronouns are particularly vulnerable. Grammatical forms are atypical, not just delayed. Whereas a typically developing young child may say “baby cry” or “a baby crying,” children with phonological syntactic syndrome produce deviant constructions, such as “the baby is cry.” Telegraphic speech is common. Comprehension is relatively spared. Semantic skills tend to be intact. Repetition, pragmatics, and prosody may be normal. Autistic children with this DLD subtype produce a significant amount of jargon. Neurologic dysfunction is especially frequent in this subtype. Sucking, swallowing, and chewing difficulties are common, and drooling is often persistent. The neurologic examination may reveal signs of oral motor apraxia, hypertonia, and incoordination.

Verbal Auditory Agnosia Children with verbal auditory agnosia (VAA) are unable to discern meaning from spoken language, despite intact hearing. VAA may be a developmental condition, apparent from early life, or an acquired disorder, as in Landau–Kleffner syndrome. VAA is common in low-functioning children with autism. The outcome from the developmental form of VAA is generally poor. The outcome from the acquired disorder is somewhat better, with approximately one third of patients having a good outcome with specific treatment.

Higher-Order Language Disorders Semantic Pragmatic Syndrome Children with the semantic pragmatic syndrome (also called repetition strength and comprehension deficit, language without cognition, cocktail party syndrome) are fluent and often verbose speakers. Vocabulary is often large and somewhat formal. Parents are often encouraged by the child’s sizeable vocabulary, only to find later that the verbosity did not indicate superior cognitive skills. Many children have trouble with meaningful conversation and informative exchange of ideas. Pragmatic skills are lacking. They often show deficits in prosody; their speech has a monotonous, mechanical, or singsong quality. They cannot convey the additional pragmatic intentions that prosody affords, such as speaking with the proper emotion or indicating by tone of voice that they are asking a question. Comprehension may be impaired. Phonological and syntactic skills are generally intact.

Lexical Syntactic Syndrome Lexical syntactic syndrome (LSS) occurs in approximately 15% of children with DLD. Speech is generally dysfluent, even to the point of stuttering, because of word-finding difficulties and poor syntactic skills. Both literal and semantic paraphasias are common. Most children have delays in word acquisition and less lexical diversity than their age-matched counterparts. Verbs appear to be the most difficult lexical category for them to learn. Syntax is immature but not deviant. Phonology is spared, and speech is intelligible. Repetition is generally better than spontaneous speech. In conversation, idiom use is better than spontaneous speech. In one study, fourth graders with LSS evidenced higher disruption rates at phrase boundaries in narratives than did their age-matched peers, reflecting lexical and syntactic deficits. Pragmatics may be impaired, particularly when this syndrome occurs in

Developmental Language Disorders

435

autistic children. Comprehension is generally acceptable, although complex questions and other linguistic forms taxing higher-level receptive syntactic skills are often deficient.

OUTCOME OF DEVELOPMENTAL   LANGUAGE DISORDERS Many children with SLI, particularly those with expressive language impairment, appear to improve in their language ability by early school age. Others have persistent language impairment that remains throughout life. There is a high incidence of other problems associated with SLI, including academic, behavioral, social-emotional, and psychiatric issues, and these may occur even when language appears to have reached the normal range. Attention deficit disorder occurs in about 40% of children with SLI and may cause additional challenges. Dyslexia is present in approximately 65% of children with SLI. Written composition may also be a challenge for these children. These problems lead to poorer-than-expected school performance and a higher dropout rate. Adolescents with a history of SLI have a higher likelihood of peer problems, emotional symptoms, and conduct problems (Snowling et al., 2006; Conti-Ramsden et al., 2013). Poor receptive language raises the likelihood of emotional and behavioral difficulties. Anxiety disorder, social phobia, and depression occur at a high rate in children and adolescents (20%–50%) with a history of SLI. Adolescents with SLI have a lower level of academic achievement than their typically developing peers. It is important to note that subtle language and communication problems may persist into adult life in up to 90% of cases and may cause the affected individuals to be shy in social situations and reluctant to enter into conversations with others because of their language problem. Preschool language skills are the best single predictor of later reading ability and disability. Even children with good receptive skills who speak late may be at risk for continuing subtle language difficulties and later reading- and languagebased academic difficulties. Thus both screening and follow-up studies of children with SLI are important. Follow up of 112 individuals with SLI into adult life demonstrated lower levels of functioning in the areas of communication, educational attainment, and occupational status compared with their typical peers. Such studies indicate the need for continued surveillance of individuals with SLI and adequate guidance in terms of academic and career choices (Young et al., 2002; Johnson et al., 2010). Early intervention, not only with speech/language therapy but also with social skills training and, when indicated, psychological and career counseling, may help to reduce the longterm morbidity of SLI.

EVALUATION OF THE CHILD WITH A SUSPECTED DEVELOPMENTAL LANGUAGE DISORDER The workup of the child with a DLD (Box 53-6) must include an assessment of hearing and an assessment of overall level of intellectual functioning, in addition to a thorough language assessment that includes both receptive and expressive language components. Other evaluations that may be warranted include tests for auditory processing and neuropsychological assessments for associated problems such as attention deficit disorder. Certain metabolic disorders can present with isolated language delay, so a metabolic screen is appropriate in some circumstances. Mitochondrial disorders and organic acidemias may have language impairment as their primary feature,

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PART VII  Neurodevelopmental Disorders

BOX 53-6  Evaluation of a Child With Suspected Language Disorder • Complete neurodevelopmental and family history and neurologic examination (including social interaction and communicative behaviors) • Hearing test • Office developmental screen (e.g., Denver Developmental Test, MacArthur-Bates Communicative Development Inventory, Children’s Communication Checklist, Preschool Language Scale, Early Language Milestones) can be helpful • Psychometric testing to establish general cognitive function (a nonverbal intelligence test such as the Leiter International Performance Scale–Revised or the Test of Non-Verbal Intelligence–P:4 or I:3 [TONI-P:4; TONI-I:3] is most appropriate in a language-impaired child) • Depending on history and examination, other tests to consider: • Sleep electroencephalogram (EEG) • Overnight video EEG monitoring • Magnetic resonance imaging (MRI) of the brain • Karyotype, fragile X, microarray study, fluorescent in situ hybridization (FISH) probes • Metabolic screen (e.g., urine organic acids, blood amino acids)

children with SLI have problems with inferencing, linking directly observed or stated information to likely outcomes. They also have limited working memory capacity, and they are more likely to make errors related to inattention. Thus children with SLI are likely to be at a disadvantage in classroom situations, particularly for information presented orally and if the information is complex. The use of pictorial aids may help them encode the information. They may also benefit from having information broken into manageable (shorter) units. When necessary, medications for treatment of attention deficit hyperactivity disorder (ADHD) should be considered. Because there is a high incidence of secondary emotional problems and self-esteem issues associated with SLI, referral for psychological counseling should be considered as soon as these problems become apparent. Families should be informed about their child’s condition and be encouraged to provide a positive and supportive environment. A multidisciplinary approach, including physician, speech/language pathologist, teacher, psychologist, and parents, provides the most effective means of helping children with SLI. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES

particularly in the first few years of life. Numerous other syndromes can present predominantly with language delay. An electroencephalogram (EEG) should be considered in a child with DLD if there is a history of a language regression or a suspicion from the history that the child might have seizures. Neuroimaging studies are not likely to be helpful unless there are abnormal findings on the neurologic examination.

TREATMENT Whether intensive early therapy changes the long-term outcome to an appreciable degree remains to be determined. Treatment of language-disordered preschool children varies according to the kind of language impairment and its degree of severity (Warren and Yoder, 2004). Preschool children with moderate to severe language impairment may benefit from a special education preschool for language-impaired children. Mildly impaired children may do well in a regular preschool program combined with individual speech/language therapy. Floor time–based language therapy provides a naturalistic and developmentally appropriate way of working on language skill development. Formal language work typically begins at the phonologic level, involving repetition of sounds and sound sequences to encourage fluency. Treatment of receptive disorders often necessitates the use of visual modalities, such as signs and gesture. Less severe disorders of comprehension are addressed through practiced structuring of conversations with the child. Children with severe comprehension deficits rarely progress as well in treatment as do children with primary expressive disorders. Children with significant auditory processing disorders may benefit from a systematic computer-based approach to improving the speed of auditory processing, although benefits from this type of intervention remain controversial. Some classroom accommodations may be necessary for the child with SLI to succeed. Children with SLI may require additional help from a resource specialist or tutor. They may require additional time for giving reports and for taking tests. Whenever possible, presentation of oral information should be accompanied by visual aids. In support of previous research,

Badcock, N.A., Bishop, D.V., Hardiman, M.J., et al., 2012. Colocalisation of abnormal brain structure and function in specific language impairment. Brain Lang. 120 (3), 310–320. Bates, E., Reilly, J.S., Wulfeck, B., et al., 2001. Differential effects of unilateral lesions on language production in children and adults. Brain Lang. 79, 223–265. Bishop, D.V.M., Hayiou-Thomas, M.E., 2008. Heritability of specific language impairment depends on diagnostic criteria. Genes Brain Behav. 7, 365–372. Conti-Ramsden, G., Mok, P.L., Pickles, A., et al., 2013. Adolescents with a history of specific language impairment (SLI): strengths and difficulties in social, emotional and behavioral functioning. Res. Dev. Disabil. 34 (11), 4161–4169. Johnson, C.J., Beitchman, J.H., Brownlie, E.B., 2010. Twenty-year follow-up of children with and without speech-language impairments: Family, educational, occupational, and quality of life outcomes. Am. J. Speech Lang. Pathol. 19 (1), 51–65. Rapin, I., 1996. Preschool Children With Inadequate Communication. Mackeith Press, London. Snowling, M.J., Bishop, D.V., Stothard, S.E., et al., 2006. Psychosocial outcomes at 15 years of children with a preschool history of speech-language impairment. J. Child Psychol. Psychiatry 47 (8), 759–765. Vernes, C., Newbury, D.F., Abrahams, B.S., et al., 2008. A functional genetic link between distinct developmental language disorders. N. Engl. J. Med. 359, 2337–2345. Warren, S., Yoder, P., 2004. Early intervention for young children with language impairment. In: Verhoeven, L., van Balkom, H. (Eds.), Classification of Developmental Language Disorders. Lawrence Erhbaum, Mahwah, NJ, pp. 367–384. Young, A.R., Beitchman, J.H., Johnson, C., et al., 2002. Young adult academic outcomes in a longitudinal sample of early identified language impaired and control children. J. Child Psychol. Psychiatry 43, 635–645.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Box 53-2 Disorders Commonly Associated with Language Delay/Impairment Box 53-5 Differential Diagnosis of Language Delay/Disorder

54 

Nonverbal Learning Disabilities and Associated Disorders Margaret Semrud-Clikeman and Doris A. Trauner

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Nonverbal learning disabilities (NLD) are increasingly being identified by clinicians. NLD generally involve difficulties with visual–spatial reasoning, executive functioning, and mathematics difficulties (Rourke and Tsatsanis, 2000; Davis and Broitman, 2011). For many children with NLD, co-occurring attention and social perception difficulties are present (Mammarella and Cornoldi, 2014; Semrud-Clikeman et al., 2010). Although there is no diagnosis in DSM V or ICD-10, frequently these children may qualify for a diagnosis of a social communication disorder from DSM V. There are likely two different types of NLD: one with a medical association and one without. Children with nonmedical NLD generally are referred to neuropsychological and psychological clinics and only rarely are seen by medical professionals other than pediatricians and physical/occupational therapists. Neurologists and other specialists frequently see children with medically based NLD because of parent concerns about visual–spatial difficulties and social deficits (Ballantyne et al., 2013; Bava et al., 2010; Beaton et al., 2010). Medical conditions frequently associated with NLD include velo-cardio-facial syndrome, some lysosomal storage diseases, and nephropathic cystinosis (Trauner et al., 2007). Neuroimaging findings have indicated differences in the corpus callosum (particularly in the splenial region), anterior cingulate gyrus, and in the parietal white matter volume and gray-matter thickness (Fine et al., 2013; Reiss et al., 1995). Further studies of structural and functional differences are needed, particularly in comparing medically related and nonmedically related cases of NLD.

WHAT ARE NONVERBAL LEARNING DISABILITIES? The diagnosis of NLD is a fairly new construct first developed by Myklebust and Johnson and further researched by Byron Rourke and colleagues. The incidence of NLD has been estimated to be approximately 5% of the learning disabled population (or around 1% of the general population). These children have been described as having difficulties with visual–spatial processing, mathematics, handwriting, social cognition, and in some cases attention. In contrast to these weaknesses, children with NLD have also been found to be verbally facile and to have good reading recognition skills and rote language abilities. The definition of NLD has continued to evolve since its original conceptualization, with diagnostic descriptions varying across clinical laboratories. The original conceptualization included difficulties with spatial and temporal perception, handwriting and mathematics weakness, problems with social perception, and a higher verbal than performance IQ. Many studies utilize an approach wherein the child must meet a selection of symptoms from an array of possibilities to

qualify for a diagnosis of NLD. Although features of NLD subtypes continue to be refined, NLD is currently characterized by three broad areas of dysfunction: motoric skills, visual/ spatial–organizational/memory skills, and social abilities. Rourke was a pioneer in developing our understanding of NLD. After several decades of clinical research he conceptualized NLD as a set of assets and deficits. These strengths and weaknesses were associated with initial or primary features, which then lead to secondary and tertiary features in many areas of functioning. Using this framework, the social competence difficulties described originally by Myklebust are hypothesized to be the result of problems with visual–spatial processing. Rourke’s conceptualization was similar to that of Johnson in that both developed a neurologic hypothesis for NLD emphasizing white matter involvement. Rourke hypothesized that the myelinated fibers of the brain are related to symptoms of NLD, which subsequently included children with some genetic and medical conditions. For this reason, in addition to children without apparent congenital or acquired neurologic dysfunction, Rourke and associates began to incorporate the several additional neurologic disorders that had some or all of the features of NLD. The overlap with these diagnoses will be discussed in the next section.

Coexistent Issues One of the controversies in NLD is whether it is a variant or a milder form of autism. Some researchers advocate the use of the NLD phenotype as a heuristic model for understanding autism spectrum disorders (ASD) or Asperger syndrome (AS), whereas others suggest that AS is a more severe form of NLD (Brumback et al., 1996). Still others suggest that these are two separate disorders. In the current version of DSM V, AS is no longer a diagnostic category; rather autism spectrum disorder: high functioning (HFA) is used. Theoretical models of NLD and HFA both suggest deficits in the developing brain, likely beginning during gestation, that consequently affect the development of normal social interaction. The amygdala is particularly pinpointed as an area of system dysfunction early on that later interferes with the ability to respond to facial expressions due to faulty neural networks involving social understanding. Early experience with social referencing is crucial for the development of empathy, theory of the mind, and social reciprocity. Similarly, Rourke (1995) emphasized difficulties with the connectivity between the limbic structures and the frontal lobe rather than an impairment of specific regions. Although there are similarities between NLD and AS/HFA in many aspects, there are also many qualitative differences between these groups. It is more common in NLD to find difficulties with mathematics and with visual–spatial processing than in AS/HFA. It is also unusual for children with NLD to show stereotyped behaviors or “bizarre” interests or an

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emphasis on routine that is frequently seen in individuals with AS/HFA. Currently there are three comprehensive reviews of NLD that have sought to evaluate the empirical evidence to determine the main characteristics of NLD and to reconcile whether this diagnosis actually exists or is a form of autism. These reviews have generally found that NLD is a complex diagnosis for which there is no consistent criteria for identification. It was also found that many children with NLD showed symptoms of attention deficit hyperactivity disorder (ADHD): predominately inattentive type. The most robust finding was that of visual–spatial deficits, lower mathematics skills compared with reading, and problems with visual–constructive abilities. Moderate support was found for problems with visual memory and social cognition. It has also been suggested by a few authors that social comprehension ability may be evident in a subtype of NLD but not necessarily in all children with NLD. Fewer studies have systematically evaluated executive functioning and/or attentional abilities, so these areas continue to need additional study.

Neuropsychological Findings Verbal-Performance IQ Split Several studies have found a difference in the verbal and performance skills on the previous versions of the Wechsler Intelligence Scale for Children. More recent studies also have found this difference for children with NLD, but also for children with AS. In each study, children with NLD showed a larger discrepancy than those with other diagnoses. The discrepancy between verbal and performance abilities alone is not sufficient for a diagnosis of NLD but should be used as one piece of evidence. It has been found that children with autism with a discrepantly high verbal or performance IQ showed significantly more apparent difficulties with social functioning. Others have found that when the nonverbal IQ was higher than the verbal IQ more social difficulties were present. Furthermore a discrepancy between verbal and performance IQ in children with AS was also found with higher verbal scores related to fewer social difficulties in another study. These findings suggest that a significant difference in verbal comprehension and perceptual reasoning on a standardized intelligence measure may be an important marker for NLD. It also is important to recognize that differences of less than 25 points happen in approximately 20% to 25% of the population and therefore are not rare. Furthermore, the discrepancy between perceptual reasoning and verbal comprehension is not in and of itself a sufficient marker for a diagnosis of NLD to be made. Unfortunately, many clinicians continue to diagnose NLD solely on this discrepancy.

Language Although children with NLD have been found to have relatively good vocabularies, studies evaluating pragmatic language have begun to demonstrate some difficulty in this area. Pragmatic language includes the ability to understand the meaning of what is being said (semantics) and the ability to use language appropriately in social situations (pragmatics). Children with NLD have difficulty understanding the nuances of what is being said or being able to “read between the lines.” Studies have found difficulty for children with NLD on measures of pragmatic language, particularly when it involves social referencing. Children with NLD had more difficulty interpreting humor that involved pragmatic language or plays on words (puns) compared with visually oriented slapstick humor.

Achievement Children with NLD show good single word reading skills with later difficulties found in reading comprehension. Simply reporting facts and information that is contained within the reading selection is generally intact, whereas questions that probe for inferential reasoning are more problematic. In addition, difficulties have been found in mathematics, particularly in mathematical computation. As math demands increase, problems occur ranging from the mechanics of lining up numbers in math problems to comprehending the higherlevel abstract concepts required in division, data presentation (charts, graphs), algebra, geometry, and trigonometry. These findings suggest it might not be the academic subject that is most problematic but rather the higher order thinking required to solve a problem. Writing is an area of particular challenge for children with NLD. For early writers, letter formation, letter spacing, and word spacing may be difficult to manage. An informal assessment of this can be accomplished by simply asking the child to write the alphabet legibly as fast as they can. A child with NLD-based problems might have difficulty physically forming letters that are legible relative to other children their age, even while they work quickly through the letters.

Visual–Spatial and Motor Skills Studies have found difficulties with visual–spatial skills and visual–motor ability. When children with NLD were compared with children with other disorders on measures of visual–motor organization and visual–spatial skills, the children with NLD scored worse than the other clinical groups and the control group. These findings support Rourke’s contention that visual–spatial and perceptual difficulties may underlie the social difficulties frequently found in children with NLD. Motor skills have also been evaluated in children with NLD. Studies found graphomotor difficulties present particularly in younger children. These findings suggest that children with NLD do have more difficulty on tasks which require visual–spatial reasoning as well as visual–motor control and fine motor dexterity. These difficulties are particularly present when tasks are more complex, requiring additional processing for successful completion. It is also important to note that children with disorders such as ADHD and/or AS/ASD can also show difficulties in visual–motor skills, possibly for other reasons than visual–spatial deficits (e.g., impulsivity).

Executive Functioning Executive functions are a relatively new area being examined in individuals suspected of having NLD. Executive functions that have been identified to be problematic for children with NLD include cause–effect reasoning, learning new material that is complex or novel, and planning and organization. Additional measures of novel problem solving have found difficulty on tasks that are of increasing complexity and that require memory and abstract reasoning skills. Attention is a related construct to executive functioning. Children with NLD have been found to have more frequent difficulties with attention. Rourke suggested that these attentional problems may be related to visual–spatial deficits rather than to attention. Studies that have examined social perception measures found them to be highly correlated to executive functioning but not strongly related to attention. In contrast the relation between visual–spatial skills and social perception abilities was not found to be significant. A sizable minority of children with NLD show sufficient attentional symptoms for an additional diagnosis of ADHD, which also requires specific



Nonverbal Learning Disabilities and Associated Disorders

targeted treatment. These attentional skill deficits have not been found to be as predictive of social difficulties.

Social Perception and Psychopathology It has been suggested children with NLD show higher rates of depression and anxiety (Pelletier et al., 2001). Others have not found significantly higher rates of internalizing behaviors when samples are studied that are community based rather than in residential treatment facilities or in psychiatric clinics. Others have found mild symptoms of social withdrawal and sadness in children with NLD, particularly those who are older and in whom peer relations become more important and valued for self-esteem. Measures that require a child with NLD to interpret a social situation that is ambiguous or does not provide verbal cues as to what is occurring have been found to be particularly difficult. In addition, these children had difficulty perceiving humor (cartoons and nonsequiturs), suggesting that problems with humor comprehension in children with NLD may be more related to social rather than visual–spatial deficits. Further studies have found difficulties with emotional modulation and/or depressed mood to be significantly related to the child’s ability to accurately recognize and interpret nonverbal cues in a social situation. If a child has difficulty with nonverbal cues and misidentifies these and acts accordingly to the mistaken perception, it is likely that the child will feel sad and may withdraw from further social interactions, particularly if there is a negative outcome.

Neuroimaging Findings in NLD and AS/ASD Some have hypothesized that AS/HFA and NLD may be on the same continuum. If this supposition is accurate, then neuro-

439

imaging studies should find similar neuroanatomical differences from typically developing children. Neuroimaging studies have generally focused on autism spectrum disorders (ASD) and/or Asperger syndrome (AS). Findings from neuroimaging studies with ASD have found a larger white matter volume in the temporal and frontal lobes, bilateral amygdala, and hippocampus. It was suggested that these larger structures may be a result of developmental adaptation of the autistic brain caused by a processing overload involving emotional learning experiences. The amygdalar–hippocampal-frontal circuit may be particularly important for mediating emotional perception and regulation and is compromised in children with social reciprocity difficulties. Evidence of enlarged amygdalar regions was not found in the one study of NLD imaging, although the anterior cingulate bilaterally was found to be smaller in the AS and NLD group compared with controls (Table 54-1). These findings have important implications for our understanding of NLD and of ASD/AS. Previous researchers have suggested that hippocampal enlargement is related to larger amygdaloid volumes. In this theory the reciprocal connections between these structures lead to excitation of both structures through a dense interchange network. Thus a larger amygdala may result in hippocampal enlargement caused by overexcitation in both structures. Supporting this hypothesis is a previous finding that these regions interact strongly when the system is stressed. Children with ASD have a high co-occurrence of anxiety, which may be related or as a result of the enlargement of these regions. In contrast, children with NLD do not evidence the same level of anxiety and show amygdaloid and hippocampal volumes similar to neurotypical children. The smaller volume of the anterior cingulate cortex in children with NLD and ASD implicates the network that is involved in

TABLE 54-1  Major Neuroimaging Findings in ASD and NLD Study

Patient Groups

Main Findings

STRUCTURAL MRI Abell et al. (1999) Groen et al. (2010); Nacewicz et al. (2006) Groen et al. (2010)

ASD, controls ASD, controls

ASD>controls in white matter volume ASD>controls in amygdalar volume

ASD, controls

Semrud-Clikeman et al. (2013)

NLD, AS, and controls

Fine, Musielak & Semrud-Clikeman (2013) Semrud-Clikeman & Fine (2011)

NLD, ASD, ADHD, controls

Reiss et al. (1995)

Turner syndrome (TS), controls TS, controls

ASD>controls on right hippocampus volume ASD>controls in temporal and frontal lobes All groups equal in white and gray matter volumes AS>NLD, controls in amygdala volume; NLD0.08

Poor, death usually within the first year

Benzoate (250– 750 mg/kg/d), dextromethorphan Avoid valproate and vigabatrin

GABA transaminase deficiency

Neonatalinfantile

Intractable seizures, lethargy, irritability, severe delay, hypotonia, hyperreflexia, accelerated growth

Increased GABA in serum and CSF

Poor, death usually within the first 5 years

Symptomatic only

Sulfite oxidase deficiency and molybdenum cofactor deficiency

Neonatal or infantile

Intractable seizures, progressive neurocognitive decline, acquired microcephaly, MRI demonstrating leukoencephalomalacia and atrophy. Later onset forms may present with encephalopathy, focal findings and seizures after a febrile illness

Elevate sulfite levels on fresh urine. Low plasma homocysteine. Confirm with specific enzyme analysis of fibroblasts

Poor

Some patients may improve with vigabatrin, dextromethorphan. Some may improve with dietary restriction of methionine

Peroxisomal disorders

Neonatal or infantile

Hepatic disease, developmental delay, retinopathy, deafness, seizures, cortical migration defects

Abnormal very long chain fatty acids and/or phytanic acid

Variable, depending on phenotype

Symptomatic only

Menkes disease

Infancy

Developmental regression, seizures, particularly spasms, hypopigmentation of skin and hair, hypothermia, characteristic “kinky” hair

Low serum copper and ceruloplasmin. Confirm with ATP7A mutation analysis

Poor with progression to death typically within 5 years

Copper histidine supplementation and supportive treatment

Glutaric acidemia type 1

Infancy and childhood

Macrocephaly, acute neurologic decompensation with infection or febrile illness, characterized by hypotonia, opisthotonic posturing, dystonia or dyskinesia, seizures, encephalopathy. MRI shows widening of sylvian fissures

Increased urinary glutaric acid

Poor, although detection and treatment before decompensation may improve outcome

Low protein diet (low lysine and tryptophan) with carnitine supplementation

Continued on following page

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PART VIII  Epilepsy

TABLE 71-2  Inborn Errors of Metabolism Associated With Infantile-Onset Epilepsies (Continued) Metabolic Disorder

Age at Onset

Clinical

Diagnostic Test

Prognosis

Treatment

Biotinidase deficiency

Neonatal through childhood

Seizures, hypotonia, developmental delay, ataxia, dermatitis, hair loss, autistic behavior, optic atrophy

Low serum biotinidase

Outcome can be good if diagnosed and treated early

Biotin supplementation (10 mg/day)

Succinic semialdehyde dehydrogenase deficiency

Infancy and childhood

Developmental delay, ataxia, hypotonia, seizures, hyperactivity, behavior problems. Increased T2 signal in globus pallidus, dentate nucleus and subthalamic nucleus with cerebral atrophy

Increased gamma hydroxybutyric acid in urine. Confirm with enzymatic analysis or Aldh5A1 gene sequencing

Variable, treatment targeted at symptoms

Symptomatic

Congenital hyperinsulinism and hyperammonemia

Infancy and childhood

Epilepsy, intellectual disability

Postprandial hypoglycemia, hyperammonemia. Confirm by mutation analysis in glutamate dehydrogenase gene

Outcome can be good if diagnosed and treated early

Protein restriction, diazoxide

Tetrahydrobiopterin deficiencies

2–12 months

Cognitive regression, microcephaly, generalized seizures, irritability, dystonia, rash, basal ganglia calcifications

Elevated Phe on plasma amino acids, abnormal pterions and neurotransmitters in CSF

Outcome can be good if diagnosed and treated early

BH4 supplementation May need additional supplementation with neurotransmitter precursors based on type

Glucose transporter deficiency

Birth to early childhood

Seizures (infantile-onset focal or generalized, or early-onset absence epilepsy), microcephaly, developmental delay, acquired ataxia, paroxysmal dyskinesia

Low CSF/plasma glucose with normal or low lactate Confirm with SCL2A1 genetic testing

Variable, depending on duration of symptoms before treatment with ketogenic diet

Ketogenic diet

Cerebral folate deficiency

Childhood to adolescence

Intractable epilepsy, intellectual disability or regression, microcephaly, dyskinesias, autism

Low CSF methyltetrahydrofolate Further testing requires mutation analysis in FOLR1 gene, assessment for antibodies to folate receptors, and if workup for secondary causes of cerebral folate deficiency

Variable, depending on exact etiology and duration of symptoms before treatment

Folinic acid supplementation (0.5–5 mg/kg/d)

Mitochondrial disorders

Infancy to adulthood

Focal or generalized seizures, spasms, deafness, myopathy, lactic acidosis, ataxia, optic atrophy, hepatic dysfunction,

Elevated plasma and CSF lactate, may have evidence of cardiac, renal or hepatic dysfunction. Elevated lactate peak on MRS. Muscle biopsy, specific genetic analysis

Variable, depending on specific type

Avoid valproate Mitochondrial cocktail (carnitine, coenzyme Q, riboflavin) Ketogenic diet may be helpful in some conditions, e.g. pyruvate dehydrogenase complex deficiency (and contraindicated in others, e.g. pyruvate carboxylase deficiency)

Congenital Disorders of Glycosylation

Infancy to childhood

Developmental delay, hypotonia, failure to thrive, multisystem disease, inverted nipples and/or abnormal fat pads, cerebellar hypoplasia

Abnormalities in carbohydrate deficient transferrin analysis. Confirm with specific genetic analysis

Variable depending on etiology

Symptomatic



waning, multifocal, slow spike and wave discharges. The status epilepticus can become life-threatening, requiring intensive care. Children in the third subgroup typically have mild neurologic impairment at baseline and experience only focal seizures. The myoclonic status begins between age 7 months to 5 years with rhythmic myoclonic jerking of the face and limbs. The EEG shows nearly continuous generalized or bilateral spike and wave discharges that can have a notched delta appearance. Over days to weeks, there is clinical deterioration with cognitive regression, frequent focal seizures, and movement disorders.

Neuroimaging Neuroimaging in the first subgroup, of genetic etiology, is normal. In the second subgroup, neuroimaging can be normal (unknown etiology) or show cortical malformations of variable severity. Imaging in the third subgroup is consistent with perinatal anoxic injury. Although there is clinical progression in this third subgroup, the neuroimaging remains unchanged.

Other Neurologic Findings Development in all children is abnormal at baseline. In the first two subgroups, there is severe neurologic impairment. In the third subgroup, the degree of neurologic impairment at baseline is mild but progresses over days to weeks with movement disorders appearing.

Other Laboratory Studies A comprehensive genetic evaluation as well as careful neuroimaging with epilepsy protocol to detect malformations of cortical development should be performed (Table 71-1). For those with unknown etiology, a comprehensive metabolic evaluation should be considered (Table 71-2).

Differential Diagnosis West syndrome can be excluded by differentiating the myoclonic seizures from epileptic spasms and the lack of hypsarrhythmia on EEG. Myoclonic status and similar initial EEG findings can be seen in Lennox-Gastaut syndrome and myoclonic-atonic epilepsy, making them difficult to exclude. However, other seizures typically seen with these syndromes occur much less frequently. Myoclonic seizures are a later occurrence in children with Dravet syndrome. Identifying the underlying etiology can be helpful in differentiating this syndrome from progressive myoclonic epilepsies.

Treatment The seizures are pharmacoresistant. Mitochondrial disorders should be excluded before initiating valproic acid. The myoclonic status epilepticus is typically refractory to benzodiazepines and often requires intensive care unit therapy.

Outcome The myoclonic status epilepticus can resolve, often within 2 to 4 years; however, refractory brief absences and infrequent myoclonic seizures continue. Intellectual disability remains severe. Unfortunately, mortality due to status epilepticus is high in the second subgroup and survivors continue to have status epilepticus into adulthood.

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FOCAL SYNDROMES Epilepsy of Infancy With Migrating   Focal Seizures Epilepsy of infancy with migrating focal seizures is an earlyonset epileptic encephalopathy that begins in previously healthy infants after the neonatal period but before the sixth month.

Seizures Initially, sporadic, focal seizures occur, with semiology suggestive of multifocal onset. Seizures may be accompanied by autonomic signs, including apnea, cyanosis, and flushing (Caraballo, et al., 2008). Seizure frequency and duration increase and frequently culminate in refractory status epilepticus requiring treatment with general anesthesia. After 1 to 5 years, seizures once again become sporadic and easier to control, although seizure clusters and intermittent status epilepticus can still occur.

Other Neurologic Findings At onset, children have normal neurologic examinations. As the seizures become refractory, hypotonia, loss of motor milestones, and subsequent developmental delay are noted in all infants. Progressive microcephaly, feeding issues, and decreased visual attentiveness are frequent.

Etiology The etiology is typically unknown with genetic causes found in a minority of children.

EEG Findings The interictal EEG can initially be normal, but over time, slowing and multifocal epileptiform discharges emerge. The ictal recording demonstrates variable electroclinical patterns (Fig. 71-5).

Neuroimaging At onset, neuroimaging is normal in all children. Over time, mild to moderate ventricular enlargement and possible mesial temporal sclerosis may evolve.

Other Laboratory Studies Extensive neurometabolic evaluations and, in most cases, genetic evaluations are normal.

Differential Diagnosis Structural etiologies such as cortical dysplasia should be ruled out with detailed neuroimaging. Infections such as meningoencephalitis and metabolic disorders can also present with multifocal seizures. Furthermore, both benign infantile epilepsy and benign familial infantile epilepsy can present at a similar age with focal seizures. However, these seizures are pharmacoresponsive and development remains normal in essentially all patients.

Treatment Although stiripentol, clonazepam, potassium bromides, and levetiracetam may be helpful, seizures are typically refractory to all therapies.

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A

B

C Figure 71-5.  EEG during a focal dyscognitive seizure in an infant with epilepsy of infancy with migrating focal seizures demonstrating high amplitude delta frequency sharp waves over the right hemisphere initially (a), followed by involvement of the midline head regions as the right temporal region seizure discharge resolves (b), followed by independent left temporal discharge (c).



Outcome The outcome is typically poor with severe hypotonia, intellectual disability, refractory seizures, and high mortality, although there may be phenotypic variability.

Benign Epilepsy of Infancy/Benign Familial Infantile Epilepsy Infants with convulsive seizures and normal neurologic examination, with or without family history of similar seizures, can sometimes follow a benign course. These syndromes have now been termed “benign epilepsy of infancy (BEI)” and “benign familial infantile epilepsy (BFEI)” (Vigevano, 2005). The seizure semiology and outcome are similar for the two syndromes, thus they will be discussed conjointly.

Seizures The seizures in BEI and BFEI may initially be sporadic, but eventually occur in clusters. Within the cluster, seizures typically occur several hours apart, and the infant returns to baseline in between events. The semiology is variable and includes staring, unresponsiveness, behavioral arrest, eye deviation, head turn, apnea, and automatisms with or without generalized convulsions.

Other Neurologic Findings Neurologic examination and development are normal. Paroxysmal kinesigenic choreoathetosis and dystonia have been reported to coexist in individuals and families with BFEI. Later development of familial hemiplegic migraine has also been reported.

Etiology The etiology of BEI is unknown, and the diagnosis can be difficult to make with certainty at onset. Comprehensive metabolic and neuroimaging studies should be done to exclude other causes of early-onset multifocal epilepsy (Tables 71-1 and 71-2). BFEI has been linked to chromosomes 2, 16 (PRRT2 mutations), and 19 and displays autosomal dominant inheritance with variable penetrance.

EEG Findings A normal interictal EEG is felt to be one of the characteristics of BEI and BFEI. Ictal EEGs have demonstrated focal onset in all seizures, including those with a generalized tonicclonic component without focal semiology (Vigevano, 2005).

Neuroimaging

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syndrome, which would not be expected from epilepsy due to structural or metabolic etiology.

Treatment The seizure clusters are typically several hours apart and can continue for 1 to 3 days. Phenobarbital has been more helpful than benzodiazepines in aborting clusters, although doses higher than 10 mg/kg may be necessary. Multiple preventative medications have been tried and all appear to be beneficial.

Outcome Children with BEI and BFEI are able to discontinue antiseizure drug therapy by their early preschool years, without recurrence of focal seizures or emergence of new epilepsy syndromes. All children continued to have normal neurologic examinations and normal development. Recurrence of seizures or emergence of learning disorders/intellectual disability should prompt further evaluation.

Hemiconvulsions, Hemiplegia, and Epilepsy Syndrome (HHE) HHE is a rare condition that usually presents under age 4 years with prolonged unilateral convulsive status epilepticus in the context of a febrile illness followed by hemiplegia. Months to years later, intractable epilepsy emerges.

Seizures HHE typically presents initially with unilateral, clonic status epilepticus lasting for more than 24 hours. Severe autonomic symptoms can also emerge. The initial seizures are acute symptomatic seizures and, therefore are not epilepsy. This stage is called hemiconvulsions and hemiplegia syndrome (HHS). Recurrent unprovoked seizures occur in two-thirds to three fourths of children after months to years of seizure freedom, at which point the epilepsy is typically pharmacoresistant. The seizures are focal dyscognitive seizures arising from the temporal regions or from multiple foci within the affected hemisphere.

Other Neurologic Findings Most children have normal growth and development before onset of the seizure. Hemiplegia ipsilateral to the side of convulsive status epilepticus occurs and must last at least 1 week. Additional neurologic findings such as visual field deficits and aphasia may be seen.

Etiology

Normal neuroimaging must be present for infants to be diagnosed with either BEI or BFEI. Malformations of cortical development may be difficult to detect on MRI before 2 years of age, so careful clinical follow up is needed to ensure the accuracy of this diagnosis.

The etiology for HHE is unknown. Even in those children with preexisting, structural abnormalities, the cause for the acuteonset, febrile, prolonged hemiconvulsion and subsequent hemiparesis is unclear. The febrile component and mild illness suggest that hyperthermia and inflammation are important contributors to the pathogenesis.

Differential Diagnosis

EEG Findings

Careful evaluation must be undertaken to assess for malformations of cortical development or other structural causes, as well as potential metabolic disorders. The normal neuroimaging, normal interictal EEG, and normal development throughout the course of this epilepsy are helpful in securing the diagnosis. Furthermore, this is a pharmacoresponsive

In the acute phase, EEG is important to ensure complete electrographic cessation of the seizure. The ictal EEG demonstrates rhythmic, high amplitude, 2 to 3 Hz slow wave activity bilaterally but higher over the affected hemisphere and often associated with rhythmic spikes and low amplitude fast activity contralateral to the clonic activity. Postictally, the slowing over

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the affected hemisphere continues, whereas the unaffected hemisphere has gradual reappearance of normal background activity. During the chronic phase, presurgical evaluation is often pursued for the intractable epilepsy. The interictal EEG typically shows multifocal spikes and sharp waves, typically most prominent over the affected hemisphere.

Neuroimaging Neuroimaging is essential for the diagnosis and should be done early. At the time of hemiconvulsive status epilepticus, the MRI reveals edema of the affected hemisphere maximally involving the subcortical white matter. There is hyperintensity on diffusion weighted imaging sequences that corresponds with decreased apparent diffuse coefficient. MRI angiography is normal. These MRI abnormalities are independent of any vascular territory and resolve within 1 month. Hemiatrophy and possible hippocampal sclerosis occur over weeks to months.

Other Laboratory Studies Additional studies to determine potential metabolic, vascular, infectious, or autoimmune etiology should be completed but are normal in these patients.

Differential Diagnosis Stroke can be excluded with neuroimaging that does not follow vascular territory, absence of hemorrhage, and normal vascular studies. Metabolic disorders such as mitochondrial cytopathies can present with stroke-like episodes and seizures, especially in the setting of illness. However, seizures due to acute stroke typically present first with motor deficit and then seizure. Acute traumatic brain injury and neoplasm are also excluded by neuroimaging. The acute edema followed by profound hemiatrophy seen in HHE would make malformation of cortical development unlikely. Infectious and autoimmune etiologies should be evaluated. Febrile infection-related epilepsy syndrome (FIRES) is characterized by onset of seizures that evolve to refractory status epilepticus in otherwise healthy, school-aged children during or shortly after a nonspecific febrile illness. Unlike HHE, cognitive deficit and pharmacoresistant epilepsy occur at onset. Finally, Rasmussen’s encephalitis typically presents with focal motor seizures and epilepsia partialis continua, but the onset of motor weakness is gradual as is the atrophy on MRI.

Treatment The treatment in the acute phase is supportive. There is no evidence that initiating chronic treatment with antiseizure drugs will prevent the later onset of unprovoked seizures. Presurgical evaluation should be pursued for pharmacoresistant seizures in the chronic phase.

Outcome Children with HHE are typically left with variable degrees of permanent motor and cognitive deficits. The seizures in HHE are usually pharmacoresistant, but seizure control may be obtained through surgical resection. Those with proven temporal lobe onset have excellent seizure outcome after temporal lobectomy, even in the presence of more extensive imaging abnormalities. Multilobar resection or hemispherectomy may be needed in those with extratemporal onset or multiple ictal foci within one hemisphere.

UNDIFFERENTIATED SYNDROMES West Syndrome West syndrome is the most common epileptic encephalopathy in infancy, with an estimated incidence of 3 to 4.5 per 10,000 live births. It consists of a triad of: (1) epileptic spasms; (2) hypsarrhythmia on EEG; and (3) arrest or regression of psychomotor development. The onset of epileptic spasms is typically between 3 to 12 months of age.

Seizures Epileptic spasms involve a sudden flexion, extension, or mixed flexion-extension movement of the proximal and truncal muscles, lasting 1 to 2 seconds, and occur in clusters shortly after waking. Focal seizures may also be seen and suggest an underlying focal pathology.

Other Neurologic Findings Developmental delay is frequently evident, even before spasm onset. Focal or generalized motor findings, impairments in visual attention, and microcephaly are common. A dermatologic examination using a Wood’s lamp should be undertaken to evaluate for neurocutaneous disorders such as tuberous sclerosis. Abnormalities such as organomegaly, unusual odor, or dysmorphic features would suggest the possibility of a metabolic or genetic etiology.

Etiology An obvious cause of spasms is identified in just over half of cases after initial clinical evaluation and MRI and in up to three fourths of infants after further investigations. Structural etiologies, including malformations of cortical development, tuberous sclerosis, and perinatal brain injury, are most common. Genetic etiologies are increasingly recognized (Paciorkowski, et al., 2011). In contrast, metabolic etiologies are less frequent.

EEG Findings The classic finding on interictal EEG in West syndrome is hypsarrhythmia, characterized by very high amplitude (often up to 500 microvolts), asynchronous slow waves, and multifocal spikes and polyspikes. Absence of hypsarrhythmia in a child with a suspicious history does not rule out a diagnosis of West syndrome, and a prolonged EEG recording should be considered. Hypsarrhythmia may also be asymmetric in patients with focal lesions. The typical ictal correlate of an epileptic spasm is a high voltage, often generalized sharp or slow wave followed by an electrodecrement, consisting of low amplitude fast activity.

Neuroimaging Brain MRI is a necessary test in all cases of West syndrome without known etiology. MRI reveals a cause in 35% to 41% of cases. If the initial MRI is normal and seizures persist, an MRI may be repeated every 6 months and should be redone after age 24 to 30 months, when myelination is more mature, to detect cortical dysplasia (Gaillard, et al., 2009).

Other Laboratory Studies In children without a clear etiology after imaging, further genetic and metabolic studies should be obtained (Tables 71-1 and 71-2). If imaging is suggestive of an inborn error of metabolism, an extensive metabolic investigation is warranted. In those with normal MRI, genetic testing, including comparative



genomic hybridization array, epilepsy gene panel, whole exome sequencing, or mitochondrial genetic studies, should be considered.

Treatment Hormonal therapy (ACTH or prednisolone) and vigabatrin have been proposed as first-line therapy for infantile spasms. Based on the evidence-based guideline from the American Academy of Neurology, ACTH may have greater short-term efficacy than vigabatrin once infants with tuberous sclerosis are excluded (Go, et al., 2012). Vigabatrin is the treatment of choice in infantile spasms due to tuberous sclerosis, with seizure cessation being seen in 95% of cases and may be effective in spasms due to focal cortical dysplasia. There is insufficient evidence to recommend other medications or the ketogenic diet as first-line agents. Children with infantile spasms due to focal cortical structural abnormalities not controlled with hormonal therapy and vigabatrin should be expediently referred for possible surgical treatment, even with nonlocalizing EEG.

Outcome Most children with West syndrome have intellectual disability at follow up and are also at risk for autism (Widjaja, et al., 2015; Riikonen, 2001). The underlying etiology is the most critical predictor of developmental outcome. Additional factors predictive of better outcome include shorter duration from spasm onset to diagnosis, favorable response to initial therapy, absence of other seizures before infantile spasms, and absence of atypical spasms, focal seizures, or asymmetric EEG abnormalities. Infantile spasms resolve in the majority of children by the early preschool years. However, 50% to 90% of cases develop other seizure types, most commonly either Lennox-Gastaut syndrome (27% to 50%) or focal/multifocal epilepsy. West syndrome also carries a significant mortality risk. One large study that followed 214 children for a mean of 25 years reported that 31% had died; the most frequent causes of death included infection and complications of therapy (Riikonen, 2001).

Dravet Syndrome Dravet syndrome is a catastrophic childhood epilepsy syndrome that leads to intellectual disability and motor deficits (Brunklaus, et al., 2012). The estimated incidence is approximately 1 to 2 per 40,000 live births.

Seizures This epilepsy syndrome begins in the first 18 months of life with prolonged, hemiconvulsive seizures initiated by fever (often associated with vaccines) or hyperthermia. Over the next several months, recurrent febrile and afebrile seizures occur, often switching sides. In early childhood other seizure types emerge, including myoclonic, atypical absence, and focal seizures. Obtundation status, in which children appear poorly responsive and have erratic myoclonus may also be seen and can persist for hours. Reflex seizures are frequent with the most common provoking factor being hyperthermia. Tonic seizures are unusual in Dravet syndrome.

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degree of cognitive and behavioral impairment has been linked to higher frequency of seizures. The neurologic examination is typically normal at epilepsy onset. However, ataxia and pyramidal signs, as well as crouch gait, may develop.

Etiology SCN1A mutations (mostly de novo) are found in 80% of patients. However, 5% show familial mutations in which affected relatives are mildly affected with a genetic epilepsy with febrile seizures plus (GEFS +) phenotype. The genetic finding must be correlated to epilepsy phenotype to reach an accurate diagnosis.

EEG Findings The EEG background is typically normal at epilepsy onset. After 1 to 2 years, patients show diffuse background slowing. Epileptiform discharges, seen in a minority at onset, are most commonly generalized and may be triggered with photic stimulation. At age 2 to 5 years, an increase in generalized paroxysmal abnormalities, as well as emergence of focal and multifocal discharges, occurs.

Neuroimaging Neuroimaging studies are normal at presentation, although scans done later in life may show abnormalities, likely due to the prolonged seizures.

Treatment Dravet syndrome is extremely pharmacoresistant (Chiron, 2011). The goals of treatment are to avoid prolonged status epilepticus, reduce frequency of briefer seizures, and avoid problematic adverse effects of multiple agents used at high doses. Sodium channel agents should be avoided as they exacerbate seizures. First-line therapy typically involves valproic acid, clobazam, or topiramate. Stiripentol is often considered if first-line therapy is ineffective and has been shown to reduce seizures and status epilepticus. Bromides and ketogenic diet have also been effective. Isolated case reports and small studies have suggested possible efficacy of fenfluramine, verapamil, fluoxetine, cannabidiol, vagus nerve stimulation, and deep brain stimulation. Careful clinical trials are needed. Caregivers of children with Dravet syndrome should be taught to administer a home dose of rescue benzodiazepine, and a treatment plan for management of prolonged seizures should be provided.

Outcome Seizures remain medically refractory. Many seizure types reduce or resolve by early adulthood, with brief, nocturnal, generalized tonic-clonic seizures remaining as the main seizure type. Most patients have moderate to severe disability and cannot live independently as adults. There is an increased mortality rate in children with Dravet syndrome, with approximately 15% dying by early adulthood, and death is often seizure-related.

Other Neurologic Findings

Genetic Epilepsy With Febrile Seizures   Plus (GEFS +)

Development is normal at epilepsy onset, but then there is a variable decline in developmental quotient over time. Autistic traits and hyperactivity have also been reported. A greater

GEFS + is a common, familial electroclinical syndrome in which two or more family members have phenotypes consistent with this diagnosis (Scheffer and Berkovic. 1997).

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Affected individuals exhibit variable phenotypes. The onset is typically between 6 months and 6 years of age.

Seizures At the mildest end of the phenotypic spectrum are children with febrile seizures alone, which may be recurrent, prolonged, focal, or occur in clusters. Next most common are those with “febrile seizures plus,” in which febrile seizures either continue beyond the age of 6 years, and/or afebrile seizures also occur. At the severe end of the spectrum are individuals with myoclonic-atonic epilepsy or Dravet syndrome. Some individuals may also present with temporal lobe epilepsy, with or without hippocampal sclerosis.

Other Neurologic Findings With the exception of rare cases on the severe end of the phenotypic spectrum, children with GEFS + are typically neurologically and developmentally normal.

Etiology GEFS + is usually inherited in an autosomal dominant manner with incomplete penetrance. GEFS + remains a clinical diagnosis, and genetic testing is not required.

EEG Findings EEG is not indicated in simple febrile convulsions but may be obtained in those with complex features—particularly focal or prolonged febrile seizures. An EEG is typically obtained in children with afebrile seizures, and the findings in GEFS + are heterogenous. The background is typically normal, although diffuse slowing may be seen in individuals with severe phenotypes. In individuals with generalized seizures, the interictal recording typically shows generalized discharge, which can become fragmented in sleep. In those with temporal lobe epilepsy, focal discharge is seen.

Neuroimaging Neuroimaging is generally not required, particularly with generalized seizures, and is typically normal. Rarely, hippocampal sclerosis can be seen in patients with GEFS + and temporal lobe epilepsy.

Treatment Simple febrile seizures alone do not require prophylactic drug therapy. If febrile seizures are prolonged or clustered, caregivers should be taught to administer a home dose of rescue benzodiazepine therapy. Prophylactic antiseizure therapy for afebrile seizures should be geared toward the seizure type. Because many mutations in GEFS + may alter sodium channel function, sodium channel blockers may potentially be more problematic. Children with epileptic encephalopathies such as myoclonic-atonic epilepsy or Dravet syndrome may also benefit from the ketogenic diet.

Outcome The majority of children with GEFS + have seizures that are easily controlled with medication. Seizures are typically selflimited and resolve at puberty. Rare individuals continue to have generalized seizures into adulthood. Development remains normal. Children who develop myoclonic-atonic epilepsy are typically pharmacoresistant initially, but many ultimately become seizure free by middle childhood and have remission of their epilepsy.

CONCLUSIONS Epilepsies that begin in infancy are associated with high rates of pharmacoresistance and are commonly associated with neurocognitive impairment. Recognition of a specific electroclinical syndrome is imperative to: (1) understand the possible pathogenic mechanisms leading to epilepsy and allow more cost-effective, less invasive, and more streamlined investigations; (2) choose more efficacious therapies to control seizures and prevent associated comorbidities; and (3) better prognosticate long-term development and seizure outcome for families. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Brunklaus, A., Ellis, R., Reavey, E., et al., 2012. Prognostic, clinical, and demographic features in SCN1A mutation-positive Dravet syndrome. Brain 135, 2329–2336. Caraballo, R., Fontana, E., Darra, F., et al., 2008. Migrating focal seizures in infancy: analysis of the electroclinical patterns in 17 patients. J. Child Neurol. 23 (5), 497–506. Chiron, C., 2011. Current therapeutic procedures in Dravet syndrome. Dev. Med. Child Neurol. 53 (Suppl. 2), 16–18. Gaillard, W.D., Chiron, C., Cross, J.H., et al., 2009. Guidelines for imaging infants and children with recent-onset epilepsy. Epilepsia 50, 2147–2153. Go, C.Y., Mackay, M.T., Weiss, S.K., et al., 2012. Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 78, 1974–1980. Paciorkowski, A.R., Thio, L.L., Dobyns, W.B., 2011. Genetic and biologic classification of infantile spasms. Pediatr. Neurol. 45, 355–367. Riikonen, R., 2001. Long-term outcome of patients with West syndrome. Brain Dev. 23, 683–687. Scheffer, I.E., Berkovic, S.F., 1997. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain 120 (Pt 3), 479–490. Vigevano, F., 2005. Benign familial infantile seizures. Brain Dev. 7 (3), 172–177. Widjaja, E., Go, C., McCoy, B., et al., 2015. Neurodevelopmental outcome of infantile spasms: A a systematic review and metaanalysis. Epilepsy Res. 109, 155–162.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 71-1 Normal background during wakefulness and sleep. Fig. 71-2 Generalized atypical spike. Fig. 71-3 EEG of a 4-month-old infant with benign myoclonus of infancy. Fig. 71-4 EEG of a 3-year-old boy with intractable epilepsy. Fig. 71-6 Seizure discharge maximally involving the left temporal region. Fig. 71-7 Interictal sleep EEG of a 6 month old with epileptic spasms. Fig. 71-8 Ictal recording of an 8-month-old with a history of West syndrome. Fig. 71-9 EEG of a 5-year-old girl with Dravet syndrome. Fig. 71-10 EEG of a 2-year-old boy with a history of two febrile and two afebrile generalized tonic-clonic seizures.

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Electroclinical Syndromes: Childhood Onset Jeffrey R. Tenney and Tracy Glauser

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Electroclinical syndromes are important constellations of spe­ cific clinical history and electroencephalographic (EEG) find­ ings with onset during a distinct time in brain development. Childhood is a particularly important stage of development in general and epilepsy specifically. The electroclinical syndromes of childhood can be consid­ ered as three distinct categories depending on seizure onset localization. These include childhood generalized epilepsy syndromes, focal epilepsy syndromes of childhood, and a cat­ egory best described as, “undetermined as to whether focal or generalized.” Making the diagnosis of a specific electroclinical syndrome allows the clinician to provide specific diagnostic and thera­ peutic recommendations to the family and enhances coun­ seling related to treatment response, remission rates, and potential psychosocial comorbidities.

CHILDHOOD GENERALIZED   EPILEPSY SYNDROMES Childhood Absence Epilepsy (CAE) Clinical Characteristics CAE is the most common pediatric epilepsy syndrome com­ prising 10% to 17% of all childhood onset epilepsies. Females are affected more frequently than males. The International League Against Epilepsy (ILAE) criteria include age of onset between 4 and 10 years that peaks between 5 and 7 years. The main clinical manifestation of childhood absence sei­ zures is an abrupt impairment of consciousness (without an aura) accompanied by one or more additional features includ­ ing behavioral arrest, staring, eyelid fluttering, and/or hand automatisms followed by no significant postictal confusion or lethargy. The impairment of consciousness can be assessed at the bedside by asking the child to repeat a code word or perform a continuous motor task such as tapping. Absences can be provoked by hyperventilation. The duration of typical absence seizures has been reported as 9.4 plus or minus 7 seconds but with a range from 1 to 44 seconds. These seizures can be very frequent and occur at least daily but in the most severe cases can occur hundreds of times per day. The ILAE Report on Terminology and Classification revised in 2010 distinguishes between typical and atypical absence seizures (Berg, et al., 2010). In contrast to typical absence seizures, atypical absences tend to have a less abrupt onset and offset, variable impairment of consciousness, and prolonged duration.

EEG Findings The characteristic ictal electroencephalogram (EEG) of a typical absence seizure demonstrates generalized, bilaterally synchronous, spike and wave complexes with frontal predomi­ nance and repeating at 3 to 4.5 Hz (Fig. 72-1). There is a gradual slowing of the frequency from onset to termination. Often the onset is not truly bilaterally synchronous but rather

with one hemisphere preceding the other by a few millisec­ onds. A duration of 3 seconds is a clinically reasonable “rule” for distinguishing a burst from a seizure and provides an objective EEG measure when it is difficult to identify a clinical change (Glauser, et al., 2010). Interictal background activity is usually normal in patients with CAE although high voltage occipital intermittent rhythmic delta activity (OIRDA) has been reported in 15% to 38% (Holmes, et al., 1987).

Etiology CAE is categorized as an idiopathic, and presumed genetic, epilepsy syndrome. Over the past 50 years multiple theories have been proposed to explain the generation of the diffuse spike and wave discharges that characterize absence seizures. Initially, the centrencephalic theory suggested that these rhythms were generated by cells in the midline thalamus that then projected diffusely to the cortex. Similarly, a more recent “thalamic clock” theory implicated the reticular thalamic nucleus as the generator that drives the cortical rhythms seen on EEG. Other investigators have highlighted focal cortical regions as generators for these seizures which then spread dif­ fusely through corticocortical connections. The “corticotha­ lamic” theory of generation highlights the interaction between oscillations in the thalamus and the presence of an excitable cortex that leads to the spike wave discharges. Investigations in animals and humans have highlighted the importance of focal cortical regions that may force larger areas of cortex into a pathologic state, which is then perpetuated by thalamocorti­ cal connections. Genetics has been known to play a role in the development of CAE for over 70 years and recent work has highlighted the genetic complexity of this syndrome. Small populations of affected patients have been shown to have various mutations in genes coding for GABA receptor subunits, nonion channel proteins, and calcium channels.

Treatment Before 2010 there were only a few, small, randomized, con­ trolled trials completed to assess the most effective monother­ apy for children with CAE, and none of them were categorized as Class I or II. These were insufficient for in­­forming routine clinical practice. However, in 2010 a NIH funded double-blind, randomized, multicenter, comparative-effectiveness clinical trial compared ethosuximide, valproic acid, and lamotrigine as initial monotherapy in 446 patients with CAE. Significantly higher freedom from failure rates were seen at the 16 to 20 week visit in patients taking ethosuximide (53%) and val­ proic acid (58%) than those on lamotrigine (29%; p 99th percentile Anti-β2 GPIb IgG/IgM >99th percentile

aCL, Anticardiolipin Antibodies; Anti-β2 GPIb, Anti–β2-glycoprotein Ib antibodies; dRVVT, Dilute Russell’s viper venom time; FVIII, Factor VIII; FVL, Factor V Leiden; Hgb, Hemoglobin; MTHFR, methylenetetrahydrofolate; PT, Prothrombin; Prot, Protein reductase.

high red cell distribution width), while testing of factor VIII, D-dimer, vWF, and PAI-1 is likely practitioner dependent.

Treatment Treatment of APA syndrome in neonatal and childhood AIS remains indeterminate, secondary to the lack of pertinent randomized trials. The AHA recommends treatment of adults who suffer AIS associated with transient APAs and AIS with antiplatelet therapy. Similarly, it recommends treatment of APA syndrome and stroke with antiplatelet therapy, while acknowledging the lack of consensus surrounding this recommendation. Indeed, the13th International Congress on Antiphospholipid antibodies recommends treatment of APA syndrome in adult AIS with anticoagulation alone, or combined with aspirin in more severe cases. It is the clinical practice of these authors to treat APA syndrome in childhood AIS with anticoagulation (usually warfarin or LMWH) while

Genetic thrombophilias vary greatly in their severity, with some abnormalities such as heterozygous prothrombin gene mutations or factor V Leiden only mildly increasing thrombotic risk, whereas others such as severe protein C or S deficiency significantly increasing the lifelong risk of clotting (see Fig. 113-1). Therefore genetic counseling surrounding these traits is best performed by a hematologist and/or genetic counselor who is familiar with these traits. In pediatric stroke, the prevalence of each of these genetic abnormalities is almost uniformly increased compared with matched controls (see Table 113-2), suggesting that thrombophilia, even when mild, may play an important role in pediatric AIS of all subtypes. Indeed, inherited thrombophilias have been associated with risk of stroke in multiple subtypes. Some inherited thrombophilias, such as severe protein S or protein C deficiency, may be the underlying cause for childhood or neonatal AIS. Protein C deficiency is a well-established risk factor for childhood and neonatal AIS (see Table 113-2) and, when present, is likely to increase recurrence risk. Similarly, protein S is a risk factor for incident AIS that is often inherited. The risk of stroke recurrence with protein S deficiency has not been studied in a large cohort of childhood stroke. Some milder thrombotic traits, such as prothrombin G20210A, factor V Leiden mutations, antithrombin deficiency, and MTHFR C677T mutation have all been associated with incident childhood AIS (see Table 113-2) but their association with recurrence risk remains uncertain. The association between lipoprotein (a), another heritable mild thrombotic trait, and recurrent childhood AIS is of particular interest. Two separate studies have demonstrated an elevated risk of recurrent AIS in children with elevated lipoprotein (a) (RR = 4.4, 95% CI = 1.9–10.5).

Evaluation Although the majority of genetic thrombophilia traits are established as independent risk factors for pediatric AIS, data supporting significant prognostic impact on recurrence risk exist only for a few individual traits such as elevated lipoprotein (a), protein C deficiency, and the presence of multiple risk factors. AHA pediatric stroke guidelines recommend that, “although the risk of stroke from most prothrombotic states is relatively low, the risk tends to increase when prothrombotic disorder occurs in children with other risk factors. Thus, it is reasonable to evaluate for the more common prothrombotic states even when another stroke risk factor has been identified” (Roach et al., 2008). Without an adequately powered study to detect the impact of genetic thombophilia on recurrence risk in pediatric AIS, definite recommendations about evaluation remain challenging (Manco-Johnson et al., 2002).

Treatment In childhood AIS, patients should be treated with antithrombotic therapy from the onset of stroke, regardless of thrombophilia traits, unless a contraindication exists. The AHA and CHEST guidelines suggest acute treatment with aspirin (2 to

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5 mg/kg) in most cases, reserving anticoagulation (typically LMWH or coumadin) in cases of dissection or cardioembolism (Monagle et al., 2012). The presence of a severe genetic thrombophilia or multitrait thrombophilia requires consideration of more aggressive treatment, such as anticoagulation in the chronic phase of secondary prevention, especially during times of increased clotting risk, such as prolonged immobility after surgery or trauma. Treatment decisions surrounding childhood stroke in the setting of multiple thrombophilia and/or genetic thrombophilia are best made by a multidisciplinary stroke team that includes a pediatric hematologist familiar with the multiple thrombophilia states and their implications across the human lifespan.

Sickle Cell Disease Presentation Sickle cell disease (SCD), particularly the hemoglobin SS variant, results in both small vessel infarctions and large vessel AIS because of moyamoya syndrome. SCD is the best studied hematological abnormality in childhood stroke, and presents one of the rare opportunities for primary prevention of stroke in children. The importance of stroke in children with SCD has been known for decades with an incidence of stroke in 285 per 100,000 per year in children with SCD. However, the great importance of silent infarcts upon cognition and outcomes has only been more recently recognized. Although children with SCD present with similar symptoms of stroke as those without AIS when infarcts are large, silent infarcts typically present with cognitive issues, including plateau and/or decline.

Evaluation and Treatment Typically, stroke is not the presenting symptom for children with SCD, although a screening CBC with blood smear review and hemoglobin electrophoresis should be considered in any child with new-onset AIS. For acute AIS in the setting of SCD, both AHA and American College of Chest Physicians (ACCP) guidelines recommend urgent erythrocyte exchange transfusion to reduce hemoglobin S levels to less than 30% of total hemoglobin. In addition, primary prevention of stroke in children with SCD is possible through transcranial Doppler (TCD) screening for intracranial artery stenosis (Monagle et al., 2012 and Roach et al., 2008). In the multicenter randomized controlled STOP trial, 130 children with elevated velocity (>170 to 200 cm/s) of intracranial arterial blood flow as measured by TCD were randomized to regular exchange transfusion program intended to reduce Hgb S to less than 30% of total Hgb versus no intervention. In the untreated group, the yearly stroke risk remained over 10%, whereas in the transfused group the stroke risk was reduced to 1% per year (Adams et al., 1998). Therefore RCP and ACCP guidelines also recommend that children older than 2 years who have SCD be screened yearly with TCD and placed on a chronic transfusion regimen if found to have elevated TCD velocities. Unfortunately, the real-world impact of this finding has been imperfect, as many children with SCD remain unscreened or underscreened for arterial narrowing. Chronic transfusions should also be considered in children with silent infarcts in addition to those with abnormal TCD screening.

COAGULATION DISORDERS IN PEDIATRIC CEREBRAL SINOVENOUS THROMBOSIS CSVT in children and neonates is a rare disorder, even compared with pediatric AIS, with an incidence of 0.67 per 100,000

children per year (DeVeber, 2001). Many risk factors outside of overt thrombophilias are associated with CSVT. In neonates, some other factors include birth trauma, delivery-related stress on the venous circulation, infection, and underdeveloped hemostatic systems. In children, trauma, dehydration, surgery, and infection are among the more common risk factors for CSVT. In addition, chronic systemic diseases, including inflammatory/rheumatologic disease, renal disease, and cardiac disease may contribute to CSVT risk. Among neonates with CSVT, prothrombotic states are found in about 20% and in children, estimates range from 24% to 64%. Prothrombotic states may be the sole risk factor for CSVT or in combination with other risk factors. Previous studies demonstrated an elevated incidence of CSVT when a genetic or acquired hypercoagulable state is combined with a concomitant clinical risk factor for thrombosis. Interestingly, the prevalence of thrombophilias is higher in children with “idiopathic” CSVT (up to 85%) than in children with a CSVT provoked by a known clinical risk factor. In addition, the finding of multiple different genetic or acquired thrombophilias likely increases the risk of CSVT. The role of prothrombotic factors likely differs between CSVT and AIS, as fibrin-rich thrombi are common in the lowflow system venous system, compared with platelet-rich thrombi as seen commonly in the high-flow arterial vascular system. Therefore workup and management of thrombophilias in patients with CSVT may differ from the management in children and neonates with AIS.

Acquired Thrombophilia Presentation In the neonatal and childhood period, the most common acquired thrombophilias are secondary to underlying medical illnesses. As example in children, cyanotic heart disease can lead to polycythemia, dehydration, cancer, or an endogenous hypercoagulable state. Similarly, infection is a well-known acquired cause of CSVT in neonates, with 23% to 73% of neonates and children with CSVT with a comorbid infection. Children with malignancies have a hypercoagulable state, which is most common in acute lymphoblastic leukemia (likely associated with L-asparaginase), followed by sarcoma and lymphoma. In addition, nephrotic syndrome in children is frequently associated with thromboembolism, occurring in up to 9%. Anemia is common in children with CSVT, most commonly iron deficiency anemia, although its role in the formation of thrombus is not clear. Few studies have quantified the incidence of APA syndrome in childhood CSVT. Multicenter studies have reported the incidence or elevated RVVT is elevated in children with CSVT (4% to 11%), compared with controls. Among children with known APA syndrome, venous thrombotic events are common, occurring in up to 60%. However, only about 7% present with CSVT. In neonates, transplacental passage of maternal APAs from a mother with APA syndrome or systemic lupus is an uncommon cause of venous thrombosis. In several series of infants with perinatal thrombosis born to mothers with APA syndrome, only 10% to 20% had venous thrombosis, and all in the peripheral circulation. Neonatal APA-related CSVT has been described rarely, however. Several reports have documented APA-negative maternal testing, suggesting that there are some cases of de novo fetal production of APA’s associated with CSVT.

Evaluation As in AIS, evaluation for APA in children and neonates with CSVT is uncertain. In children or neonates with a history of



multiple-site thrombosis or repeat CSVT, testing should include conventional APA testing for β2GP IgG/IgM, ACA antibodies IgG/IgM, and a dRVVT assay for LA (see Fig. 113-2). This same evaluation should be undertaken in children with idiopathic CSVT, or in those with other symptoms of APA syndrome. As in AIS, children who are found to have APAs in the acute setting should have repeat testing at least 12 weeks later to evaluate for true APA syndrome (Miyakis et al., 2006). When to test for APAs in neonates with CSVT and no other systemic thrombi is uncertain and somewhat controversial. Guidelines recommend that all neonates and children with CSVT should have a complete blood count to evaluate for anemia.

Treatment Guidelines suggest treating childhood CSVT acutely with anticoagulation unless there is a contraindication, continuing for 6 weeks to 6 months regardless of the etiology. In neonates with CSVT, anticoagulation is more controversial. Variability in treatment strategies for neonates exists across geographic regions, with some areas utilizing anticoagulation in almost all patients and others only initiating anticoagulation if clot propagation is seen on a 5- to 7-day scan. In childhood CSVT, however, anticoagulation is almost uniformly suggested at onset of CSVT, unless a contraindication exists. For children with CSVT without significant hemorrhage, CHEST guidelines suggest initiating anticoagulation. For children with CSVT and significant hemorrhage, CHEST guidelines suggest initiation of anticoagulation or radiologic monitoring of the thrombosis at 5 to 7 days and anticoagulation for thrombus extension (Monagle et al., 2012). APA syndrome has been found among adults with first ever idiopathic DVT or pulmonary embolism to increase the risk of recurrence by 4- to 7-fold, and so adult guidelines recommend anticoagulation for the duration of APA syndrome. As previously mentioned, these authors use a similar approach. There are no clear guidelines on the longterm treatment of neonates with CSVT and APA syndrome.

Genetic Thrombophilia Presentation Many inherited procoagulant disorders have also been found to be risk factors for venous thromboembolism in adults and children. In several systematic reviews, protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, prothrombin G20210A mutation, and lipoprotein (a) have been found significantly associated with first venous thromboembolism in children. Fewer data are specifically available regarding inherited thrombophilias in CSVT in children, though in a meta-analysis of the existing studies, all of these factors except prothrombin G20210A mutation remained significantly associated (Table 113-3). Although the prothrombin G20210A mutation is rare, it is the only inherited thrombophilia with evidence supporting its role in CSVT recurrence (OR 5.5). The role of inherited thrombophilias is even less clear in neonates. In fact, one prospective multicenter study of children and neonates with CSVT found no recurrence of venous thromboembolism in children under the age of two at onset of CSVT.

Diagnosis Children with CSVT, especially those with no clear provoking factor, should have an evaluation for inherited prothrombotic conditions. The most important thrombophilias to evaluate are prothrombin G20210A mutation, factor V Leiden mutation, protein C, protein S, and antithrombin III. The utility of

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evaluation of other abnormalities such as lipoprotein (a), hyperhomocysteinemia and factor VIII is less clear, and interpretation and management of results is difficult. D-dimer may be drawn as a marker of clot formation and lysis to follow during therapy. In neonates, the utility of these studies is unclear. Because most children with CSVT are treated initially with anticoagulation, it is important to note that protein C, protein S, and antithrombin III levels can be falsely depressed if checked during the acute phase. Therefore it is critical to check these studies using serum from before the start of anticoagulation or 2 to 4 weeks after anticoagulation is discontinued.

Treatment As discussed above, guidelines and standard practice suggest treating childhood CSVT in the acute period with anticoagulation in children and possibly neonates. As in genetic thrombophilia and pediatric AIS, the treatment team should include an experienced hematologist and/or genetic counselor who is familiar with clotting disorders in children. Given the current relative lack of data, it is reasonable to follow adult guidelines, which suggest consideration of long-term anticoagulation in patients with severe inherited thrombophilias, such as homozygous prothrombin G20210A or factor V Leiden mutations, or severe deficiencies of protein C, protein S, or antithrombin III. Long-term treatment should also be considered in those who have multiple genetic or acquired thrombophilias or recurrent events.

COAGULATION DISORDERS IN PEDIATRIC HEMORRHAGIC STROKE Introduction Hemophilia is the most prevalent coagulation disorder in pediatric hemorrhagic stroke. Hemophilia A and B, caused by deficiency of clotting factors VIII and IX, respectively, are X-linked bleeding disorders known for joint and soft tissue hemorrhages, but are also associated with intracranial hemorrhage (ICH) in 3% to 12% of patients with hemophilia that may cause disability and long-term neurologic sequelae. Morbidity in these cases is high, with neurologic deficit in 60% to 75% of the cases, and death in up to 20%. Patients with hemophilia are 20 to 50 times more likely to develop ICH than those without, particularly in the newborn period (4% rate compared with 0.1%), likely due in part to germinal matrix immaturity. Outside the neonatal period, the risk of ICH is approximately 300 to 800 per 105 patient years. The next sections will consider the different evaluation, management, and prevention approaches for patients with known disorders of hemostasis and those children who present with a priori ICH.

Evaluation In any case of known or suspected ICH, emergent imaging is imperative, but the sequence of events differs based on the underlying diagnosis. If a known coagulation factor deficiency exists, that defect must be corrected immediately even as imaging is being arranged. If, however, the child has no known bleeding disorder, then the priority becomes imaging (rapid noncontrast CT unless MRI is immediately available, in which case it is preferred) and expert consultation with neurology, hematology, and neurosurgery to determine the next steps in what may be the result of either an accident in a healthy child or the first manifestation of a congenital or acquired bleeding diathesis. In this case once the child is stabilized, the focus

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should turn to the workup to rule out an undiagnosed underlying bleeding disorder or alternative cause of hemorrhage, including full history, physical examination, and a stepwise series of laboratory evaluations (see Fig. 113-1).

Treatment The standard treatments for general ICH are limited, consisting of close observation, standard medical management, and consideration of neurosurgical intervention. In the particular setting of hemophilia, clotting factor replacement (or inhibitor bypass strategies if necessary) is an essential first therapeutic step. Treatment for known or suspected ICH in a patient with hemophilia must include immediate clotting factor replacement to the 100% level (with goal of trough level of 50% or greater), even at the same time the clinician arranges for diagnostic imaging. Expert consultation from pediatric hematology, neurology, and neurosurgery should also be sought. High levels of factor replacement should be continued for approximately 7 days and then taper to goal of 30% to 50% factor trough to complete 2 to 3 weeks, depending on the nature of the inciting event (if any) and interim clinical progression. Additionally, the use of antifibrinolytic agents may reduce the risk of rebleeding in subarachnoid hemorrhage and has been recommended as adjunctive therapy for hemophiliacs who suffer ICH. Patients with specific clotting factor inhibitors present a special challenge and may require the use of rFVIIa or prothrombin complex concentrates. If the hemorrhage is spontaneous, strong consideration should be given to subsequent prophylactic clotting factor infusion to prevent another event, because the rate of rebleeding after initial ICH may be as high as 26%. Primary prevention strategies for patients with known bleeding disorders begin with frank discussions at initial diagnosis about the dangers of head injury (as well as the possibility of spontaneous ICH in patients with severe disease) and continued reinforcement at subsequent clinic visits. Regarding the perinatal period specifically, it is important to avoid instrumental delivery (vacuum extraction, forceps, etc.) and fetal scalp monitors if possible. Screening of other potential hazards, such as cephalopelvic disproportion, is also recommended. It is essential to avoid complication by superimposed hemorrhagic disease of the newborn with standard newborn vitamin K supplementation. Secondary prevention is the focus in any child who suffers an ICH, especially those with an idiopathic presentation. It is imperative that the child with idiopathic ICH be worked up appropriately to determine the underlying coagulation disorder (see Fig. 113-1) and subsequently take appropriate preventative measures to decrease the likelihood of a recurrence. In cases with a known nonhematologic etiology such as traumatic brain injury or vascular malformation, children should be screened with a PT/PTT/INR, and further evaluation considered if the hemorrhage is out of proportion to what is expected from the inciting cause.

Other Rare Bleeding Disorders ICH has also been described with other rare bleeding disorders, including neonates with vitamin K deficiency as well as severe deficiencies of factor II, factor V, and factor VII. ICH is also particularly common in factor X (up to 20% of affected

individuals) and factor XIII (30% of affected) deficiencies, which are often also associated with umbilical cord bleeding. Specific diagnosis is important because it may change the therapeutic approach such as using factor XIII concentrate, for example. Physiologic concentrations of vWF and the proportion of high-molecular-weight multimers are increased in the neonatal period, likely secondary to the physiologic stress of the birth process, severe/type 3 form (complete vWF deficiency) may be apparent in the newborn period. ICH in the context of vWF requires much of the same management above, but the factor replacement product must also contain vWF. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Adams, R.J., McKie, V.C., Hsu, L., et al., 1998. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N. Engl. J. Med. 339, 5–11. Bernard, T.J., Manco-Johnson, M.J., Goldenberg, N.A., 2011. The roles of anatomic factors, thrombophilia, and antithrombotic therapies in childhood-onset arterial ischemic stroke. Thromb. Res. 127, 6–12. DeVeber, G., Andrew, M., Adams, C., et al., 2001. Cerebral sinovenous thrombosis in children. N. Engl. J. Med. 345, 417–423. Kenet, G., Lutkhoff, L.K., Albisetti, M., et al., 2010. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and metaanalysis of observational studies. Circulation 121, 1838–1847. Manco-Johnson, M.J., Grabowski, E.F., Hellgreen, M., et al., 2002. Laboratory testing for thrombophilia in pediatric patients. On behalf of the Subcommittee for Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis (ISTH). Thromb. Haemost. 88, 155–156. Miyakis, S., Lockshin, M.D., Atsumi, T., et al., 2006. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J. Thromb. Haemost. 4, 295–306. Monagle, P., Chan, A.K., Goldenberg, N.A., et al., 2012. Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 141, e737S–e801S. Roach, E.S., Golomb, M.R., Adams, R., et al., 2008. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 39, 2644–2691.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 113-2. Three-dimensional time-of-flight MR. Fig. 113-4. Nonenhanced CT images. Table 113-2. Summary ORs (95% CIs; meta-analysis) Table 113-3. Summary ORs (95% CIs; meta-analysis)

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Infections of the Nervous System

Bacterial Infections of the Nervous System Geoffrey A. Weinberg and Robert Thompson-Stone*

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

The brain is normally a sterile site that is protected from infection by specialized barriers, including the bony skull and the blood–brain barrier. Consequently, infections of the central nervous system (CNS) are comparatively rare, but they remain potentially devastating medical emergencies that can lead to death or severe neurologic sequelae. Injury to the brain from meningitis is a consequence of both the invasion by the particular pathogens and the host’s ensuing overwhelming inflammatory response. The impact on mortality varies greatly by patient age, global location, and the causative organism, with high-risk patients including neonates and children in lower-income countries.

Pathogenesis

Bacterial meningitis involves inflammation of the leptomeninges, triggered by the presence of bacteria in the subarachnoid space. Prevention, prompt diagnosis, and aggressive management of acute bacterial meningitis remain the critical goals to prevent children from dying or suffering permanent neurologic sequelae (Brouwer, Thwaites, Tunkel, and van de Beek, 2012; Brouwer, Tunkel, and van de Beek, 2010; Kim, 2010).

Most cases of bacterial meningitis likely arise from bacteremia, which is caused by invasion of the bloodstream by the pathogen after colonization of the nasopharyngeal mucosa. From the nasopharyngeal surface, encapsulated organisms adhere to, colonize, and cross the epithelial cell layer and invade blood vessels. Viral coinfection of the respiratory tract also may promote invasive disease, possibly by increasing epithelial invasion. After surviving host defenses in the bloodstream, the “successful” meningeal pathogen must cross the blood– brain barrier either transcellularly or paracellularly. In neonates, however, colonization or transmission may occur vertically during birth, or from bacteremia associated with intravenous lines or mechanical ventilation. However, not all bacterial infections of the CNS are the result of bacteremia. Nonhematogenous invasion of the cerebrospinal fluid (CSF) by bacteria occurs in situations of compromised integrity of the barriers surrounding the brain (e.g., otitis media, mastoiditis, and sinusitis). Bacteria also can reach the CSF as a complication of neurosurgery, spinal anesthesia, cochlear implantation, or ventriculostomy placement.

Epidemiology

Clinical Manifestations

The epidemiology of bacterial meningitis in children and adults in the United States and elsewhere has changed drastically over the last 25 years with the global spread of conjugate vaccine initiatives, first significantly affecting infection with Haemophilus influenzae type b and then, later, Streptococcus pneumoniae and Neisseria meningitidis. In the United States, the median age at diagnosis of bacterial meningitis is now 25 years rather than 15 months as a result of the 99% reduction of H. influenzae type b meningitis incidence in children after initiation of routine conjugate vaccination. In newborns, the most common causative organism for early-onset neonatal sepsis and/or meningitis (defined as occurring within the first 7 days of life) is Streptococcus agalactiae (group B beta-hemolytic streptococcus), followed by Escherichia coli and Listeria monocytogenes. With the use of intrapartum maternal antimicrobial prophylaxis for women found to be carriers of group B streptococcus, the incidence of group B streptococcus early-onset disease declined from 2 in 1000 live births in 1990 to 0.3 in 1000 live births in 2004 (Thigpen et al., 2011).

The cardinal manifestations of bacterial meningitis are fever, nuchal rigidity, toxicity, and alteration of consciousness (Box 114-1). However, the presentation differs based on age of onset and causative organism. Other focal neurologic signs sometimes can develop, including cranial nerve dysfunction. In particular, CNV III can be affected, leading to deafness and/ or vestibular dysfunction. Seizures will develop in approximately one-third of patients either before or within the first few symptomatic days. Children may demonstrate more nonspecific findings than do adults. The majority of children greater than 1 year of age (≥80%) exhibit fever, vomiting, and meningismus and toxicity on examination. Signs of meningeal irritation on examination include Kernig’s and Brudzinski’s signs. Kernig’s sign is elicited by flexing the patient’s hip and extending the knee to approximately 135 degrees in the supine position. The test is positive if the movement leads to pain in the hamstring and back (although in an ill or preverbal child, resistance of extension of the knee is considered positive). Brudzinski’s sign is elicited by flexing the patient’s neck in the supine position, and the test is positive if the patient involuntarily flexes the hips and knees. In contrast, the absence of meningeal signs does not exclude a diagnosis of bacterial meningitis, especially in infants younger than 12 months of age, who often do not exhibit nuchal rigidity with bacterial meningitis.

ACUTE BACTERIAL MENINGITIS

*The authors acknowledge work performed by Dr. M. Täuber and Dr. U. B. Schaad, the authors of this chapter in previous editions.

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BOX 114-1  Signs and Symptoms of Bacterial Meningitis • Fever • Nuchal rigidity • Alteration of consciousness • Irritability, photophobia, headache • Vomiting, anorexia • Kernig’s sign • Brudzinski’s sign • Seizures, focal neurologic deficits

Clinical Presentations of Neonatal Meningitis In neonates and infants, the clinical features of bacterial meningitis can be quite subtle, which necessitates a higher index of suspicion. Meningitis in neonates is classified as early-onset infection (within the first 72 hours of life) and late-onset infection (from 1 week to 3 months of life). Those with early onset may be more likely to be associated with risk factors related to pregnancy and delivery, and more frequently exhibit nonneurologic, nonspecific signs, mostly related to sepsis and respiratory distress. Late-onset neonatal meningitis is more likely to present with neurologic features in addition to the nonspecific signs, including seizures (approximately 50%), focal neurologic signs (e.g., weakness), extensor rigidity, and cranial neuropathies. A bulging or full fontanel is present in one-third to one-half of cases and confers a 3.5 times greater likelihood of bacterial meningitis.

Infection of Implantable Devices Infections of CNS shunts may occur in as many as 5% to 10% of patients, usually within 1 to 2 months of surgical insertion. Most of these infections are a result of coagulase-negative Staphylococcus or Staphylococcus aureus; however, a variety of other organisms, including gram-negative bacteria and other skin flora, can be causative. Clinical manifestations of CNS shunt infection usually include low-grade fever, vomiting, irritability or lethargy, and other signs of increased intracranial pressure. The onset is often insidious but can be more acute, particularly if shunt malfunction also is present. Neck stiffness is uncommon. Shunt infection should be suspected in any child with an indwelling CNS drainage system and fever. Some children with CNS shunt infection may present with abdominal pain or even peritonitis, resulting from infected CSF draining into the abdomen. Cochlear implants (neural stimulators whose electrode is placed surgically in the lumen of the cochlea) for severe to profound sensorineural hearing loss can also predispose children to develop bacterial meningitis, especially that caused by S. pneumoniae (~80%) and H. influenzae (~16%, both type b and nontypeable strains). Infectious complications from cochlear implantation are unusual, but the incidence of S. pneumoniae meningitis in children with cochlear implants is as much as 30-fold that of the greater U.S. pediatric population.

Diagnostic Evaluation The differential diagnosis of bacterial meningitis includes viral meningitis, encephalitis, brain abscess, febrile seizure, head trauma, subarachnoid hemorrhage, and leptomeningeal neoplastic disease. In addition, unusual infectious agents, such as fungi, rickettsia, Toxoplasma gondii, or Mycobacterium tuberculosis, should be considered in selected patients. Many other conditions may cause nuchal rigidity, including

chemical meningitis (from idiopathic reactions to oral trimethoprim-sulfamethoxazole, nonsteroidal antiinflammatory drugs, intravenous immune globulin, and certain injected monoclonal antibody therapeutics), ingestion of heavy metals, infection of internal neck and throat structures, cervical lymphadenitis, and Kawasaki disease. The diagnosis of bacterial meningitis is based on examination of CSF, together with the clinical context of the patient. Minimizing sequelae of bacterial meningitis depends on the prompt initiation of effective antibiotic therapy, which therefore demands consideration of lumbar puncture early in the evaluation and diagnosis of ill children. Lumbar puncture for CSF examination is typically a safe procedure and should therefore be performed whenever there is even low clinical suspicion of meningitis. Four reasons for delaying lumbar puncture exist: (1) clinically important cardiorespiratory compromise; (2) signs of significantly and focally increased intracranial pressure; (3) infection in the skin, soft tissues, or epidural area at the site of lumbar puncture; or (4) suspicion or history of bleeding disorders. In these circumstances, blood cultures should be obtained, and antibiotics are provided empirically. Even 12 to 24 hours after initiation of antimicrobial therapy, the interpretation of CSF white blood cell (WBC) counts and protein and glucose concentrations is helpful in making a diagnosis. The CSF can sterilize as early as 2 to 4 hours after initiation of intravenous antibiotics, and the chance of obtaining a positive CSF culture can decline by one-third to one-half after 24 hours of therapy. Neuroimaging studies are neither necessary nor adequate for the diagnosis of bacterial meningitis, but may be undertaken for patients when there is concern for impending herniation or intracranial mass lesions (e.g., subdural empyema, abscess, stroke). It must be noted that many patients with meningitis have some degree of increased intracranial pressure by virtue of the disease process; the level of concern among providers regarding herniation is typically out of proportion to its likelihood, which is only 1% to 4% or less. Herniation of the brain on removal of a small amount of CSF is rare in meningitis. Thus performing computed tomography (CT) scans routinely before lumbar puncture is not necessary in all patients with suspected meningitis. Nevertheless, lumbar puncture should be performed cautiously if significantly increased intracranial pressure is suspected, especially if the examination is difficult and the patient cannot be adequately evaluated for focal signs. Obtaining CT scans before lumbar puncture in selected patients is reasonable, especially for those children or adults with a history of immunosuppression, hydrocephalus, ventricular shunts, or head trauma, and in those who have focal neurologic signs or who have signs of greatly increased intracranial pressure.

Cerebrospinal Fluid Analysis and Other Laboratory Testing The CSF opening pressure in children varies slightly with body mass index (BMI) and level of sedation, but should generally be less than 25 cm of water (with the 98 percentile in children of 28 cm water) (Avery et al., 2010). The CSF should be sent promptly to the laboratory for Gram stain, bacterial culture, cell count and differential, and protein and glucose concentrations. The Gram stain and bacterial culture are very useful in confirming bacterial meningitis and identifying a causative organism early in the disease course. The Gram stain is positive in approximately 70% to 90% of cases resulting from S. pneumoniae, N. meningitidis, gram-negative bacilli, and H. influenzae type b, but it is positive in only 33% of cases resulting from L. monocytogenes. Generally, bacterial cultures will be positive within 2 days if pathogens are present.



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TABLE 114-1  Characteristic Cerebrospinal Fluid (CSF) Findings in Children With and Without Meningitis CSF Findings

Normal

Bacterial

Viral

Fungal or Tuberculous

LEUKOCYTES/µL Usual Range

500 10–20,000

80 20–100

90% DILS

Anticentromere

44%–98% CREST syndrome

Anti-Scl-70

27% SSc

Antic-ANCA

>90% Granulomatosis with polyangiitis

Antip-ANCA

10% Granulomatosis with polyangiitis, 70% CSS, 75% UC, 20% Crohn’s disease, 30% SLE

Anti-NR2 NMDAR

10% SLE

RF A

20% polyarticular JRA, 50% SS; 10%–30% SLE, MCTD

LAC

Correlates with thromboembolic risk in SLE

aCL

Correlates with thromboembolic risk in SLE, malignancy; variable in many other diseases

aCL, anticardiolipin antibody; ANA, antinuclear antibody; c-ANCA, cytoplasmic staining antineutrophil cytoplasmic antibody; CREST, calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, telangiectasia; CSS, Churg–Strauss syndrome; CTD, connective tissue disease; DILS, drug-induced lupus syndrome; ds-DNA, double-stranded (native) DNA; JDMS, juvenile dermatomyositis; JRA, juvenile rheumatoid arthritis; LAC, lupus anticoagulant; MCTD, mixed connective tissue disease; NMDAR, N-methyl-D-aspartate receptor; p-ANCA, perinuclear staining antineutrophil cytoplasmic antibody; RF A, rheumatoid factor A; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; Sm, Smith; SS, Sjögren’s syndrome; SSc, systemic scleroderma; UC, ulcerative colitis. (Adapted from: Okano, Y., 1996. Antinuclear antibody in systemic sclerosis [scleroderma]. Rheum Dis Clin North Am 22, 709; Moder, K.G., 1996. Use and interpretation of rheumatologic tests: A guide for clinicians. Mayo Clin Proc 71, 391; Bylund, D.J., McCallum, R.M.. Vasculitis. In: Henry JB, editor: Clinical diagnosis and management by laboratory methods. Philadelphia, WB Saunders; 1996.)

nonsteroidal antiinflammatory drugs but often requires steroids, methotrexate, or biologic agents. Etanercept or infliximab is used in resistant cases. High-dose methylprednisolone, intravenous immunoglobulin, and cyclophosphamide are helpful; newer agents that block IL-1 and IL-6 have shown benefit. Some children develop psychological problems; counseling and physical and occupational therapy are beneficial.

PERIODIC FEVER SYNDROMES Neonatal-Onset Multisystem Inflammatory Disease or Chronic Infantile Neurologic Cutaneous and Articular Syndrome Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an unusual autosomal dominant disorder (NLRP3 gene mutation) that mimics systemic JIA. It occurs



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TABLE 121-2  Key Neurologic and Laboratory Findings in the Rheumatic Disorders

121

A.  CHRONIC AND REACTIVE ARTHROPATHIES Disease

Neurologic Findings

Laboratory Findings

Systemic juvenile idiopathic arthritis

Encephalopathy, seizures, macrophage activation syndrome (Reye-like syndrome), neuropathies

Inflammatory bowel disease

Myasthenia gravis, myopathy, neuropathy, seizures, cognitive changes Chorea, personality changes, seizures

Elevated WBC and ESR, anemia, DIC, elevated CSF protein and cell count, marked increase in ferritin and LDH Elevated ESR, microcytic anemia, melena

Acute rheumatic fever Lyme disease

Positive ASO titers, elevated ESR and CRP, abnormal ECG Positive IgG Lyme titer by ELISA, protein by Western blot in serum, positive PCR in CSF

Early infection: aseptic meningitis, headache, chorea, cranial nerve palsies, late neuroborreliosis myelitis, MS-like symptoms, subtle encephalopathy, radiculopathy, mononeuritis multiplex ASO, antistreptolysin O; CRP, C-reactive protein; CSF, cerebrospinal fluid; DIC, disseminated intravascular coagulation; ECG, electrocardiogram; ELISA, enzyme-linked immunosorbent assay; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; LDH, lactate dehydrogenase; MS, multiple sclerosis; PCR, polymerase chain reaction; WBC, white blood cell count. B.  CONNECTIVE TISSUE DISEASES Disease

Neurologic Findings

Laboratory Findings

SLE

Encephalopathy, chorea, seizures, aseptic meningitis, Elevated ANA, low C3 and C4, pancytopenia, psychosis, behavioral or cognitive dysfunction, hematuria, proteinuria, autoantibodies, LAC, headaches, strokes, neuropathy, myelitis elevated aCL Scleroderma: coup-de-sabre Seizures, blurred vision, bulbar palsy, optic neuritis, Elevated ANA and rheumatoid factor deformity trigeminal neuropathy Mixed connective tissue disease Same as SLE Same as SLE plus elevated anti-RNP, elevated CK Sjögren’s syndrome Encephalopathy, optic neuritis, aseptic meningitis, Positive ANA, rheumatoid factor, antibodies to recurrent paresis, myelopathy, neuropathy, SSA/Ro and SSB/La autonomic dysfunction aCL, anticardiolipin antibody; ANA, antinuclear antibody; C3, third component of complement; C4, fourth component of complement; CK, creatine kinase; LAC, lupus anticoagulant; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus. C.  CHILDHOOD VASCULITIDES Disease

Neurologic Findings

Laboratory Findings

Polyarteritis nodosa

Headache, encephalopathy, stroke, seizures, Elevated WBC, ESR, positive HBsAg and c-ANCA neuropathies Kawasaki disease Aseptic meningitis, focal neurologic findings Coronary aneurysms, thrombocytosis Cogan syndrome Neurosensory hearing loss None Henoch-Schönlein purpura Encephalopathy Elevated IgA in 50%, hematuria, melena Churg-Strauss syndrome Headache, encephalopathy, stroke, seizures, various Eosinophilia, eosinophils on skin biopsy, p-ANCA peripheral neuropathies, coma, intracranial hemorrhage Granulomatosis with polyangiitis Encephalopathy, intracranial hemorrhage, meningitis c-ANCA Primary angiitis of the CNS Headache, encephalopathy, seizures, stroke, Elevated ESR myelopathy Sarcoidosis Obstructive hydrocephalus, seventh nerve palsy, Noncaseating granuloma meningitis, seizures, peripheral neuropathies Temporal arteritis Blindness, encephalopathy, headache Elevated ESR Takayasu arteritis Headache, stroke, syncope, visual loss Elevated ESR and factor VIII-related antigen Behçet disease Headache, meningitis, psychiatric disorders, Elevated ESR encephalopathy, pseudotumor cerebri, brainstem signs c-ANCA, cytoplasmic staining antineutrophil cytoplasmic antibody; CNS, central nervous system; ESR, erythrocyte sedimentation rate; HBsAg, hepatitis B surface antigen; IgA, immunoglobulin A; p-ANCA, perinuclear staining antineutrophil cytoplasmic antibody; WBC, white blood cell count.

during the first year of life. Manifestations include hectic fever, intermittent rash, lymphadenopathy, hepatosplenomegaly, uveitis, cognitive and developmental delay, chronic meningitis, hydrocephalus, seizures, hemiplegia, papilledema, optic neuritis, uveitis, and deforming arthropathy with periosteal changes and bony overgrowth. Seventy-five percent of patients develop progressive sensorineural deafness. Longterm prognosis is poor.

Familial Mediterranean Fever Familial Mediterranean fever is an autosomal-recessive disorder due to mutations in the MEFV gene. Symptoms include fever, abdominal pain, peritonitis, pleuritis, and

arthritis. Myalgias after exertion are common. Headache, febrile seizures, aseptic meningitis, and posterior reversible leukoencephalopathy occur, as has progressive sensorineural deafness.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome has an unclear etiology. It is characterized by febrile episodes persisting for 4 to 6 days, separated by afebrile periods lasting 4 weeks to 4 months. Headaches occur during febrile episodes. Recurrent aseptic meningitis accompanied by seizures has been described.

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PART XV  Immune Mediated Disorders of the Nervous System

Hyper-IgG (Autoimmune Lymphoproliferative) Syndrome This genetic syndrome presents with splenomegaly, skin rashes, enlarged lymph nodes, and autoimmune hemolytic anemia. Neurologic symptoms are associated with other autoimmune phenomena, including Guillain-Barré syndrome.

ARTHRITIS ASSOCIATED WITH   INFECTIOUS AGENTS Acute Rheumatic Fever Acute rheumatic fever (ARF) is an inflammatory illness that follows a group A beta-hemolytic streptococcal pharyngitis. Manifestations include migratory polyarthritis, fever, carditis, and, less frequently, Sydenham chorea, subcutaneous nodules, and erythema marginatum. The modified 1992 Jones criteria are used to confirm the diagnosis (two major and one minor criteria; or one major and two minor criteria), as well as antibody evidence of preceding streptococcal infection (Box 121-2). In the case of isolated Sydenham chorea, demonstration of streptococcal infection may not be possible and is not a requirement for diagnosis (Dajani, et al., 1992).

Neurologic Manifestations Sydenham Chorea Clinical Manifestations.  Sydenham chorea is characterized by involuntary, distal, purposeless, rapid movements; hypotonia; and emotional lability. It may be associated with other ARF manifestations or as the sole manifestation. Isolated chorea represents 20% to 30% of acute rheumatic fever cases and occurs long after the pharyngitis has resolved. Laboratory evidence of preceding streptococcal infection may not be demonstrable in up to 35% of children. Onset may be explosive or insidious. Chorea may be misdiagnosed as an emotional disorder, tics, decreased attention span, or a degenerative process. Choreiform movements involve the face, hands, and feet. Facial movements include grimacing, frowning, grinning, and pouting. Children commonly are unable to sustain prolonged hand contraction (“milkmaid” sign). Emotional lability, personality changes, restlessness, and irritability may herald the onset of chorea. Occasionally, “spooning” with hyperextension of the hands is observed. In adolescents, chorea occurs almost exclusively in females and may be associated with hemichorea or hemiparesis. Choreiform movements subside in 2 to 4 months but can persist. Chorea and arthritis usually do not accompany each other; however, carditis frequently develops as the chorea is improving. Laboratory Findings.  Laboratory studies include docu­ mentation of antecedent streptococcal infection with an antistreptolysin-O titer, demonstration of a prolonged PR interval on electrocardiogram, elevated C-reactive protein or erythrocyte sedimentation rate, and leukocytosis. Although throat culture may show group A beta-hemolytic streptococci, an elevated or increasing antistreptolysin-O titer is required. An elevated anti-DNase-B increases the sensitivity of an antistreptolysin-O titer alone. To exclude other choreiform conditions, patients may need additional studies (serum ceruloplasmin, thyroxine, calcium, and antinuclear antibody titers). EEGs may demonstrate diffuse paroxysmal features and generalized slowing. Cerebrospinal fluid (CSF) examination and neuroimaging are rarely necessary. Of interest is the finding of antineuronal antibodies in the CSF of patients with chorea. The specificity of these antibodies is unknown, and they are frequently documented in patients with CNS lupus.

BOX 121-2  Jones Criteria for Diagnosis of Acute Rheumatic Fever (Revised 1992) MAJOR* Carditis Murmur consistent with aortic regurgitation or mitral insufficiency; echocardiogram findings without significant auscultatory findings are not adequate Chorea May be the only manifestation; proof of prior streptococcal infection in only 80% Erythema Marginatum Rare manifestation; never on the face; transient and migratory Migratory Polyarthritis Almost always migratory, involving larger joints, responds within 48 hours to aspirin and usually resolves in 1 month Subcutaneous Nodules Rare manifestation; nontender, on extensor surfaces, usually over elbows, wrists, knees, occipital region, or spinous processes MINOR Fever Usually greater than 39° C Arthralgia Consider if arthritis not present Prolonged PR Interval Does not correlate with the development of carditis Elevated Erythrocyte Sedimentation Rate or C-Reactive Protein Acute phase reactants *Prior episodes of acute rheumatic fever are not criteria; if a patient has had a prior attack of acute rheumatic fever, a new attack may be difficult to diagnose on the basis of changing carditis. In this setting, proof of recent streptococcal infection and either one major or one minor criterion may allow a presumptive diagnosis. Proof of recent streptococcal infection is necessary, except for isolated chorea. (Adapted from: Dajani, et al. and The Special Writing Group, 1992. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. JAMA 268, 2069.)

MRI abnormalities include cystic changes, restricted diffusion in the caudate and putamen, and multiple subcortical and peripheral white matter signal intensity abnormalities.

Neuropathology Findings in ARF are rare and include small cortical and meningeal endarteritis with spotty patches of gray-matter degeneration.

Treatment All patients, including those only with chorea, should receive a 10-day course of penicillin or erythromycin. Prophylaxis with penicillin or sulfadiazine should be started immediately and continued until adulthood because of the risk of reinfection and of rheumatic heart disease. When residual valvular disease exists, prophylaxis should continue for at least 10 years after the last episode and at least until age 40. If there is no residual valvular disease, the duration of treatment beyond 10 years or into adulthood is uncertain. When Sydenham chorea is diagnosed and there is no valvular disease, the duration of



prophylaxis should be at least 5 years or until age 21, whichever is longer. Children who develop chorea as the sole manifestation of ARF have a 50% risk of developing rheumatic heart disease. Sydenham chorea has been treated with chlorpromazine, haloperidol, phenobarbital, diazepam, valproic acid, cyproheptadine, and prednisone. Clonidine, pimozide, and pulsed intravenous methylprednisolone followed by an oral taper, intravenous immunoglobulin, or plasma exchange may be beneficial in refractory cases. Recovery can be expected within 2 to 6 months, although some children have residual manifestations.

Postinfectious Tourette Syndrome and PANDAS Chorea, obsessive-compulsive disorder, tic disorder, and Tourette syndrome may all have a common autoimmune pathway. Some children with chorea have obsessive-compulsive disorder that resolves before or simultaneously with the resolution of the chorea. An increased prevalence of obsessivecompulsive disorder occurs in children with tics and Tourette syndrome; an increased prevalence of antineuronal antibodies, as well as increased levels of antistreptococcal antibodies, occurs in all four of these conditions. The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been suggested when there is a combination of behavioral problems, obsessivecompulsive behavior, and tics when associated with a group A beta-hemolytic streptococcal infection.

Other Central Nervous System Manifestations About 3% to 5% of patients with ARF develop other neurologic problems including meningoencephalitis, encephalitis, seizures, pseudotumor cerebri, papilledema, diplopia, central retinal occlusion, transient intellectual loss, and acute psychosis.

Lyme Disease Lyme disease is an important cause of neurologic symptoms in children (Bingham, et al., 1995). The illness follows a tick bite and occurs in endemic areas during the summer. The early stage begins with a flu-like illness and the appearance of an oval, expanding rash. Systemic infection with Borrelia burgdorferi may be documented by culture. Within several weeks, the patient develops neurologic manifestations, with facial nerve palsy, aseptic meningitis, other cranial neuropathies transverse myelitis, and sometimes direct invasion of the organism into CSF. Acute sinovenous thrombosis with consequent pseudotumor cerebri can occur. The illness resolves spontaneously but may be hastened by antibiotic treatment (amoxicillin or erythromycin in children younger than 9 years old; tetracycline in children age 9 years or older, either for 10 to 30 days). Weeks to months later, untreated patients may develop episodic arthritis of the large joints. The knee becomes acutely effused but not particularly tender or hot. Joint swelling lasts for several days and resolves but returns repeatedly if treatment with antibiotics is not started. Diagnosis may be confirmed after the first few weeks with a positive serum IgG titer against B. burgdorferi. Western blotting from blood or polymerase chain reaction (PCR) amplification of the B. burgdorferi genome in the CSF is available. Some patients develop neuroborreliosis years later. This rare complication manifests as a subtle encephalopathy with stuttering and memory disturbances. The diagnosis is confirmed by demonstration of an elevated intrathecal IgG titer compared with serum titers. Treatment with intravenous

Neurologic Manifestations of Rheumatic Disorders of Childhood

949

ceftriaxone for 1 month is indicated, but the response is variable.

Reactive Arthritis (formerly called   Reiter Syndrome) Reactive arthritis is characterized by arthritis, uveitis, and urethritis. Progressive myelopathy, cerebral vasculitis, axonal polyneuropathy, and seizures have been reported as rare neurologic complications in adults.

CONNECTIVE TISSUE DISORDERS The key neurologic and laboratory findings in connective tissue disorders are summarized in Table 121-2(B).

Systemic Lupus Erythematosus Revised criteria for diagnosing SLE (2012) (Box 121-3) call for having at least 4 of 17 criteria (at least 1 clinical and 1

BOX 121-3  Revised Criteria for the Classification of Systemic Lupus Erythematosus (2012) Diagnosis requires at least 4 criteria (at least 1 clinical and 1 immunologic) OR biopsy-proven lupus nephritis with positive antinuclear or anti-DNA antibodies. CLINICAL CRITERIA Acute cutaneous lupus: lupus malar rash (not discoid), bullous lupus, toxic epidermal necrolysis variant of lupus, maculopapular lupus rash, photosensitive lupus rash (in the absence of dermatomyositis), nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring Chronic cutaneous lupus: classic discoid rash, hypertrophic (verrucous) lupus, lupus panniculitis (profundus), mucosal lupus, lupus erythematosus tumidus, chillblains lupus, discoid lupus/lichen planus overlap Oral or nasal ulcers: in the absence of a cause other than lupus Nonscarring alopecia: diffuse thinning or fragility of hair with visible broken hairs in the absence of a cause other than lupus Arthritis: synovitis involving 2 or more joints Serositis: pleural or pericardial inflammation, effusions, or rub in the absence of a cause other than lupus Renal: urine protein–to-creatinine ratio (or 24 h urine protein) representing 500 mg protein/24 h or red blood cell casts Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, or acute confusional state in the absence of a cause other than lupus Hemolytic anemia Leukopenia: leukopenia childhood

Infant, childhood

Gender

F>M

F=M

M>F

M>F

Molecular findings

Intranuclear β-catenin Staining; Monosomy 6; CTNNB1 mutation

SHH pathway mutations; PTCH1/SMO SUFU/GLI1; Occasional TP53 Mutation

MYC amplification; i179; GFI1; GFI1B

CDKG amplification SNCAIP

Genetic Expression

WNT signaling; MYC +

SHH signaling MYCN +

MYC +++

MYC↓

Histology

Classical, LCA

Desmoplastic; Desmoplastic/ nodular

Classical; LCA

Classical/LCA

Mets

Occasional

Occasional

Very frequent

Frequent

Prognosis

Excellent

Good in infants, Adults; poor if MYCN + or TP53 mutation (primarily childhood)

Poor if M + or MYC +; Average otherwise

Average

Recent integrative genomic and epigenomic analyses have identified GFI1 and GFI1B as additional highly recurrent driver genes for Group 3 medulloblastoma. For Group 4 medulloblastoma, in addition to known overrepresentation of CDK6 and MYCN amplifications, inactivating mutations in the histone3 lysine 27-specific histone demethylase KDM6A (located on the X chromosome) and ZMYM3 have been repeatedly identified. Duplication of a region on chromosome 5 around the SNCAIP gene represents another frequent genetic event.

CLINICAL PRESENTATION AND DIAGNOSIS Clinical Features Medulloblastoma most commonly presents with nonspecific findings of vomiting and headache, which occur in 80% of patients by the time of diagnosis. This is usually associated with obstruction of cerebrospinal fluid flow at either the third or fourth ventricular outlets, and hydrocephalus. Symptom duration is classically 1 to 3 months before diagnosis; patients with metastatic disease are more likely to be diagnosed earlier and have a poorer prognosis. Usually, by diagnosis, the headache has transformed into one more classically associated with increased intracranial pressure, occurring upon wakening and accompanied by morning nausea and vomiting. Unsteadiness is noted in 50% to 80% of patients at diagnosis and is usually truncal, with significant gait abnormalities. Medulloblastoma may present acutely with a severe alteration in consciousness and even coma. This is usually a result of macroscopic hemorrhage into the tumor and rapid tumor expansion with acute hydrocephalus and/or compression of the brainstem. Although diagnosis can be difficult in infants, symptoms such as unexplained macrocephaly, intermittent lethargy, vomiting, and head tilt are noted in most infants by the time of diagnosis. The classical “setting sun” sign, with downward deviation of the eyes as a result of tectal pressure, is seen in only a minority of infants. Medulloblastomas may be disseminated to other regions of the CNS at diagnosis. In the majority, there are no symptoms associated with dissemination.

Radiographic Features Medulloblastomas are usually radiographically distinguishable from other posterior fossa tumors because they tend to be relatively well-defined masses arising in the medullary

velum or roof of the fourth ventricle, often with some invasion of the middle cerebellar peduncle and compression or invasion of the brainstem. The tumor is hyperdense compared with normal cerebellum on computed tomography (CT), which distinguishes it from juvenile pilocytic astrocytoma. Calcifications may be present in up to 20% of cases, but are usually not conspicuous. On magnetic resonance imaging (MRI), medulloblastomas tend to be homogenous with iso- to hypointense signal on T1-weighted images and hypointense signal on T2-weighted images (Fig. 123-2). The majority of medulloblastomas enhance with contrast agent, although 5% to 10% do not enhance. In infancy, medulloblastoma with extensive nodularity may occur and display discrete contrasting-enhancing masses with an almost grapelike, clustered appearance. Because between 15% and 30% of medulloblastomas are disseminated to other regions of the nervous system before diagnosis, neuroradiographic evaluation of the entire neuraxis is indicated, if possible, before surgery. Evaluation of dissemination can be difficult after surgery because of changes caused by postoperative blood. Pitfalls in the evaluation of extent of disease include nonenhancing dissemination, especially in patients with initially nonenhancing primary-site tumors, and spinal cord vascularity being interpreted as leptomeningeal disease.

MANAGEMENT AND OUTCOME The treatment of children with medulloblastoma is multidisciplinary and multimodality, requiring surgery, radiation, and chemotherapy. Treatment is also dependent on the age of the child, predominantly because of the potential neurotoxic effects of radiotherapy, and disease stratification.

Surgery Surgery is the initial step in management, to relieve hydrocephalus if present and to remove as much of the tumor as possible. Although temporary external ventricular drainage might be necessary, removal of the tumor results in avoidance of permanent ventricular-peritoneal shunting in 50% of cases. In some children with persistent hydrocephalus, third ventriculostomy is another option to avoid ventricular-peritoneal shunting. In nondisseminated patients, who comprise 70% to 80% of all patients with medulloblastoma, multiple studies have demonstrated that the extent of surgical resection is prognostic of outcome, with those patients undergoing more



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965

123

A

B

C

Figure 123-2.  Panel of MRIs of medulloblastoma. A, Axial FLAIR image demonstrating somewhat hyperintense mass filling the fourth ventricle. B, Sagittal T-weighted image, after gadolinium enhancement, demonstrating inhomogeneous enhancement. C, Axial ADC image demonstrating diffuse restriction (dark area) within tumor.

complete or near-total resections having better outcome than patients whose tumors were subtotally resected. Arbitrarily, patients with greater than 1.5 cm2 of residual disease after surgery are considered to have subtotally resected tumors. In older series, children with nondisseminated disease and greater than 1.5 cm2 of residual disease fared less well than those with less measurable disease. With current means of adjuvant therapy, there is no clear-cut statistical difference in outcome between patients who undergo a total resection and those undergoing a near-total resection. Patients who undergo a minimal resection or biopsy have an extremely poor prognosis. In those with disseminated disease, the degree of surgical resection has never been shown to have independent significance. Although the goal of surgery is to remove all of the tumor, tumor resections (be they partial or complete) can be associated with significant immediate or delayed postoperative complications (Wells et al., 2010). Direct brainstem and cerebellar damage has been noted in 5% to 10% of patients. Increasingly, posterior fossa mutism syndrome has been recognized. This syndrome can be clinically difficult to separate from postoperative direct damage to the brainstem and is a delayed constellation of mutism, which characteristically is first recognized between 6 and 48 hours after surgery. Mutism is usually associated with hypotonia, cerebellar deficits, supranuclear palsies, emotional labiality, and severe irritability. The irritability and personality change may be so predominant that they overshadow the other clinical findings. Likely a form of cerebellar affective disorder, posterior fossa mutism syndrome is believed to be secondary to unilateral (primarily right-sided) or bilateral cerebellar dentate nuclei damage and/or disruption of critical pathways between the cerebellum and cortex. Subsequent MRIs, especially those performed 1 year or later after diagnosis, will frequently disclose cerebellar atrophy. Nearly 25% of patients in one recent North American trial had the syndrome, initially thought to be a rare entity, and one half of all patients with this syndrome had sequelae 1 year later. Over 50% of patients with posterior fossa mutism have impaired neurocognitive outcomes.

Staging and Stratification Following surgery, patients with medulloblastoma have been traditionally staged by the amount of residual tumor after surgery, extent of dissemination assessed on both

neuroimaging evaluation of the entire neuraxis and cerebrospinal fluid cytologic examination, and, in some classification schemes, histology. Historically, children with medulloblastomas who are 3 years of age or older at diagnosis have been classified as having either average-risk or poor-risk disease (see Table 123-2). Patients with average-risk disease are those with nondisseminated, totally or near-totally resected tumors, with a nonanaplastic histology. All other patients are considered to have poor-risk disease. This stratification system has not incorporated biologic data. In younger children, separation into major risk groups on the basis of similar criteria is also accepted. Young children, usually less than 3 years of age, with extensively nodular/ desmoplastic medulloblastoma, presumably whose tumors are driven by signaling of the SHH pathway, have a better prognosis. Molecular studies that have identified the four stable molecular subgroups are being incorporated into stratification schema. It is now feasible to perform molecular subgrouping from very small amounts of formalin-fixed and paraffinembedded tissue. These subgroups have distinct demographics and associated clinical variables, including disease course, and demonstrate enrichment for histopathological subtypes (e.g., desmoplastic and extensive-nodular medulloblastomas almost exclusively fall in the SHH subgroup, and Group 3 is strongly enriched for large-cell and anaplastic histiotypes). As demonstrated in several independent studies, WNTdriven medulloblastoma (probably even when associated with microscopic metastases, i.e., M1) has a favorable clinical course. Recent evidence suggests that nuclear beta-catenin accumulation as assessed by immunohistochemistry alone is not specific enough to define this population. Thus the currently accepted recommendation is that any of two independent methods have to indicate the presence of a WNTsubgroup medulloblastoma to qualify for reduction of therapy intensity. These methods include CTNNB1 immunohistochemistry, sequencing of CTNNB1 exon 3, gene-expression profiling, and DNA methylation profiling. SHH-driven medulloblastomas show a remarkable age distribution, with one peak in infants and a second peak in adults. Infant SHH disease is largely overlapping with infant desmoplastic or extensive nodular histology and associated with favorable prognosis. Most children with this subgroup can be cured by adjuvant chemotherapy alone. Because hereditary TP53 germline mutations (i.e., Li Fraumeni syndrome) are

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PART XVI  Pediatric Neurooncology

almost entirely restricted to SHH medulloblastoma, mainly in older children, p53 immunohistochemistry is required in all SHH subgroup patients as a screening measure. In case of evidence for the presence of a TP53 mutation, TP53 should be sequenced in the tumor. SHH-driven medulloblastomas in adults (which in this age group comprise about two thirds of cases, with tumors often located in the cerebellar hemispheres rather than in the vermis) demonstrate good outcomes. In infants, downstream SUFU mutations are quite prevalent in addition to PATCHED 1, whereas in older children with TP53 mutations, downstream amplifications of MYCN and GLI2 are prototypic (Kool et al., 2014). Within Group 3, an additional marker to identify veryhigh-risk patients is high-level focal MYC amplification. As for CTNNB1, the detection method and definition of MYC amplification is crucial to identify this very-high-risk population. Medulloblastoma risk categorization (see Table 123-2 and Fig. 123-4) is still a work in progress and has not been uniformly incorporated into national/international multicenter studies. However, the combination of molecular and clinical parameters (age and extent of dissemination at diagnosis) results in the clearest separations and opens the best possibility for more personalized therapies. The significance of extent of resection is unclear within this framework, although patients undergoing biopsy alone or a minimal resection likely have a poorer prognosis.

Postsurgical Management Standard treatment for children with average-risk disease, over 3 years of age, includes radiation and chemotherapy. Survival rates improved dramatically when craniospinal irradiation therapy became a standard component of medulloblastoma treatment, independent of whether there was evidence on staging studies of dissemination. Initial doses of craniospinal radiation were chosen arbitrarily; conventionally, following surgery, average-risk patients were treated with 3600 cGy of craniospinal radiation and 1800 to 1960 cGy of boost radiotherapy to the primary tumor site, which, in most patients, included the entire posterior fossa (local tumor dose 54005580 cGy). With such treatment, 5-year progression-free survival rates were between 55% and 65%, with some, but not all, 5-year survivors being cured of their disease. Attempts to reduce the craniospinal dose of radiation therapy to 2340 cGy were considered unsuccessful because there was an increased early incidence of leptomeningeal disease failure; however, long-term follow up of the cohort of patients treated in a randomized study comparing 3600 cGy to 2340 cGy did not show a statistical difference in 8-year survival in patients treated with lower-dose radiotherapy compared with those who received higher-dose treatment. Chemotherapy has improved survival for children with average-risk medulloblastomas (Packer et al., 2006; Gajjar

Radiographically Presumed Medulloblastoma

MR brain/spine

Surgery *

Post-op MRI; LP (if safe)

Histologic/Molecular characterization

WNT Tumor Mo

SHH

Group 3

Group 4

M+

Reduced Dose, CSRT; Reduced intensity chemotherapy

Standard treatment

Mo

PTCH SMO; SUFU mutation; Wild type TP53;Mo

Standard therapy

GLI mutation; TP53 mutation; or M+

MYC Anaplastic; i17q

Intensified Therapy; ?Molecular targeted therapy

Intensified Therapy; ?Molecular targeted therapy

None

Standard therapy

Standard therapy

* Patients who are biopsied alone or undergo subtotal resections likely should be considered high risk and are candidates for re-resections or more intensified therapies.

Figure 123-4.  Algorithm for medulloblastoma, children 3 years of age or older.

M+

Intensified therapy



et al., 2006). Treatment with craniospinal radiation therapy and chemotherapy, given during and after radiation therapy and utilizing various multiagent drug regimens, which included vincristine (given during radiation therapy) and CCNU, cisplatin, cyclophosphamide, and vincristine post radiotherapy, has demonstrated progression-free survival rates at 5 years in the 80% to 85% range in children greater than 3 years of age without disseminated disease, with few patients relapsing after 5 years. The sequencing of radiation and chemotherapy seems critical; studies that have delayed radiation by the use of preradiation chemotherapy have demonstrated poorer survival rates. The addition of chemotherapy has allowed a reduction of the dose of craniospinal radiation therapy to 2340 cGy without any apparent deterioration in overall disease control in children with average-risk disease. This reduction was undertaken to reduce radiation-associated sequelae, and ongoing prospective randomized studies are reducing the dose of craniospinal radiation therapy even further, to 1800 cGy. An important caveat with these studies is that the staging of patients is of extreme importance. Upon central review in two international studies, approximately 20% of patients were judged to have been inappropriately entered into these studies as a result of either misinterpretation of tumor extent or inadequate imaging. Patients who were placed on these reduced-dose craniospinal radiation studies with inadequate imaging or errors in interpretation had a significantly poorer outcome. It has become clear that the molecular subtype of the tumor dramatically affects the likelihood of successful therapy (Gajjar et al., 2014). WNT-driven tumors have nearly a 100% survival rate after treatment with radiotherapy and chemotherapy. In this subset of patients, studies are already under way to further reduce the amount of craniospinal radiotherapy and/ or chemotherapy utilized. For SHH-driven tumors, although infants and adults tend to fare well, children often harbor tumors with TP53 abnormalities and/or downstream SHH pathway mutations; such patients carry a poorer prognosis, which is less than 30% surviving with current therapies, and should not be considered “average risk.” Within the Group 3 tumors, a subgroup with MYC-amplified or possibly overexpressed tumors will do poorly, even if identified by other criteria as “average risk,” and will require alternative approaches. For children with poor-risk medulloblastoma, survival after craniospinal and local boost radiotherapy alone is only in the 30% to 40% range at 5 years. Within the poor-risk group, there are mis-stratified children who carry a favorable diagnosis, such as those with WNT-subclass tumors with metastatic disease. Studies that have added chemotherapy, once again primarily either during and/or after radiation therapy, have demonstrated survival rates ranging between 50% and 70%. A variety of different chemotherapeutic approaches have been utilized and are still being studied, including the use of radiosensitizing agents, such as carboplatin, during radiation therapy, and a variety of drugs after radiation therapy, in various combinations, including cisplatin, CCNU, cyclophosphamide, vincristine, and etoposide. For infants and young children with medulloblastoma, treatment remains quite problematic. Because of concerns regarding the detrimental long-term effects of craniospinal radiation therapy, chemotherapeutic approaches have been used to delay, if not completely obviate, the need for radiotherapy. Approximately 20% of infants can be treated with chemotherapy alone, with a variety of different regimens. These approaches have now evolved into the use of postoperative chemotherapy and, for those patients who remain in remission or respond to the initial chemotherapy, consolidation with even higher doses of chemotherapy supported by autologous bone marrow transplantation or peripheral stem

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cell rescue. Another approach to augment the efficacy of chemotherapy is to add methotrexate, in some studies intravenously at high dose and in other trials both intravenously and intrathecally/intraventricularly, to improve survival and avoid the need for radiation. It is likely the variable survival rates are a result of previously unappreciated differences in biologic subtypes. The infants most likely to survive are those with the nodular/desmoplastic form of the disease (Rutkowski et al., 2005). Survival for children with nonnodular/desmoplastic (SHH-driven) disease is not as favorable, but some (perhaps 30%) of these children do survive after treatment with chemotherapy alone. Treatment for infants and young children with disseminated disease remains suboptimal. Chemotherapeutic approaches alone have cured only a small group of these patients.

Relapsed Medulloblastoma Another extremely problematic group of patients to treat for medulloblastoma are those with relapsed disease. Although late relapses, 5 or more years after diagnosis, are reported, it is likely that many of such relapses are secondary, treatmentinduced tumors. The majority are high-grade gliomas and resistant to therapy. Histologic confirmation of the type of tumor present at relapse is required in late relapse or in patients with unusual patterns of recurrence, such as intrinsic brainstem disease or cortical infiltrative disease. Because of the nearly universal use of chemotherapy as a part of initial treatment, extraneural relapse is rare. Given that the majority of older patients are now treated with both radiation therapy and multiagent chemotherapy at time of initial diagnosis, most children over 3 years of age with relapsed disease are highly resistant to further therapy. Furthermore, approximately two thirds of patients with medulloblastoma, be they high-risk, low-risk, or falling in the infant and young child category, will relapse with at least some component of disease outside the primary tumor site. Patients with SHH-driven tumors are more likely to have only primary-site relapse and may respond better to retrieval therapies such as reirradiation at the primary tumor site. For patients with disseminated disease at relapse, there are no proven effective retrieval regimens. For children who have relapsed only at the primary tumor site, possibly because they are biologically different, retrieval strategies have been somewhat more successful and have included attempts at reresection followed by chemotherapy, followed by local radiotherapy. This approach has been most successful in young children who have not received prior radiation therapy.

Future Therapy Newer approaches are clearly needed for both older children and infants with disseminated tumors, and possibly, in the future, for those with unfavorable prognostic molecular indicators. Biologic agents are slowly being incorporated into therapeutic trials using drugs such as retinoic acid as maturation agents and specific inhibitors of aberrant cellular signaling pathways, such as SHH pathway inhibitors. Adult SHH patients probably comprise the best cohort for adjuvant or even neo-adjuvant administration of targeted Smoothened inhibitors, because in this age group, SHH mutations upstream of Smoothened (mainly in Patched or Smoothened itself) are most prevalent.

Sequelae in Medulloblastoma Survivors As more children survive medulloblastoma, it has become clearer that their quality of life is far from optimal. Although

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the dose of craniospinal radiation therapy has been reduced by almost one-third for patients with nondisseminated disease, it is yet unclear how beneficial such reductions are. At the same time, although the radiotherapy dose has been decreased, there has been an increased use of chemotherapy, which carries its own inherent short- and long-term side effects. In addition, the presence of posterior fossa mutism syndrome negatively affects outcome. Neurocognitive sequelae are frequently seen in children of all ages treated for medulloblastoma. It has been well documented that the majority of infant survivors are neurocognitively impaired at the time of diagnosis, probably as a result of multiple factors, including the tumor, associated hydrocephalus, and possibly the sequelae of surgery. Although radiation therapy has been avoided in some infants who survived medulloblastoma, follow-up testing demonstrates that the majority remain developmentally and, ultimately, neurocognitively impaired. The addition of potentially neurotoxic drugs, such as methotrexate, to the treatment of these children or the early use of focal radiotherapy may further cause neurocognitive issues. In children with medulloblastoma who are between 3 and 7 years of age at the time of treatment, significant declines in overall intelligence have been demonstrated after 3600 cGy of craniospinal radiation (Ris et al., 2001). This drop in intelligence can be seen as early as 1 year posttreatment, is progressive, and may not plateau over time. Decline in intelligence in those children treated at full-dose radiation therapy (3600 cGy) has ranged between 20 and 30 IQ points within 3 years of treatment. Preliminary results suggest a lesser decrease in overall intelligence in younger children who are treated with reduced doses (2340 cGy) of craniospinal radiation, but still a 10- to 20-point overall drop in global intelligence is likely. Older children have not demonstrated as severe a drop in global intelligence; however, these patients often have selective learning and attentional difficulties. Global intelligence is a crude estimate of intellectual function, and patients of all ages have been noted, in follow up, to have selective sequelae, including memory difficulties, processing dysfunction, executive functioning abnormalities, visual-spatial difficulties, and attentional disorders. The attentional problems are often overlooked because of the lack of associated hyperactivity. Many of these children are hypoactive, and studies are under way to determine whether the use of stimulants or other agents will decrease fatigue and lethargy and improve attention. Endocrinologic sequelae are the second most common long-term consequence of medulloblastoma treatment. Growth hormone production is most commonly affected, but over time there can also be deficits in thyroid function, follicle-stimulating hormone–luteinizing hormone (FSH-LH) production, and adrenocortical function. Although there is hesitancy to utilize growth hormone replacement in children with cancer, studies in children with medulloblastoma have not shown an increased incidence of tumor relapse associated with its use. Growth hormone insufficiency is exacerbated by the direct effects of radiation on vertebral growth, and many long-term survivors have disproportionate growth, with a decrease in truncal growth compared with extremity growth. The effects on growth are also exacerbated by associated obesity, which is more common in long-term survivors (Packer et al., 2003). Increasingly, secondary tumors have been reported in children who have survived brain tumors, including medulloblas-

tomas. In a recent prospective Children’s Oncology Group study of 379 children, 14 secondary malignancies occurred within 8 years of follow up, including multiple malignant gliomas. Because this patient population was less than 10 years from diagnosis at the time of the study, it is likely there will be an even greater rate of secondary tumor occurrence, especially the development of meningiomas, over time. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Gajjar, A., Chintagumpala, M., Ashley, D., et al., 2006. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 7 (10), 813. Gajjar, A., Pfister, S.M., Taylor, M.D., et al., 2014. Molecular insights into pediatric brain tumors have the potential to transform therapy. Clin. Cancer Res. 20 (22), 5630. Kool, M., Jones, D.T., Jager, N., et al., 2014. Genome sequencing of SHH medulloblastoma predicts genotype related response to smoothened inhibition. Cancer Cell 393. Packer, R.J., Gajjar, A., Vezina, G., et al., 2006. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 24 (25), 4202. Packer, R.J., Gurney, J.G., Punyko, J.A., et al., 2003. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study. J. Clin. Oncol. 21 (17), 3255. Ris, M.D., Packer, R., Goldwein, J., et al., 2001. Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J. Clin. Oncol. 19 (15), 3470. Rutkowski, S., Bode, U., Deinlein, F., et al., 2005. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N. Engl. J. Med. 352 (10), 978. Taylor, M., Kool, M., Korshunov, A., et al., 2012. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 123 (4), 465–472. Wang, J., Wechsler-Reya, R.J., 2014. The role of stem cells and progenitors in the genesis of medulloblastoma. Exp. Neuro. 260, 69–73. Wells, E.M., Khademian, Z.P., Walsh, K.S., et al., 2010. Post-operative cerebellar mutism syndrome following treatment of medulloblastoma: Neuroradiographic features and etiology. J of Neurosurgery, Pediatric 5, 329.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Box 123-1 WHO classification of medulloblastoma. Table 123-1 Stratification of Children over 3 Years of Age with Medulloblastoma Fig. 123-1 Photomicrographs of medulloblastoma. Fig. 123-3 MRI of medulloblastoma with dissemination. Fig. 123-5 Improving survival rates for children with “average-risk” medulloblastoma treated in international, prospective randomized treatment trials by the Children’s Cancer Group (CCG, now merged with POG to form the Children’s Oncology Group) over past 24 years.

Embryonal and Pineal Malignancies of the Central 124  Other Nervous System Emily Gertsch, Yoon-Jae Cho, and Scott L. Pomeroy An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Embryonal tumors of the central nervous system (CNS) are recognized as the most common types of malignant pediatric brain tumors. As a group, they are poorly differentiated, highly cellular tumors with aggressive growth behaviors (Li et al., 2009). They include medulloblastomas and atypical teratoid rhabdoid tumors (ATRTs), which are discussed in detail in their own chapters, and an evolving group of tumors formerly classified as primitive neuroectodermal tumors (PNETs). The PNET classification is being phased out; more recently these tumors have been reclassified as CNS embryonal tumors. These other CNS embryonal tumors include embryonal tumors with multilayered rosettes (ETMRs), medulloepithelioma, CNS neuroblastoma, CNS ganglioneuroblastoma, and CNS embryonal tumor Not Otherwise Specified (NOS). These types of CNS embryonal tumors are rare, accounting for approximately 3% of childhood brain tumors. Their rarity combined with their substantial heterogeneity has resulted in a poor understanding of these tumors. However, classification of these tumors is rapidly evolving based on molecular profiling studies, and the mechanisms driving tumorigenesis of these CNS embryonal tumors are just beginning to be recognized. Historically, CNS embryonal tumors have been treated with protocols used to treat medulloblastoma, perhaps a by-product of these tumors’ similar histologic appearances. However, outcomes for patients with CNS embryonal tumors other than medulloblastomas have remained uniformly poor. This has led to the appreciation that these tumors respond poorly to medulloblastoma-based therapies and highlights the need for a better definition of the clinical, histologic, and genetic characteristics of these tumors to appropriately tailor effective therapies for patients.

CLINICAL PRESENTATION CNS embryonal tumors generally involve the frontal, temporal, and parietal lobes, more so than the deep or posterior fossa structures, and clinical manifestations are dependent on the site of tumor origin. Most children present with nonspecific complaints such as headache, nausea, vomiting, and problems with balance, all of which are manifestations of increased intracranial pressure (ICP). Complications of increased ICP include herniation, and care should be taken to approach lumbar puncture with extreme caution (or avoid completely) if an intracranial lesion is suspected. Other clinical manifestations of a supratentorial tumor might include motor deficits, alteration of consciousness, and seizures. Deeper-seated tumors such as those involving the pineal region may present with Parinaud’s syndrome from compression of the pretectal region. Tumors in the suprasellar region may result in visual disturbances and/or endocrine abnormalities. Posterior fossa tumors may present with ataxia, cranial nerve deficits, and signs and symptoms of increased ICP.

TYPES OF CNS EMBRYONAL TUMORS Embryonal Tumors with Multilayered Rosettes Embryonal tumors with multilayered rosettes (ETMRs) were first identified in 2000 by Eberhart et  al. as a distinct type of supratentorial embryonal tumor. Ependymoblastoma, formerly classified as a distinct entity, has been reclassified as being within the category of ETMR. These tumors, which also are known as embryonal tumors with abundant neuropil and true rosettes (ETANTRs), are rare CNS embryonal tumors that typically arise in the cerebrum but are occasionally seen in the cerebellum and brainstem. They occur in very young children (Ryzhova et  al., 2011) and have a slightly higher predominance in girls than in boys (Gessi et  al., 2009). Neuroimaging of an ETMR shows a large, well-delineated, solid mass with heterogeneous contrast enhancement (Gessi et  al., 2009). Some tumors demonstrate a cystic component (Figure 124-1). Their histologic characteristics are very distinctive and include focal high cellularity with abundant bands of neoplastic neuropil and the presence of both true rosettes and pseudorosettes (Louis et al., 2007) (Figure 124-2). These tumors are distinguished by high-frequency focal amplification at chromosome locus 19q13.42 of the C19MC oncogenic microRNA cluster, often associated with high levels of expression of LIN28 (Li et al., 2009; Ceccom et al., 2014). It has recently been shown that C19MC amplification occurs as a fusion of C19MC with the promoter of TTYH1, a brain-specific gene that encodes a chloride channel. The TTYH1 promoter is highly active, driving high levels of C19MC expression, which in turn activates DNMT3B, a DNA methyl transferase that modulates the cells to induce a state of dedifferentiation and, ultimately, tumorigenesis (Kleinman et al., 2014). Thus the high-level amplicon activates a primitive developmental mechanism as part of the oncogenic mechanism (Archer and Pomeroy, 2014). The prognosis of ETMR is exceptionally poor, with median survival of less than 1 year despite aggressive treatment.

Medulloepithelioma The most common site of origin for medulloepitheliomas is the periventricular region in the cerebrum. These tumors are typically quite large in size and may involve multiple lobes in one or both cerebral hemispheres. They sometimes occur intraventricularly and can be seen in sellar, infratentorial, and spinal regions, and in the optic nerve. Their histologic features include neural tube formation, including papillary, tubular, or trabecular arrangements of neoplastic neuroepithelium. These rare malignant tumors are seen primarily in young children between the ages of 6 months and 5 years, and half occur in children less than 2 years old (Louis et al., 2007). There is an equal distribution between males and females.

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Medulloepitheliomas have variable neuroimaging characteristics. They are generally well circumscribed and may be isodense or mildly hypodense on computed tomography (CT). Magnetic resonance imaging (MRI) shows hypointense or isointense lesions on T1-weighted sequences and hyperintense lesions on T2-weighted sequences. The tumors may not enhance with intravenous contrast on initial presentation but tend to enhance later as disease progresses (Figure 124-3). Calcifications and cysts are not typical features but have been reported. Medulloepitheliomas are often well circumscribed and have hemorrhagic and necrotic areas. They are frequently diffusely infiltrative in advanced disease. These tumors have distinctive histopathologic features mimicking the embryonic neural tube, with pseudostratified epithelium arranged in papillary, tubular, or trabecular patterns. They may contain elements of glial, neural, and mesenchymal cell lines. The mitotic index is high, with a high rate of cellular proliferation, and both ependymoblastomatous and ependymal rosettes may be seen.

Figure 124-1.  Axial T2-weighted MRI of ETANTR showing a large, well-circumscribed heterogeneous-appearing bifrontal mass. Note that the tumor extends into the frontal sinuses, an aggressive feature.

A

The prognosis of medulloepithelioma is very poor. Cerebrospinal dissemination is common at the time of death, which most often occurs within 1 year of diagnosis.

CNS Embryonal Tumors Not   Otherwise Specified CNS embryonal tumors NOS are highly heterogeneous and may be difficult to distinguish from other high-grade tumors by histology alone (Picard et al., 2012). They may arise in the suprasellar region and deep structures, although they are most commonly found in the cerebrum. The mean age of patients with CNS embryonal tumor NOS is 5.5 years, with a range of 4 weeks to 20 years, and there is a slight male predominance (1.2 : 1) (Louis et al., 2007). CNS embryonal tumors NOS appear isodense or hyperdense on CT. They may have cystic or necrotic areas, and many of these tumors have calcifications. On MRI, cystic and necrotic areas appear hyperintense on T2-weighted imaging, whereas solid portions of the tumor appear hypointense relative to gray matter on both T1- and T2-weighted imaging (Figure 124-4). The tumors typically enhance with gadolinium contrast. Cerebrospinal dissemination occurs in up to one-third of patients, and metastasis to extraneural sites, including bone, liver, and cervical lymph nodes, has been infrequently reported (Louis et al., 2007). On histologic examination, these tumors are poorly differentiated, with Homer Wright rosettes often found in varying frequency, and with undifferentiated small anaplastic cells with minimal differentiation of the cell body. GFAP expression is occasionally detected by immunohistochemical techniques. Proliferation as measured by Ki-67 is typically high but may vary extensively. At times the tumors are difficult to distinguish histologically from other malignant supratentorial tumors, including CNS neuroblastomas, which have neuronal differentiation, or CNS ganglioneuroblastomas, which are poorly differentiated tumors that additionally contain differentiated neuronal cells. The molecular features of CNS embryonal tumors NOS are poorly understood, and molecular profiling studies have revealed that many tumors initially diagnosed as CNS embryonal tumors NOS by histology are actually ETMRs/ETANTRs, glioblastomas, or ATRTs (Picard et al., 2012). Nevertheless, despite this molecular heterogeneity, all of these diagnoses share a poor clinical prognosis even with aggressive treatment, including neurosurgical resection, external beam radiation, and prolonged multidrug chemotherapy. Children less than 2

B

Figure 124-2.  Histopathologic features of ETANTR showing abundant bands of neuropil with rosettes and pseudorosettes.



Other Embryonal and Pineal Malignancies of the Central Nervous System

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Figure 124-5.  Histopathologic features of pineocytoma showing small, well-differentiated cells with low mitotic index.

Figure 124-3.  Sagittal T1-weighted postcontrast image of a pinealregion medulloepithelioma. Compression of the aqueduct causes the obstructive hydrocephalus.

chemotherapy followed by proton radiation (Jimenez et al., 2013). Overall, however, patients with supratentorial embryonal tumors have very poor clinical outcomes and low survival rates.

PINEAL TUMORS Pineal tumors are tumors of pineal parenchymal origin that arise in the region of the pineal gland. They are relatively rare and heterogeneous. The two primary types of pineal tumors are pineocytomas and pineoblastomas.

Pineocytomas

Figure 124-4.  Axial T1-weighted postcontrast MRI of a left parietooccipital CNS embryonal tumor showing heterogeneous enhancement. Note that the tumor involves both cortex and white matter and extends through the skull into the subperiosteal space.

Pineocytomas are tumors of pineal parenchymal lineage histologically classified as World Health Organization (WHO) grade I tumors. They are primarily seen in adults and rarely occur in children. Pineocytomas typically arise in the pineal area. They may extend into the posterior third ventricle and compress adjacent structures. Pineocytomas appear as hypodense, globular, well-defined masses, with occasional cystic components, peripheral calcifications, or hemorrhagic foci seen on CT. MRI shows a well-circumscribed mass that is isointense on T1-weighted sequences and hyperintense on T2-weighted sequences. Tumors demonstrate homogeneous contrast enhancement. Histopathologic features of pineocytomas include small, well-differentiated cells reminiscent of pineocytes that grow in sheets or lobules (Figure 124-5). In addition, large pineocytomatous rosettes are often seen. Mitotic index is usually low, and microcalcifications are sometimes present.

Pineoblastoma years of age at the time of diagnosis have worse clinical outcomes compared with older children.

TREATMENT AND OUTCOMES Treatment is typically multimodal and includes surgical resection, followed by irradiation appropriate for age and risk stratification, and chemotherapy (McGovern et al., 2014), although standard treatment regimens have not been established. Generally, gross total resection is a common feature of long-term survivors. One study showed good disease outcomes for a small cohort of young patients less than 5 years of age with CNS embryonal tumor NOS who received

Pineoblastomas are rare aggressive tumors of pineal parenchymal origin classified as WHO grade IV tumors based on histologic features. They more commonly occur in children, with the majority of pineoblastomas diagnosed in the first two decades of life (Louis et al., 2007). There is equal distribution between males and females. Pineoblastomas appear as contrast-enhancing, large, illdefined, lobulated masses on CT. Masses are hypointense or isointense on T1-weighted MRI. Cystic changes and calcifications are infrequently seen (Figure 124-6). Cerebrospinal and leptomeningeal dissemination, and local infiltration, are common for these poorly delineated tumors. They are comprised of highly cellular small cells that

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after diagnosis, and patients who develop recurrent disease have an especially poor prognosis (Farnia et al., 2014).

SUMMARY In conclusion, embryonal tumors found in the supratentorial compartment represent, for the most part, histologically similar yet molecularly heterogeneous groups of tumors whose classification (and nomenclature) is rapidly evolving. Despite their molecular heterogeneity, they share in common an aggressive clinical course that is generally refractory to conventional chemotherapy and radiotherapy schedules. As our understanding of the genetic underpinnings of these diseases rapidly evolves, so too will our ability to more effectively treat them. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Figure 124-6.  T2-weighted axial image of a pineoblastoma showing a hypointense lesion, indicating hypercellularity, with intralesional hemorrhage.

are compactly arranged. Pineocytomatous rosettes are absent, whereas Flexner-Wintersteiner rosettes and Homer Wright rosettes are more typically seen. Tumors tend to exhibit necrosis and high mitotic activity. Trilateral retinoblastoma syndrome describes the occasional presence of pineoblastoma in patients with bilateral retinoblastoma. Prognosis in patients who have aberrations in the RB1 gene is even less favorable than that for patients with sporadic occurrence. Pineoblastoma has also been reported to occur in patients with familial adenomatous polyposis (Louis et al., 2007).

TREATMENT AND OUTCOMES Treatment of pineal tumors typically includes a combination of surgical resection, irradiation, and chemotherapy. Given the location of these tumors, it is also important to manage the hydrocephalus commonly associated with pineal tumors. The clinical prognosis of patients with pineocytoma is generally quite favorable. Pineocytomas are not known to metastasize. Five-year survival ranges from 86% to 100%, and there have been no relapses reported for patients who undergo a gross total resection (Louis et al., 2007). In contrast, pineoblastomas are extremely aggressive tumors associated with poor clinical outcomes, particularly when seen in trilateral retinoblastoma syndrome. Craniospinal dissemination is common, as is leptomeningeal seeding, and metastasis to extracranial sites can occur. Survival largely depends on extent of disease at diagnosis and the extent of resection and radiation therapy. Patients with familial and sporadic trilateral retinoblastoma rarely survive beyond 1 year

Archer, T.C., Pomeroy, S.L., 2014. A developmental program drives aggressive embryonal brain tumors. Nat. Genet. 46 (1), 2–3. Ceccom, J., Bourdeaut, F., Loukh, N., et al., 2014. Embryonal tumor with multilayered rosettes: diagnostic tools update and review of the literature. Clin. Neuropathol. 33 (1), 15–22. Eberhart, C.G., Brat, D.J., Cohen, K.J., et al., 2000. Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr. Dev. Pathol. 3 (4), 346–352. Farnia, B., Allen, P.K., Brown, P.D., et al., 2014. Clinical outcomes and patterns of failure in pineoblastoma: a 30-year, single-institution retrospective review. World Neurosurg. 82 (6), 1232–1241. Gessi, M., Giangaspero, F., Lauriola, L., et al., 2009. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am. J. Surg. Pathol. 33 (2), 211–217. Jimenez, R.B., Sethi, R., Depauw, N., et al., 2013. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy. Int. J. Radiat. Oncol. Biol. Phys. 87 (1), 120–126. Kleinman, C.L., Gerges, N., Papillon-Cavanagh, S., et al., 2014. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat. Genet. 46 (1), 39–44. Li, M., Lee, K.F., Lu, Y., et al., 2009. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell 16 (6), 533–546. Louis, D.N., Ohgaki, H., Wiestler, O.D., et al., 2007. WHO Classification of Tumours of the Central Nervous System, fourth ed. International Agency for Research on Cancer (IARC), Lyon, France, p. 312. McGovern, S.L., Grosshans, D., Mahajan, A., 2014. Embryonal brain tumors. Cancer J. 20 (6), 397–402. Picard, D., Miller, S., Hawkins, C.E., et al., 2012. Markers of survival and metastatic potential in childhood CNS primitive neuroectodermal brain tumours: an integrative genomic analysis. Lancet Oncol. 13 (8), 838–848. Ryzhova, M.V., Zheludkova, O.G., Ozerov, S.S., et al., 2011. A new entity in WHO classification of tumors of the central nervous system–embryonic tumor with abundant neuropil and true rosettes: case report and review of literature. Zh Vopr Neirokhir Im N N Burdenko 75 (4), 25–33, discussion.

125  Ependymoma

Richard Grundy and Nicholas K. Foreman

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Ependymomas are enigmatic tumors, and despite advances in neurosurgery, neuroimaging, and postoperative adjuvant therapy, their clinical management remains one of the more difficult in pediatric neuro-oncology.

INCIDENCE AND EPIDEMIOLOGY Ependymomas are the second commonest malignant brain tumor occurring in children, accounting for approximately 10% of all such tumors. They have a predilection for young age at onset; indeed, over half of intracranial ependymomas arise in children under 5 years of age. There is slight male preponderance. Children with ependymoma have a worse outcome than adults. Childhood ependymomas predominantly arise in the intracranial compartment, in contradistinction to the situation for adults, in whom spinal origin predominates. Approximately two-thirds of childhood intracranial tumors arise in the posterior fossa, where they are intimately associated with the fourth ventricle. Signs and symptoms at presentation are consequent on obstruction of cerebrospinal fluid (CSF) movement. The most common presentation is nonspecific with raised intracranial pressure, but patients may present with cerebellar or lower cranial nerve dysfunction. In very young children, irritability and lethargy may be the only presenting symptoms. The duration of these symptoms before presentation varies greatly depending on site and may be prolonged, particularly in spinal tumors (Box 125-1).

LOCATION Ependymomas probably arise from the ependymal lining of the ventricles and lining of the central canal. However, ependymomas may arise anywhere in the neuraxis, and supratentorial tumors are frequently not related to ventricular cavity. Dissemination via CSF is reported in 7% to 22% of cases. Spinal ependymomas may occur as intramedullary or as intradural extramedullary tumors. The latter arise predominantly of the caudal region (filum terminale) and are usually of the myxopapillary histologic subtype (Box 125-2).

PATHOLOGY The World Health Organization (WHO) 2016 (Ellison et al., 2016) classification defines grades I through III, with classic ependymoma (grade II) and anaplastic ependymoma (grade III) being prevalent (Box 125-2). A new entity of supratentorial ependymoma a has been added defined by the presence of a RELA-fusion gene, comprising 80% of supratentorial ependymomas. Consistent histologic differentiation of ependymoma between Grade II and grade III has proven difficult because a spectrum of pathologic features exists (Wiestler et al., 2000). It is likely that grade will be determined by a combined morphologic and molecular profile in the near future.

DIAGNOSTIC EVALUATION Imaging Studies The imaging of intracranial ependymoma is challenging. On magnetic resonance imaging (MRI), ependymomas typically display iso- to hypointensity on T1-weighted images and hyperintensity on T2-weighted images. They usually enhance heterogeneously with gadolinium. Fourth-ventricle ependymomas can often be distinguished from medulloblastoma radiographically by their tendency to “squeeze” through the foramina of Luschka and Magendie. Complete neuraxis imaging is essential to exclude leptomeningeal disease, even in spinal tumors because these occasionally metastasize to the brain. An unresolved issue is exactly what surveillance protocol is optimal for children with ependymomas to maximize detection of recurrence without unduly wasting resources. The detection of asymptomatic recurrences through routine surveillance does appear to confer some benefit. A widely accepted strategy is acquiring an MRI every 3 to 4 months for up to 2 to 3 years and less frequently until age 6 to 7 years. MRI-visible spinal metastatic disease in the absence of intracranial metastases is uncommon.

PROGNOSTIC FACTORS Although a number of prognostic factors have been identified, these tend to be based on single-institution retrospective series involving limited numbers of patients accrued over a time span covering many different approaches to both the diagnosis and treatment of ependymoma. However, the most widely accepted prognostic factor is the degree of surgical resection. Axiomatically, gross total resection is associated with a better prognosis. Older children (above 3 years of age) appear to have a better prognosis, with a 5-year survival rate of 55% to 83% compared with 12% to 48% for children under 3 years of age. In this regard, factors likely to be important include surgical accessibility and a general reluctance to irradiate very young children. However, it is possible this difference is based on biology, with molecular stratification into two distinct subtypes of ependymoma, groups A and B, with a poorer outcome in group A, more commonly seen in the very young (Witt et al., 2011). Supratentorial location is thought more favorable despite these tumors often being extensive at diagnosis. Based on small numbers, there is a possibility that completely resected grade II supratentorial ependymomas have a particularly favorable outlook. Recent work suggests that in supratentorial tumors, the presence or absence of RELA gene fusions may have prognostic significance (Parker et al., 2014).

Tumor Grade Despite a number of studies, the relationship between histologic grading and tumor outcome is unclear. Some studies have found that the presence of anaplasia carries a worse

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BOX 125-1  Symptoms and Signs of Intracranial Ependymoma

TABLE 125-1  Examples of Genetic Heterogeneity Between Spinal and Intracranial Ependymomas Intracranial

Spinal

Headache Nausea and vomiting Lethargy Behavioral changes Slurred speech/visual disturbance Papilledema Cranial nerve palsies Ataxia Cerebellar signs Torticollis

Up-regulation of RAF-1

Up-regulation of PLA2GS, ITIH2, and members of HOX family

Altered expression of Protein 4.1 members

Altered expression of Protein 4.1 members

CDKN2A down-regulated (see Table 125-2)

CDKN2A up-regulated

Loss of chromosomes 22, 3, 6q, 9p, 10q, 13q, and 16q

Loss of chromosomes 1, 2, 10, and 22q12

Gain of chromosomes 1q, 7, and 9q

Gain of chromosomes 7, 9, 11, 18, and 20

Tenascin C, NELL, and LAMMA

Somatic NF2 mutations (adult and spinal tumors only)

SYMPTOMS AND SIGNS OF SPINAL EPENDYMOMA Pain: localized (backache) and radicular (sciatica) Gait disturbance Weakness Sensory change Bladder/bowel dysfunction Spastic paraparesis Hyperreflexia Suspended sensory level Scoliosis

BOX 125-2  World Health Organization (2016) Classification of Ependymal Tumors WHO GRADE II AND III Ependymoma papillary ependymoma clear-cell ependymoma tanycytic ependymoma RELA fusion Positive Anaplastic ependymoma WHO GRADE I Myxopapillary ependymoma Subependymoma With permission from Ellison DW, McLendon R, Wiestler OD, Kros JM, Korshunov A, Ng H-K, Witt H, Hirose T. Ependymoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavanee WK, eds. WHO Classification of Tumours of the Central Nervous System, 4th Edition. Lyon, France: IARC Press, 2016

prognosis, whereas others have found no difference. The lack of uniformity in the grading system used across series makes it difficult to conclude which histologic features are prognostic.

GENETICS It has been postulated that embryonic neural stem cells (NSCs) arising from different parts of the central nervous system are transformed by different gene mutations, thereby giving rise to biologically distinct types of ependymoma. For example, RELA gene fusions are common in supratentorial ependymomas but virtually absent in fourth-ventricle tumors (Parker et al., 2014). Radial glia-like cancer stem cells have been proposed as the candidate cell of origin for supratentorial and spinal ependymoma.

Cytogenetics Comparative genomic hybridization (CGH) studies have identified three broad groups of tumors. The first group of

TABLE 125-2  Genetic and Epigenetic Heterogeneity Between Ependymoma From Different Intracranial Locations Supratentorial

Posterior Fossa

Overexpression of EPHB-EPHRIN, Notch cell signaling pathways, and genes involved in the cell cycle

Loss of chromosomes 22, 6, and 17q

Genomic loss of 9p more common, resulting in loss of TSG CDKN2A (p14ARF) and P16INK4A.

High degree of epigenetic silencing of the 17p tumor-suppressor gene HIC-1

C11orf95-RELA (types 1-7) fusion C11orf95-YAP1 fusion

Loss of chromosome 6q CPG island methylator phenotype positive and negative

structural tumors showed few, mainly partial, imbalances. A second numerical group showed 13 or more chromosome imbalances, with a nonrandom pattern of whole chromosome gains and losses that are also highly associated with adult ependymoma. The third group showed a balanced genetic profile that was significantly associated with a younger age at diagnosis, suggesting that ependymomas arising in infants are biologically distinct from those occurring in older children (Kilday et al., 2009). There is a correlation between the structural group and group A, as identified by array technology. Overall, pediatric ependymomas most frequently demonstrate gain of chromosomes 1q, 7, and 9 and loss of chromosomes 22, 3, 9p,13q, 6q, 1p, 17, and 6, whereas the commonest genomic aberrations in adult ependymomas are gain of chromosomes 7, 9, 12, 5, 18, X, and 2 and loss of 22/22q, 10, 13q, 6, and 14q (Table 125-1). One of the most striking differences between the two age groups analyzed by CGH is the genomic gain of 1q seen in over 20% of pediatric ependymomas but in only 8% of adults. Importantly, the genomic imbalances found in adult and spinal ependymomas regularly involve whole chromosomal rearrangements; in contrast, partial and complex imbalances are frequently seen in pediatric cases. Indeed, a recent metaanalysis of pediatric and adult ependymoma revealed marked differences, underscoring the point that these should be considered separate conditions (Kilday et al., 2009). Comparing childhood intracranial ependymomas from different locations has revealed significant genetic diversity. It has also been suggested that posterior fossa ependymomas can be subdivided based on their gene expression profiles (Witt et al., 2011) (Table 125-2).



Whole-genome sequencing of supratentorial and posterior fossa ependymomas, with the aim of identifying driver mutations of these tumors, has recently been performed (Parker et al., 2014; Mack et al., 2014). Both studies found very few single-nucleotide variations (SNVs), insertion/deletions, or focal ( 36 months) were highly enriched in IDH mutant tumors and G34 mutant tumors without oncogene amplification. K27M mutant GBM had a dismal outcome nearly identical to that of DIPGs, and the fact that nearly all tumors were MGMT promoter nonmethylated provides a biologic explanation for the failure of temozolomide and other alkylator-based chemotherapy in prior DIPG trials. The G34 mutant subset had frequent MGMT promoter methylation, which may explain the more favorable outcome with alkylator-based therapy.

FUTURE DIRECTIONS Targeted Therapies for Children With   High-Grade Gliomas As outlined previously, current treatment strategies do not lead to acceptable clinical outcomes for children with HGGs, and with the exceptions of surgical resection and focal



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radiation therapy, there is currently no established SOC. Children with HGGs are usually enrolled in an investigational trial as first-line therapy. Many of the agents being evaluated in clinical trials are chosen empirically, and, not surprisingly, there has been little progress in improving outcomes over the last decades. Presently, there is no validated mechanism to prioritize treatment recommendations for an individual patient with pediatric HGG. We now understand that there are significant biologic differences between adult and pediatric malignant gliomas and differences based on tumor location (Wu et al., 2014). These findings highlight that treatment needs to be tailored to each individual child’s tumor. Individualized treatment based on single-gene expression or mutation has proven to be an effective strategy in multiple cancer types. For children with HGGs, recent studies have shown that approximately 10% to 15% carry the BRAF-V600E mutation, a genetic alteration that is also shared with other tumor types, such as melanoma, thyroid cancer, and colon cancer. There are now several specific BRAF-V600E inhibitors in clinical use, and individual case reports are encouraging regarding the clinical response of pediatric BRAF-V600Emutated tumors to such targeted therapy. The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is currently conducting a phase I clinical trial of the specific BRAF-V600E inhibitor vemurafenib in children with BRAF-V600E-mutated gliomas. With advances in bioinformatics and molecular technologies, such as shortened turnaround times for whole-genome sequencing (WGS), combined with our expanding knowledge of molecular networks and mechanisms of action of the existing pharmacopeia (drugs approved by the U.S. Food and Drug Administration [FDA]), strategies using more in-depth profiling of the tumor to guide therapy are slowly entering the clinic, including for children with HGGs (clinical trials NCT02274987, NCT02060890, and NCT02162732). Molecular profiling has provided clinical benefit for patients with various advanced adult cancers, but the clinical benefit derived from such analyses remains unknown in the pediatric population. One of the major challenges in the application of precision medicine remains the classification and prioritization of identified variants by genomic analyses and possible association with drug response. But despite the ongoing challenges, this strategy opens an exciting new area for the treating neurooncologist when therapy is informed by the individual characteristics of the child’s tumor. Results of these ongoing precision medicine trials will be critical to inform how this approach can be integrated in the care of children with HGGs.

crossing the BBB and BTB while minimizing systemic exposure and toxicity. A major advance in the safe and potentially efficacious use of CED in neurosurgery has been the development of real-time convective delivery (RCD), which utilizes MRI to visualize the CED process with the aid of coconvected contrast agents (Krauze et al., 2008). The use of RCD allows physicians to directly monitor the distribution of therapeutics within the brain. Thus, reflux along the CED catheter or leakage outside the target area, especially at higher flow rates, can be monitored and corrective steps taken, such as retargeting the catheter or altering the rate of infusion. CED of carmustine has shown to prolong survival in mice with brainstem tumors, and other studies have shown that CED of nanoliposomal irinotecan is superior compared with intravenous administration in an orthotopic model of HGG. A feasibility study using coinfused imaging tracers with interleukin-13-Pseudomaonas exotoxin in children with DIPGs has shown that with use of CED, clinically relevant distributions of agents can be achieved in humans. An ongoing clinical trial is currently investigating the feasibility of CED of 124 I-8H9, a radiolabeled antibody, in children with DIPGs (NCT01502917).

CNS-Directed Delivery Strategies

SELECTED REFERENCES

A fundamental limitation in the treatment of children with HGGs is that most therapeutic agents do not cross the blood– brain barrier (BBB) and blood–tumor barrier (BTB), and therefore never reach the tumor target. Several delivery strategies have been explored to overcome the BBB and BTB, of which convection-enhanced delivery (CED) and intranasal delivery show promise and have already entered the clinic.

Convection-Enhanced Delivery CED improves chemotherapeutic delivery to brain tumors intraparenchymally by utilizing bulk flow, or fluid convection, established as a result of a pressure gradient, rather than a concentration gradient. The advantages of CED over diffusion based delivery include (1) an expanded volume of distribution (Vd), (2) a uniform concentration of the infused therapeutic within the target Vd, and (3) the delivery of the vast majority of the infused therapeutic within the target volume. Additionally, CED obviates the challenges of systemic agents

Intranasal Delivery Intranasal delivery is a noninvasive method of bypassing the BBB and BTB, and studies have shown that intranasal delivery of an antisense oligonucleotide-targeting telomerase (GRN163) inhibits orthotopic brain tumor growth and significantly prolongs survival in vivo (Hashizume et al., 2008). Other studies have supported intranasal delivery strategies in animal studies using different agents, such as insulin-like growth factor 1, interferon beta, and methotrexate. Intranasal delivery strategies have already entered the clinic for patients with neurodegenerative diseases and have been tested in adult patients with recurrent GBM. For example, intranasal administration of perillyl alcohol in adult patients with recurrent GBM showed good tolerability and regression of tumor size in some patients. Intranasal delivery is an attractive delivery strategy for long-term administration of therapeutics and is especially well suited for children because of the noninvasive nature of the procedure. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details.

Cha, S., Knopp, E.A., Johnson, G., et al., 2002. Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echoplanar perfusion MR imaging. Radiology 223 (1), 11–29. [Epub 2002/04/04]; eng. Hashizume, R., Ozawa, T., Gryaznov, S.M., et al., 2008. New therapeutic approach for brain tumors: Intranasal delivery of telomerase inhibitor GRN163. Neuro Oncol. 10 (2), 112–120. Jones, C., Baker, S.J., 2014. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat. Rev. Cancer 14 (10), [Epub 2014/09/19]; eng. Krauze, M.T., Vandenberg, S.R., Yamashita, Y., et al., 2008. Safety of real-time convection-enhanced delivery of liposomes to primate brain: a long-term retrospective. Exp. Neurol. 210 (2), 638– 644. Park, I., Mukherjee, J., Ito, M., et al., 2014. Changes in pyruvate metabolism detected by magnetic resonance imaging are linked to DNA damage and serve as a sensor of temozolomide response in glioblastoma cells. Cancer Res. 74 (23), 7115–7124. Paugh, B.S., Zhu, X., Qu, C., et al., 2013. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res. 73 (20), 6219–6229.

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Schwartzentruber, J., Korshunov, A., Liu, X.Y., et al., 2012. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482 (7384), 226–231. [Epub 2012/01/31]; eng. Snuderl, M., Fazlollahi, L., Le, L.P., et al., 2011. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20 (6), 810–817. [Epub 2011/12/06]; eng.

Taylor, K.R., Vinci, M., Bullock, A.N., et al., 2014. ACVR1 mutations in DIPG: lessons learned from FOP. Cancer Res. 74 (17), 4565–4570. [Epub 2014/08/20]; eng. Wu, G., Diaz, A.K., Paugh, B.S., et al., 2014. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46 (5), 444–450. [Epub 2014/04/08]; eng.

127  Pediatric Low-Grade Glioma Nicole J. Ullrich and Bruce H. Cohen

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Pediatric low-grade glioma (PLGG) represents the most common brain tumor in childhood and constitutes more than 20% of primary brain tumors in children. Most PLGGs occur in the cerebellum, visual pathways, and diencephalon and comprise a histologically diverse and biologically heterogeneous group of neoplasms. Many low-grade gliomas (LGGs) have defined borders and are amenable to complete surgical resection, with excellent overall survival when treated with surgery alone. However, some LGGs are either invasive to critical structures or located in inaccessible regions, and are thus not amenable to surgical resection. Historically, these tumors were treated with radiotherapy, but in the last three decades, chemotherapy has become increasingly common as the initial postsurgical intervention. The goal of chemotherapy is to both to overcome residual or recurrent disease, and to minimize the toxicity associated with radiation therapy. Although radiation therapy may ultimately be necessary, the current practice among physicians who treat children with brain tumors generally aims to delay cranial irradiation until multiple attempts at other therapies have failed. There have been significant advances in our understanding of the molecular underpinnings of LGGs, which provide compelling preclinical evidence that targeted treatments directed at critical points along the molecular signaling pathways may be a successful approach to management. This chapter reviews the classification, clinical and pathologic features, molecular biology, and current standard and experimental therapeutic strategies for these tumors. The incidence of LGGs in the United States approximates 2 per 100,000 persons aged 0 to 19 years of age (SEER Program, 2012; Ostrom et al., 2014). The majority of PLGGs arise sporadically; however, they can be associated with an underlying familial cancer predisposition syndrome or neurocutaneous syndromes. For example, children with a diagnosis of neurofibromatosis type 1 (NF1) are at increased risk to develop an LGG involving the visual pathway, which is found in 15% to 20% of children with NF1 and children with tuberous sclerosis complex (TSC) have a higher incidence of subependymal giant cell astrocytoma (SEGA), a subtype of LGG (Listernick et al., 1997; Gutmann, 2014).

CLINICAL PRESENTATION PLGGs typically are slow-growing tumors, and the clinical presentation depends largely on the tumor location and age of the patient. Symptoms result because of either invasion into the surrounding brain parenchyma, local compression of brain tissue, or generalized increased intracranial pressure (ICP). Children can present with focal or diffuse signs and/or symptoms, or a combination of both (Table 127-1). Generalized increased ICP can result in headaches, vomiting, irritability, and behavioral symptoms that are very different from a child’s usual demeanor. Tumors in eloquent regions of the brain often produce focal neurologic signs and symptoms reflecting the anatomic function of the involvement. Older

children aware of their visual and motor function are more likely to communicate these symptoms. For example, cerebellar tumors will present with progressive gait changes, ataxia, and/or nystagmus. Tumors within the optic pathway often present with loss of visual acuity, changes in visual fields, hormonal abnormalities, and/or behavioral changes. Lesions within the brainstem typically cause the combination of progressive cranial nerve palsies such as bulbar dysfunction, upper motor neuron signs such as contralateral hyperreflexia or weakness, and ipsilateral ataxia. Supratentorial hemispheric lesions often present with localizing signs that include hemiparesis or seizures. Seizures are more common with tumors involving the temporal lobe, especially mesial structures and the frontal lobe. Seizures with LGG typically have a focal onset but may quickly generalize and thus appear as a generalized seizure from onset. Last, tumors in the region of the pineal gland, including the posterior third ventricle, or with mass effect compressing the nearby tectal plate, may lead to Parinaud syndrome, which is the triad of upgaze paresis, pupillary dilatation with poor or absent response to light, and retraction convergence nystagmus. Slow-growing, space-occupying lesions often result in poorly localizable symptoms. In general, these symptoms are a result of increased ICP caused by disruption of CSF pathways and resulting hydrocephalus, and lead to a combination of headaches, lethargy, and vomiting. Nausea resulting from increased ICP is often position sensitive and is accompanied by other neurologic symptoms. At times, persistent increased ICP can produce irritability, uncharacteristic behavioral changes, and progressive cognitive dysfunction. In young infants with an open fontanelle, increased head circumference may be the first manifestation of hydrocephalus. Infants may also demonstrate stagnation of development, irritability, failure to thrive, and the “sun-setting sign,” where the gaze is in a near-fixed downward position, and so the sclera above the iris is visible.

CLASSIFICATION AND HISTOLOGIC FEATURES Gliomas are among the most diverse histologic group of brain tumors affecting children and the term LGGs refer to those tumors classified by the World Health Organization (WHO) system as grade I or II gliomas, and can be divided into several distinct entities based on both the dominant cell type observed histologically and by location (Table 127-2). Approximately 15% to 25% of all pediatric brain tumors are grade I juvenile pilocytic astrocytomas of the cerebellum, followed by grade II LGG of the cerebrum (10% to 15%), deep midline structures (10% to 15%), and grade I and II LGGs of the optic nerves and visual pathways (5%) (Bandopadhayay et al., 2014).

Pilocytic Astrocytoma (WHO Grade I) Pilocytic astrocytomas are the second most common brain tumors, with the embryonal neoplasms (primarily medulloblastomas) the most common brain tumor in children. These tumors are considered histologically benign. Histologic

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lack the Rosenthal fibers and eosinophilic grandular bodies. A less favorable subset is represented by young children who present with hypothalamic syndrome, also known as diencephalic syndrome, a distinct clinical phenotype that includes normal or excessive food consumption with failure to gain weight. There is a worse overall prognosis in this tumor subtype, and in one report, the 1-year progression-free survival was only 37.8%; of the total cohort, 6/18 patients had died.

TABLE 127-1  Clinical Presentation of Primary Brain Tumors in Children Focal Symptoms

Diffuse Symptoms

Seizures

Headache

Ataxia

Neck stiffness

Hemiparesis or weakness Nystagmus

Vomiting

Cranial nerve palsies

Lethargy

Focal sensory changes

Cognitive deterioration

Decreased visual acuity/visual fields

Behavior change

Parinaud syndrome Diabetes insipidus

Seizure

Growth retardation

Irritability

Aphasia

Infants: increased head circumference, split sutures, Bulging fontanelle, “setting-sun” sign

TABLE 127-2  Classification of Pediatric Low-Grade Glioma (Based on World Health Organization 2007 Central Nervous System Classification) Tumor Subtype

Dysembryoplastic Neuroepithelial Tumor   (WHO Grade I) Dysembryoplastic neuroepithelial tumors are usually cortical tumors that usually present with refractory seizures, often without other neurologic signs. Pathologically, this neoplasm is composed of glial nodules, with associated cortical dysplasia and glioneuronal elements. In many cases these tumors are small and are amenable to complete surgical resection, which often effectively treats the epilepsy. Because of the cortical location, however, gross total resection (GTR) may be challenging. In general, these tumors have a low recurrence rate after surgery and despite incomplete resection, sometimes the remaining tumor does not grow.

Ganglioglioma (WHO Grade I)

Tumor Grade

Astrocytic tumors   Subependymal giant cell astrocytoma

I

  Pilocytic astrocytoma

I

  Pilomyxoid astrocytoma

II

  Diffuse astrocytoma

II

  Pleomorphic xanthroastrocytoma

II

  Protoplasmic astrocytoma

II

Oligodendroglial and oliogoastrocytic tumors   Oligodendroglioma

II

  Oligoastrocytoma

II

Neuronal and mixed neuronal-glial   Ganglioglioma

I

  Desmoplastic infantile ganglioglioma

I

  Dysembryoplastic neuroepithelial tumor

I

  Central neurocytoma

II

characteristics include well-differentiated astrocytes, with Rosenthal fibers and eosinophilic granular bodies as the characteristic findings in these tumors, but usually without any cellular atypia. Cystic formations are common, and in some cases, the majority of the tumor volume is a cyst. The goal of surgery is complete resection, typically with minimal or no sequale. Survival with this histology is excellent overall, with 1-year and 10-year survival of 98.6% and 95.8%, respectively.

Pilomyxoid Astrocytoma (WHO Grade II) Pilomyxoid astrocytomas are grade II neoplasms most often located in the hypothalamic and nearby midline regions, and occur in younger children (typically less than 1 year old). Pathologically, these tumors are closely related to pilocytic astrocytoma with bipolar cells within a myxoid matrix, but

The ganglioglioma is a grade II neoplasm consisting of mixed neuronal and glial elements with mature ganglion cells and abnormal glial cells. These are most frequently located in the temporal lobes, present around 10 years of age, and typically present with seizures. As with DNETs, these tumors are most often completely resectable with a favorable prognosis.

Pleomorphic Xanthroastrocytoma   (WHO Grade II) Pleomorphic xanthroastrocytomas occurs most commonly in teenagers and young adults, and usually involves the cortex, especially the temporal lobes. These tumors were once classified as a giant cell glioblastoma. They are cellular tumors with more nuclear atypia than other LGGs, and can be misdiagnosed as high-grade gliomas. Many of these tumors have clear borders and are amenable to gross-total resection, with a favorable prognosis.

Diffuse Fibrillary Astrocytoma Diffuse fibrillary astrocytomas are a WHO grade II neoplasm and can be morphologically similar to their adult counterparts. They occur most commonly in the supratentorial space, deep midline structures, and lower brainstem. Microscopically, they are characterized by modest cellularity, lack of significant mitoses, and presence of both fine and course neuroglial fibrils that form a matrix between the cells. These tumors, because of their infiltrating nature, are more difficult to resect completely and have a less favorable outcome than pilocytic astrocytoma. Over time, these tumors can transform into malignant gliomas. Recent data suggest that these tumors are similar to their adult counterparts in terms of pathologic appearance, but have distinct genetic molecular alterations.

Pediatric Low-Grade Glioma;   Not Otherwise Specified As many as one quarter of PLGGs may not fit into a particular WHO LGG subtype classification and are designated as pediatric LGG; not otherwise specified (PLGG, NOS). This category



includes tumors that have not been biopsied and then are designated also by the site of origin, such as the optic glioma, which accounts for 3% to 5% of all childhood brain tumors. These tumors can be located anywhere along the visual pathway, including the optic nerve, optic chiasm, optic tract, and optic radiations and often involve the hypothalamus, and the terms visual pathway glioma, optic pathway glioma, or hypothalamic-chiasmatic glioma may be more fitting. Approximately 15% to 20% of children with NF1 have an optic glioma as seen on imaging, although only one fifth of these children require treatment; this treatment is typically initiated when a change in visual acuity or change in visual function occurs, and not because of incremental growth of the mass. Because of the distinct clinical phenotype and tumor location, a surgical biopsy is typically not required to make the diagnosis. In general, in the absence of any signs of progressive neurologic dysfunction or vision loss (e.g., absence of optic nerve pallor, loss of visual acuity, or visual fields), clinical observation with serial ophthalmologic assessments and neuroimaging studies is generally recommended.

EVALUATION, DIAGNOSIS, AND MANAGEMENT The diagnosis of an LGG is likely when characteristic neuroimaging findings are seen during the evaluation of a neurologic disturbance such as a seizure or motor dysfunction. PLGGs tend to be isodense or hyperdense on CT, with varying degrees of cystic changes and contrast enhancement. The solid portion of pilocytic astrocytoma enhances vividly with contrast, which should not be mistaken as a sign of a malignant or high-grade nature. Less malignant tumors tend to have a more focal appearance with variable enhancement, with the lowest grade neoplasms demonstrating more confluent enhancement patterns or no enhancement at all. In contrast to higher grade tumors, PLGGs are not typically accompanied by mass effect, edema, or restricted diffusivity. Pilocytic astrocytomas may demonstrate a classical cyst with a mural nodule. The mural nodule may be quite small, and in some instances only the wall of the cyst demonstrates enhancement. Postoperative MRI is suggested, preferably within a day or so from the time of initial surgical resection, to adequately assess extent of surgical resection. After a GTR, these tumors seldom recur, with a survival approaching 100% at 5 years in many series. If the tumor does recur, subsequent attempts at GTR are usually attempted. Some of these tumors may extend into the brainstem and are therefore less amenable to surgical resection. Although these are typically considered “benign” tumors, they may be accompanied by metastatic foci of tumor; this is particularly true for suprasellar tumors in infants and young children. Depending on the tumor location, other assessments may be needed. An ophthalmologic evaluation and testing of endocrine function are needed for tumors located along the visual pathway and hypothalamic region. Children should be examined for neurocutaneous stigmata of NF1 and TSC. Electroencephalogram may be helpful at diagnosis or any time if there is a question of seizures. Because many of these tumors will affect higher cortical function, including those located in the posterior fossa, all children should have a neuropsychological assessment near the beginning of their illness, at the conclusion of primary therapy and at points post-therapy if educational, social, or employment issues arise.

DIFFERENTIAL DIAGNOSIS LGGs must be distinguished from other lesions, such as (1) “high-grade” gliomas, including anaplastic astrocytoma, glioblastoma multiforme, and anaplastic oligodendroglioma; (2)

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other brain neoplasms; (3) nonneoplastic lesions, including infarction; (4) inflammation; and (5) cerebritis/encephalitis, acute demyelinating encephalitis, and antibody-mediated encephalitis (such as NMDA-receptor encephalitis). Occasionally, a large area of focal demyelination can demonstrate mass effect and resemble a glioma. Tumorifactive multiple sclerosis is an aggressive form of multiple sclerosis in which the lesion mimics a brain neoplasm, often accompanied by mass effect and contrast enhancement. None of these entities has a pathognomonic clinical or radiographic presentation, and so histologic, antibody, or other biomarker diagnosis is required.

PATHOGENESIS Intensive efforts to elucidate the genetic underpinnings of PLGGs are in progress. The gene BRAF, which is an oncogene linked to melanoma and some carcinomas, functions to upregulate the RAS/RAR/MEK pathway. Genetic rearrangements, typically duplications and rearrangements, are the most common genetic finding in sporadic PLGGs, and are found in 50% to 100% of pediatric pilocytic astrocytoma. These duplications, however, are not typically identified in NF1-associated LGGs or other PLGGs, which, by contrast, often demonstrate an abnormal gain of function or duplication in the MAP-kinase signaling pathway, with the implication that targeted therapies could be developed along this pathway. Investigation as to environmental impact on LGG occurrence has not been informative.

TREATMENT Because of the excellent overall prognosis of PLGGs, the goals of therapy must take into account the dual aims of tumor control and reduction of treatment/tumor-associated morbidity. In some children, especially in NF1, PLGGs are found incidentally and may not be causing any acute symptoms, and do not require tumor-directed therapy. In general, treatment approaches include observation, surgery, chemotherapy, and cranial irradiation.

Surgery Surgery is the mainstay of treatment for many PLGGs. Surgery provides tissue for histopathologic interpretation and molecular characterization. When possible, a gross total or complete resection should be considered, as this is often curative. When a GTR is not safe to perform, removal of some or most of the tumor often provides a therapeutic benefit. The tumor location typically determines the extent of surgical resection; tumors in surgically accessible areas such as the cerebellum or noneloquent cortex can often be excised without sequela. A report from a large cooperative group supported the postulate that the extent of tumor resection is the most significant factor associated with favorable outcome. In children with LGGs who had undergone GTR, the 5-year progression-free survival is about 90%, whereas more than half of children with subtotal resection had disease recurrence during that interval (Wisoff et al., 2011). However, progressive disease or relapse is not indicative of an overall poor prognosis. An analysis of over 4000 children with PLGG showed no overall survival advantage in those children with an initial GTR compared with children not having a complete resection. The 20-year overall survival in this subset of patients was 87% ± 0.8%, with deaths attributable to the glioma at 12% ± 0.8%. The risks of permanent surgical morbidity need to be considered when approaching the goal of complete resection, and if the risk is above minimal, the prognostic data for overall survival favor a less aggressive surgical approach.

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Chemotherapy Many LGGs, especially those located in the optic pathway, brainstem, and other cerebral midline structures may not be amenable to surgery or GTR, and adjuvant therapy is used to achieve tumor control and prolong survival. The successful use of chemotherapy before radiotherapy, both at initial diagnosis and recurrence, demonstrated the efficacy of chemotherapy, which can delay or completely avoid the need for subsequent cranial irradiation. Studies conducted since the 1980s have demonstrated that chemotherapy is an effective mode of treatment to achieve disease stability, either when GTR is not possible or cannot be safely achieved, or when these tumors become symptomatic with regrowth (Ater et al., 2012). Standard chemotherapy is administered for approximately 1 year;

A

however, chemotherapy can be halted a cycle or two after maximum therapeutic effect is confirmed by imaging or when dose-limiting toxicity occurs. Some patients may progress during or after completion of chemotherapy, and require one or more additional treatment regimens at time of tumor recurrence (Figs. 127-1 and 127-2). Although there is no standard of care, most pediatric neuro-oncologists advise using several chemotherapy regimens before proceeding with radiotherapy. Progression-free survival for most chemotherapeutic regimens tested is typically in the range of 30% to 40% at 5 years. There are several chemotherapy regimens used to treat PLGG. The combination of vincristine and carboplatin (CV), administered weekly, has been used since the late 1980s, as well as the combination of thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (referred to as TPDCV),

B

Figure 127-1.  a, b, FLAIR (left) and T1 gadolinium-enhanced (right) images from a 19-year-old male who was diagnosed initially at 11 months of life after a single seizure with a low-grade astrocytoma. After a gross-total resection he was stable for 4 years and experienced subsequent tumor progression. Follow-up treatments included reresection and three different chemotherapeutic regimens. After cystic progression, his imaging has remained stable at 5 years. FLAIR imaging demonstrates multiple cysts (curved red arc shows one hyperintense cyst). After administration of gadolinium, multiple solid enhancing nodules are visible (one is marked by an arrow on both images). He is currently a college student with a normal neurologic exam.

Figure 127-2.  A 20-year-old man diagnosed at age 6 years with a left temporal lobe astrocytoma. He has experienced nine recurrences, and treated with two additional surgeries, cranial irradiation, and five different chemotherapy regimens at time of relapse or progression. He developed severe myelodyspastic syndrome preventing further treatment with cytotoxic agents. FLAIR image demonstrates increased signal surrounding tumor resection bed (shown only in left image with arrows). The corresponding gadolinium-enhanced images demonstrate several small enhancing nodules (not shown). His examination demonstrates mild cognitive impairment with speech difficulties and a mild right hemiparesis.



and when dibromodulcitol became unavailable, TPCV. A randomized study comparing these two regimens was conducted through the Children’s Oncology Group in 274 children with newly diagnosed grade 1 or grade 2 LGG having less than a 95% resection, residual tumor measuring more than 1.5 cm2, or radiographically progressing tumors after surgery. There were 137 children in each treatment arm and overall results in the combined groups showed a 45% ± 3.2% 5-year eventfree survival and a 86% ± 2.2% 5-year overall survival. The difference in the two treatment arms was not significant (stratified log-rank p = 0.1). The 5-year event-free survival in those treated with TPCV was 52% ± 5% and in those treated with carboplatin–vincristine, 39% ± 4%. The 5-year overall survival was essentially identical showing 86% ± 3% for those treated with CV and 87% ± 7% for those treated with TPCV (log-rank p = 0.52). This report added several details that add clarity to the understanding of how location, pathology, and extent of resection affect outcome. The 5-year event-free survival (and overall survival) for pilocytic astrocytoma was 49% ± 6% (88% ± 4%), for hypothalamic/optic chiasmal tumors was 44% ± 5% (87% ± 3%), and for fibrillary astrocytoma was 34% ± 10% (79% ± 8%). The relative risk for progression or relapse was 0.65 times lower (95% CI, 0.44–0.97) in children with tumor volume (after surgery is performed) of less than 3.0 cm2 than in patients with a residual tumor of greater than or equal to 3.0 cm2. Independent factors associated with overall survival included age at diagnosis, tumor site, and amount of residual tumor. The risk of secondary neoplasm caused by the use of the alkylating agents in the TPCV treatment arm has been a source of ongoing concern, but in this trial only one patient developed leukemia. The issue of secondary neoplasms caused by alkylating therapy remains a concern, especially in children with NF1, who have an underlying tumor suppressor inactivating syndrome and a higher risk for development of leukemia and who therefore should avoid the use of alkylating agents. A number of other chemotherapy-based treatments have been explored, including vinblastine; tamoxifen and carboplatin; cisplatin and etoposide; temozolomide; bevacizumab and irinotecan; carboplatin, vincristine, and temozolomide; and procarbazine, carboplatin, vincristine, etoposide, cisplatin, and cyclophosphamide. Some of these regimens have been studied primarily in the immediate postoperative period, but have not demonstrated added therapeutic advantages over the more conventional initial therapies such as CV or TPCV. These treatment regimens, however, are an important part of the armamentarium, as they are useful in the setting of the multiply relapsed patient (see Figs. 127-1 and 127-2). Progression or relapse after any initial treatment is common, and additional therapy is required. This treatment may include surgery aimed at further debulking of the recurrent tumor or to drain tumor-associated cysts. In most circumstances, when a child has been treated with chemotherapy, s/he will be treated with a subsequent, typically different, chemotherapy regimen. This approach to treatment with several different chemotherapy regimens will be repeated until the child is free of progressive disease or until such a decision is made to proceed with radiation.

Radiation Therapy Although radiotherapy was the earliest treatment approach used after incomplete resection or at the time of tumor recurrence, the data supporting its use as an immediate postsurgical treatment for residual disease are not clear, with conflicting data regarding any benefit for progression-free survival. Radiotherapy has not been shown to improve overall survival. Currently irradiation is typically reserved for those children who

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have no remaining surgical or chemotherapeutic options. Irradiation is generally avoided in young children because of concern for the long-term risks of cognitive effects, secondary radiation-related tumors, vasculopathy, and endocrine dysfunction (Ullrich, 2009; Armstrong et al., 2011). The duration of disease control after radiation therapy is similar to that of chemotherapy. Because controlled trials randomizing children to receive radiotherapy versus chemotherapy (or observation) after maximal surgery have not been performed, and initial treatment paradigms have not stratified randomized treatments to GTR versus subtotal surgical resections, it is not possible to draw any definitive conclusions about the comparative efficacy of radiotherapy or chemotherapy. The use of newer radiotherapy techniques permits delivery of the ionizing radiation to a smaller brain volume, which can often avoid or lessen the injury to eloquent brain regions. These techniques include three-dimensional conformal techniques, the use of nonparallel rotating photon arcs, intensitymodulated radiotherapy, and proton beam irradiation.

SUPPORTIVE CARE Seizures Seizures follow headache as the most common presenting symptom in supratentorial tumors in childhood and the prevalence may be as high as 75% in children with LGG. The wide variation is in part that some centers have concentrated efforts in the surgical management of epilepsy, and therefore there is a referral bias in the evaluation of patients with both seizure and brain tumor.

GENETIC FEATURES OF PEDIATRIC   LOW-GRADE GLIOMA Years before there was any clear understanding of the molecular genetics of brain tumors, the observation was made that visual pathway gliomas occurred in NF1 at a rate of about 4000-fold greater than in the general population. The most common findings are a gain of chromosome 7 (most true for pilocytic astrocytomas), followed by gains of chromosomes 4, 5, 6, 8, and 11, and deletion of 17p or 1.q. This is quite different from adult LGGs such as oligodendroglioma, where the loss of 19q and 1p is most common. Mutations in IDH1 and IDH2, common in adult gliomas, are rare in childhood gliomas. The mitogen-activated protein kinases (MAPK) and mTOR pathways were found to be activated in NF1, and known to be the major contributory pathway to the formation of LGG in NF1. Similarly, the mTOR pathway is dysregulated in tuberous sclerosis (Bergthold et al., 2015).

CURRENT CLINICAL TRIALS Targeting the RAS/MAP-Kinase Pathway The majority of PLGGs have alterations of the RAS/MAPkinase pathway. In NF1-associated LGG, this pathway is constitutively activated because of loss or altered function of neurofibromin. In non-NF1-associated PLGG, the most common alteration is a fusion and tandem duplication of BRAF with KIAA1659. This fusion results in a constitutively active BRAF. A group of diffuse astrocytomas has activating mutations of the MYB or MYBL1 transcription factors and resulting MAP-kinase activation that is equivalent to that observed in BRAF-driven tumors. This suggests that MAPkinase may also be a driver pathway in PLGG. The presence of common mutations provides a rational treatment target.

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The BRAF inhibitor dabrafenib has been used in melanoma and is currently being investigated in a national pediatric phase I/II trial in patients with known BRAF tumors (NCT01677741). Development of more defined MAP-kinase pathway inhibitors has led to successful preclinical testing and currently a clinical trial of one such inhibitor, selumetinib, which appears to inhibit ERK phosphorylation, in patients with LGG (NCT01089101).

mTOR Pathway Inhibition Increased activation of the mTOR pathway has been welldefined in PLGGs as demonstrated by the success of rapamycin trials in treating subependymal giant cell astrocytomas. These results suggested that mTOR inhibitors might have activity in other PLGGs. A trial of everolimus in refractory/ recurrent PLGG has recently completed enrollment (NCT00782626) as has a second phase II trial with larger numbers of patients (NCT01734512). Last, a separate study using everolimus in children with NF1-associated LGG has recently completed enrollment (NCT01158651).

Antiangiogenic Therapy There is increased expression of vascular growth factors in PLGG, suggesting that neovascularization may be a crucial step for continued growth stimulation in these tumors. The use of the VEGF inhibitor bevacizumab along with irinotecan resulted in radiologic and clinical responses in small numbers of children. Monotherapy with bevacizumab has also led to tumor regression and disease stability in some patients.

Immunomodulatory Therapy PLGGs contain characteristic mutations that are not found in nontumor cells, which raises the possibility of using these abnormal peptides as a target for therapy. Lenalidomide alters the immune environment and antiangiogenesis, with direct antitumor effects. Results from a phase I trial using lenalidomide demonstrated decreased tumor progression in PLGG. A phase II study is currently underway comparing two dose levels of lenalidomide (NCT01553149).

OUTCOME PLGGs are clinically and genetically different from LGGs in adulthood. One of the biggest distinctions is the response to chemotherapy and overall excellent overall survival. Results from the Surveillance, Epidemiology and End Results (SEER) database have provided important prognostic information about PLGGs. Prognosis for children is excellent, with an overall survival at 30 years of 87%. This favorable survival is not intuitively expected because of the high rate of progressive disease, 5-year progression-free survival of 45%. Although the pilocytic astrocytoma is truly a benign neoplasm that can often be surgically cured with minimal surgical morbidity, this is not universally the case. Because of their location, tumors along the midline diencephalon with a similar histologic appearance often are not amenable to surgical resection. Patients with tumors in these locations often require multiple surgical interventions, repeated courses of chemotherapy, and, occasionally, irradiation. Children with tumors in these locations can experience significant tumor morbidity from the tumor and its treatments; therefore, although they are histologically consistent with LGG, they do not necessarily behave in a benign manner and patients can experience severe morbidity and/or mortality.

Ultimately, the genetic features of the tumor itself may direct therapy and correlate with outcome, but this hypothesis will be tested in future trials.

CONCLUSIONS PLGGs encompass several histologic subgroups of tumors. Most children with an LGG present with specific neurologic signs and symptoms, such as seizure or headaches. Optimal management is often guided by tumor location, size, and clinical presentation. Current management for most PLGGs includes consideration and attempt of a GTR. Survival in PLGG is generally very good, though this is influenced by degree of resection, age, and histologic classification. Current management of PLGGs continues to evolve, with advances in neurosurgical techniques, targeted chemotherapy, tailored radiation, and molecular biology discoveries, which will hopefully improve the overall quality of life and survival. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Armstrong, G.T., Conklin, H.M., Huang, S., et al., 2011. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol. 13, 223–234. Ater, J.L., Zhou, T., Holmes, E., et al., 2012. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children’s Oncology Group. J. Clin. Oncol. 30, 2641–2647. Bandopadhayay, P., Bergthold, G., London, W.B., et al., 2014. Longterm outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr. Blood Cancer 61, 1173–1179. Bergthold, G., Bandopadhayay, P., Hoshida, Y., et al., 2015. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro Oncol. 17, 1486–1496. Gutmann, D.H., 2014. Eliminating barriers to personalized medicine: learning from neurofibromatosis type 1. Neurology 83, 463–471. Listernick, R., Louis, D.N., Packer, R.J., et al., 1997. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann. Neurol. 41, 143–149. Ostrom, Q.T., Gittleman, H., Liao, P., et al., 2014. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol. 16 (4), iv1–iv63. SEER Program. SEER Cancer Statistics Review 1975–2012, Childhood Cancer by the ICCC, Age-Adjusted and Age-Specific SEER Cancer Incidence Rates, 2008–2012. accessed 8/18/15. Ullrich, N.J., 2009. Neurologic sequelae of brain tumors in children. J. Child Neurol. 24, 1446–1454. Wisoff, J.H., Sanford, R.A., Heier, L.A., et al., 2011. Primary neurosurgery for pediatric low-grade gliomas: a prospective multiinstitutional study from the Children’s Oncology Group. Neurosurgery 68, 1548–1554, discussion 1554–1555.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 127-3 T1 gadolinium-enhanced images from a 10-yearold boy.

128  Diffuse Intrinsic Pontine Glioma

Nicholas A. Vitanza, Paul G. Fisher, and Michelle Monje Deisseroth

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

BACKGROUND Since the initial report by Wilfred Harris and W.D. Newcomb nearly a century ago, the clinical outcome for children with diffuse intrinsic pontine gliomas (DIPG) has changed very little, and the 2-year overall survival remains less than 10%. As a biopsy was previously suspected to carry a significant morbidity, diagnosis over the past 2 decades has been made by magnetic resonance imaging (MRI), such that laboratory investigation has been hampered by a lack of surgical specimens. Although radiation therapy and oral steroids provide symptomatic relief and modestly prolong survival, the majority of patients survive less than a year from their onset of symptoms. However, armed with new molecular findings, made possible now through an increasing trend toward biopsy, autopsy tissue collection, and international collaboration to share these precious tissue resources, advances finally are being made against the most fatal childhood brain tumor.

EPIDEMIOLOGY DIPG affect 200 to 400 children in the United States each year, comprising approximately 10% to 15% of all pediatric central nervous system (CNS) tumors and 80% of brainstem gliomas. Peak incidence of DIPG occurs in middle childhood, with median age of diagnosis around age 7 years. Occasional cases have been reported in patients as young as 1 year or as old as 26 years, with an equal distribution between males and females.

PRESENTATION AND DIAGNOSIS The median duration of symptoms before diagnosis of a DIPG is 1 month and, although these can last for greater than a year in atypical cases, prodromes almost universally last for less than 6 months. On presentation, patients often display a classic triad of symptoms comprised of ataxia, cranial nerve palsies, and pyramidal tract signs. An abducens palsy, reflected in dysconjugate gaze and diplopia, is typically the first symptom, the most common symptom, and associated with a worse outcome. Facial nerve palsies, characterized by facial muscle weakness and asymmetry, are not uncommon. Patients with DIPG experience pyramidal tract dysfunction, resulting in weakness and hyperreflexia and can also experience dysuria, consistent with the location of the pontine micturition center. Pathologic laughter (pseudobulbar affect) can also be a symptom of patients with DIPG, including laughter as the presenting symptom, even during sleep. As these tumors frequently extend into the cerebellum at time of progression, patients often experience ataxia, dysarthria, or dysmetria. Less than 10% of patients also present with obstructive hydrocephalus due to dorsal extension of disease. Until recently, DIPG were not routinely biopsied, and diagnosis relied upon neuroimaging. Zimmerman provided the initial radiologic description of brainstem gliomas and, although this has been built upon, there remains no formal

radiologic classification. However, DIPG share some typical characteristics on magnetic resonance imaging (MRI), including infiltration of the majority of the pons, hypointense to isointense signal on T1-weighted imaging, and hyperintensity on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) (Fig. 128-1). Unlike pilocytic astrocytomas, DIPG are generally tumors that do not enhance with gadolinium contrast, except for areas of necrosis, and frequently engulf the basilar artery, which is a poor prognostic finding. A history of symptoms greater than 6 months or atypical radiographic features should prompt evaluation of a broader differential, which would include pilocytic astrocytomas, primitive neuroectodermal tumors (PNET), or much less commonly demyelinating or vascular diseases of the brainstem. On MRI, the exophytic appearance, definitive boarders, frequent mural nodule and cyst formation, and contrast enhancement can distinguish a pilocytic astrocytoma from a DIPG. The location is most frequently pontomidbrain, pontomedullary, or, less commonly, at the cervicomedullary junction and often present more indolently and have a higher association with neurofibromatosis type 1 (NF1). Histologically, pilocytic astrocytomas (WHO grade I) may display vascular proliferation and even several mitotic figures but will lack necrosis and invasion. PNET (WHO grade IV) on MRI is frequently heterogeneously enhancing with significant peritumoral edema. In up to 22% of cases, the postmortem diagnosis of PNET is made in tumors previously thought to be DIPG, though this percentage is certainly dropping with greater diagnostic techniques and better understanding of the distinct malignancies of the brainstem. Diffuse tensor imaging (DTI) fiber tracking can be used to differentiate between brainstem malignancies and demyelinating processes.

PROGNOSIS The natural course of a DIPG is swift and devastating, with a median survival of 4 months if radiation therapy is not delivered. With the advent of focal irradiation the progression free survival (PFS) has improved to 5 to 9 months with a median overall survival (OS) of only 8 to 11 months. A small subset of patients, constituting only 2% to 3%, are reported to achieve long-term survival and, though difficult to predict, may share atypical radiologic features. Otherwise, only approximately 30% of children survive beyond 1 year and less than 10% survive beyond 2 years.

HISTOPATHOLOGY The WHO grading system of diffuse, or fibrillary, astrocytomas fails to distinguish clinically significant subgroups in DIPG, which can be diffuse astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III), or glioblastomas (WHO grade IV). In fact, WHO grading is not consistent between primary lesions and metastases, and it remains unknown if the grade II or III lesions for which later histology suggests grade IV underwent evolution or if there is simply an unreconciled

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obtaining tissue for laboratory investigation and for clinical testing of novel therapeutic agents. Advances in neurosurgery have allowed for relatively safe biopsy of DIPGs, even in typical-appearing cases, and in skilled hands the morbidities are most often transient though reported in 3.9% to 20% of patients. Biopsies are increasingly performed in the setting of clinical trials at specialized medical centers and should be performed to confirm diagnosis if features are nonclassical, such as a prodrome lasting greater than 6 months and/or atypical radiologic features. The greatest immediate clinical influence of doing a biopsy to the patient would be revealing a pilocytic astrocytoma (WHO grade I) or a nonastrocytic lesion, such as PNET, which alters both the treatment and the prognosis.

DEVELOPMENTAL CONTEXT OF DIPG

Figure 128-1.  Diffuse Intrinsic Pontine Glioma (DIPG). Axial fluidattenuated inversion recovery (FLAIR) MRI.

degree of tumor heterogeneity that breeds sampling error. There does, however, seem to be a correlation between increasing histologic grade and increasing age, although this has not been confirmed to be a truly developmental phenomenon. Regardless of grade II, III or IV histology, DIPG portends incredibly high mortality.

EXTENT OF SPREAD DIPGs can infiltrate beyond the pons, commonly extending into the middle cerebellar peduncles, thalami, basal ganglia, or directly into the supratentorium. Metastatic disease is also common; one recent series identified neuraxis dissemination detected by neuroimaging in 17.3% of patients, with a median time of 15 months to the development of metastases. Metastatic disease is likely to be even more common, as a recent autopsy series of patients with DIPG revealed 63% had developed extension into their midbrain and medulla, 63% in the subventricular zone of the lateral ventricles, 56% in the thalamus and/or cerebellum, and 25% in the frontal cortex (Caretti, et al., 2014). As chemotherapy is not curative for DIPG, assessing the tumor size and its change on serial MRI scans is highly important in clinical trials with any therapeutic agents. Although their poorly defined borders often lead to interobserver variability, both FLAIR sequences and volumetric methods based on region of interest (ROI) currently provide the greatest agreement between observers. Specific MRI sequences may also be useful in disease stratification, as both increased enhancement and decreased apparent diffusion coefficient (ADC) values, derived from diffusion-weighted imaging, may coincide with more aggressive disease. Although currently not routine, fluorodeoxyglucose positron emission (FDG-PET) uptake of greater than 50% at the primary site correlated with a decreased PFS and OS, and the majority of DIPG metastases are also FDG-PET positive. Surgery had been generally deferred due to the impossibility of a gross total or meaningful subtotal resection of a lesion diffusely affecting the pons, potential morbidity associated with a biopsy, and the lack of clinical benefit to the patient in the majority of cases. Coinciding with the molecular revolution in childhood CNS tumors, there is a renewed interest in

The region-specific and age-specific nature of brainstem gliomas suggests that the underlying pathophysiology involves dysregulation of a postnatal neurodevelopmental process. Examination of normal human brainstem samples from all three brainstem regions—midbrain, pons, and medulla—in subjects aged 1 day to 19 years revealed a population of neural precursor cells, expressing the oligodendroglial lineage marker Olig2, restricted to the ventral brainstem. This precursor cell type, characterized by immunostaining for the primitive neural cell markers nestin, vimentin, and Olig2 and by a distinct morphology with long thin processes in a bipolar arrangement, is present in the ventral brainstem during infancy and then wanes by 2 years of age. In the human pons, this cell type again increases in density in middle childhood, peaking around age 6 (Monje, et al., 2011). This second peak in the ventral pontine precursor cell population corresponds strikingly with the incidence of DIPG, suggesting a candidate Olig2 + cell of origin for DIPG in the oligodendroglial lineage. In contrast, this cell type is conspicuously absent from the childhood midbrain, a region in which high-grade gliomas essentially never occur (Monje, et al., 2011). In a recent study incorporating MRI-based morphometric and histologic analyses, robust proliferation of Olig2 + progenitors and increased myelination of white matter tracts were found to accompany a striking postnatal volume expansion of the ventral pons observed from birth to middle childhood. A putative oligodendroglial lineage precursor cell of origin for DIPG fits well with observations of PDGFRA expression and signaling in DIPG cells (Monje, et al., 2011). Also consistent with the idea that DIPG originate from an Olig2 + neural precursor cell, analysis of postmortem DIPG specimens reveal that most express the markers Olig2 and/or Sox2 (Monje, et al., 2011; Ballester, et al., 2013).

MOLECULAR CHARACTERISTICS OF DIPG The molecular investigation of DIPG has been limited historically by the paucity of tissues samples; however, as more specimens have become available for molecular analyses, it has become clear that DIPGs and other pediatric high-grade glioma (HGG) are genomically distinct from adult HGG. The most revolutionary insight gleaned from whole exome and whole genome sequencing studies has been the recognition of specific mutations affecting genes encoding for histone H3 in pediatric HGG, with midline HGG (i.e., DIPG and thalamic HGG) exhibiting H3K27M mutations affecting the genes encoding either H3.3 or H3.1, and cortical HGG exhibiting H3K34R/V mutations (Khuong-Quang, et al., 2012; Wu, et al., 2012). In DIPG, about 80% of tumors exhibit this K27M mutation. H3.3K27M mutations tend to occur in conjunction with p53 aberrations, whereas H3.1K27M tends to coincide



with ACVR1 activating mutations and occurs in patients who tend to be younger females (Taylor, et al., 2014). The substitution of methionine for lysine at position 27 of the histone 3 N-terminal tail results in pan-hypomethylation of K27 in all histone H3 variants, despite the fact that heterozygous mutation in one copy of a histone H3 gene (H3F3A for H3.3 or Hist1H3B for H3.1) accounts for only approximately 10% of total cellular histone H3 (Lewis, et al., 2013). This dominant effect of the mutant histone is due to “poisoning” of the EZH2 methyltransferase by the methionine residue, which binds to EZH2 and sequesters it at the mutant histone and suppresses the polycomb repressive complex 2 (PRC2), an epigenetic gene silencer. As a result of pancellular histone H3 hypomethylation, broad epigenetic dysregulation of gene expression occurs, resulting in a “K27M” gene expression signature exhibiting dysregulation of numerous oncogenic pathways (Chan, et al., 2013). In terms of other genomic aberrations, DIPGs frequently display chromosomal aberrations with the most common gain being of 1q in 13% to 43% of cases and the most com­mon loss being of 16q in about 25% of cases. Other common chromosomal gains include 2p, 2q, 8q, and 9q, while other common losses include 14q, 17p, and 20p. DIPG also exhibits inactivating mutations of p53 (40% to 77%) and PTEN (10% to 54%), which are associated with a worse prognosis in pediatric HGG (Khuong-Quang, et al., 2012). Unlike adult HGG, DIPG does not harbor deletions of CDKN2A/B, but 30% will have gains in other cell-cycle regulatory components, such as CDK4, CDK6, of D-type cyclins. As noted previously, 24% of patients with DIPG harbor mutations in ACVR1, the gene encoding the receptor serine/threonine kinase ALK2, which occurs twice as commonly in female patients, is associated with a better overall survival, and occurs in the setting of histone H3.1 mutations (Fontebasso, et al., 2014; Taylor, et al., 2014; Wu, et al., 2014). Although EGFR amplifications appear infrequent, several series have shown a majority of pediatric DIPG exhibit immunopositivity for EGFR, though this may be tempered by the fact that EGFR expression can be induced by irradiation, which many of these patients received. Radiation treatment has been shown to correlate with PDGFRA expression, possibly explaining the variable frequency of PDGFRA expression, ranging from 15% to the majority of patients in varying studies (KhuongQuang, et al., 2012). Interestingly, amplifications of PDGFRA and loss of PTEN appear mutually exclusive from PI3KCA mutations, although PDGFRA amplifications occur entirely in the setting of histone H3.3 mutations (Khuong-Quang, et al., 2012). Aurora B, a cell-cycle regulatory kinase, has been shown to be overexpressed in two-thirds of DIPG. Aurora kinase B acts both by recruitment of checkpoint protein complexes and by phosphorylation of mitotic centromere-associated kinesin (MCAK), a controller of spindle microtubule-kinetochore attachments during mitosis. Furthermore, aurora kinases also phosphorylate histone H3, offering a layer of epigenetic control. Therefore as a high percentage of DIPG have cell-cycle dysregulation, either through deletion of p53 or aberrant expression of other cell-cycle kinases or cyclins; the overexpression of aurora kinase B may contribute to either DIPG tumorigenesis or tumor maintenance. Several proteins have also been associated with DIPG, most interestingly clusterin, encoded by CLU, and talin 1, encoded by TLN1. Clusterin is a secreted chaperone protein associated with apoptosis and malignant transformation. Talin 1 is an actin binding protein, already suspected to promote cell migration and adhesion in gliomas, which is a proposed biomarker for colon cancer and whose loss of function increases chemotherapy sensitivity in resistant breast cancer.

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Ultimately, DIPG likely are comprised of distinct molecular subgroups, differentiated by predominant molecular pathways, though current subgrouping proposals have limited power due to small numbers of samples (Buczkowicz, et al., 2014). There may be separate MYCN oncogene and hedgehog pathway groups, which form distinct clusters through mRNA expression profiling and can be regularly separated by immunohistochemistry as hedgehog pathway lesions demonstrate PTCH1 positivity and GLI1 nuclear expression. DIPG may also be divided into groups characterized by two smaller subgroups of MYCN overexpression and genetically stable lesions, as well as a third larger group with histone H3K27 mutations (Buczkowicz, et al., 2014). Interestingly, other midline gliomas, especially thalamic gliomas and WHO grade III and IV spinal cord gliomas, also display mutations in histone H3, suggesting potential benefit to classifying together as “diffuse midline gliomas, H3-K27M mutants” (Shankar, et al., 2016).

CURRENT TREATMENT The only treatment modality that has consistently prolonged survival in DIPG is radiation therapy (RT), most frequently delivered conformally to the tumor at 54 Gy divided in 1.8 Gy daily fractions over 6 weeks. Hyperfractionated RT at doses as high as 7800 cGy has been attempted with no improvement in survival and likely prolongation of steroid requirement. Hypofractionated RT of 39 Gy delivered over 13 fractions, however, appears to have comparable results to standard dosing and significantly decreased burden on patients and families, especially in the patient’s requiring sedation for their treatments. However, a further hypofractionated approach with an elevated daily dose of 5 Gy for 5 days increased necrosis and possibly shortened overall survival. Although many studies have examined the benefit of cytotoxic and myeloablative chemotherapy for patients with DIPG, no standard regimen extends overall survival. Chemotherapy during radiation therapy has not provided a clear benefit, as Pediatric Oncology Group’s POG 9239 trial of cisplatin during RT showed an unexpected worsening of outcome and radiosensitizing agents failed to prolong survival. The Istituto Nazionale dei Tumori in Milan, Italy, attempted multiple, ambitious treatment plans including: etoposide, cytarabine, ifosfamide, cisplatin, and dactinomycin given with RT in study 1; cisplatin, etoposide, vincristine, cyclophosphamide, high-dose methotrexate, and then autologous stem cell transplant after thiotepa, followed by RT and maintenance with vincristine and lomustine in study 2; cisplatin and vincristine along with isotretinoin and RT in study 3; and vinorelbine during RT in study 4. The 1- and 2-year OS were 43% and 21%, respectively, with no differences amongst studies and with the two longterm survivors never having biopsy confirmation. German trials using oral trofosfamide and etoposide (HIT-GBM-A), intravenous (IV) carboplatin, etoposide, and ifosfamide (HITGBM-B), and IV carboplatin, etoposide, ifosfamide, and vincristine (HIT-GBM-C) resulted in a 1- and 2-year OS of 39.9% and 9.2%, respectively. Intensive chemotherapy with tamoxifen, carmustine, cisplatin, and high-dose methotrexate with radiation given at time of progression had the greatest 1-year OS of 70% but showed no difference in long-term OS, and the average length of stay for chemotherapy and/or complications was 43 days. Temozolomide also has not improved outcomes in either conventional or metronomic dosing. Several phase I studies utilizing more targeted agents, including imatinib, erlotinib, tipifarnib, and vandetanib, have been completed and patients enrolled in a phase II study of gefitinib, an EGFR-inhibitor, by the Pediatric Brain Tumor Consortium (PBTC) had 1- and 2-year OS of 56.4% and 19.6% OS, respectively.

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EMERGING THERAPEUTIC STRATEGIES Although the aberrant genetic signature produced by histone H3 mutations—also found in other pediatric HGG and a subgroup of posterior fossa ependymomas (PFA-CIMP +)—may share some of the responsibility for radiation resistance and poor prognosis, it may also provide actionable targets with epigenetic agents. JMJD3 and UTX, two histone H3K27 demethylases, may also be targeted in order to restore methylation to H3K27 to the nonmutant histones in the cell. GSKJ4, a selective histone demethylase inhibitor, has already been shown to inhibit JMJD3, increase H3K27me3 levels, and subsequently extend survival in H3K27M-mutant orthotopic xenograft brainstem tumor models. Therapies targeted at molecular anomalies specific to the development of this tumor afford hope for some improvement in the course or survival of this challenging cancer. Acknowledgment Kristen Yeom, MD, Assistant Professor of Radiology, Department of Radiology, Pediatric Radiology, Stanford University School of Medicine, provided the MRI photographs comprising Figure 128-2.

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Ballester, L.Y., Wang, Z., Shandilya, S., et al., 2013. Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am. J. Surg. Pathol. 37 (9), 1357–1364. Buczkowicz, P., Hoeman, C., Rakopoulos, P., et al., 2014. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat. Genet. 46, 451–456. Caretti, V., Bugiani, M., Freret, M., et al., 2014. Subventricular spread of diffuse intrinsic pontine glioma. Acta Neuropathol. 128, 605–607. Chan, K.M., Fang, D., Gan, H., et al., 2013. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985–990.

Fontebasso, A.M., Papillon-Cavanagh, S., Schwartzentruber, J., et al., 2014. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat. Genet. 46, 462–466. Khuong-Quang, D.A., Buczkowicz, P., Rakopoulos, P., et al., 2012. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439–447. Lewis, P.W., Muller, M.M., Koletsky, M.S., et al., 2013. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861. Monje, M., Mitra, S.S., Freret, M.E., et al., 2011. Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proc. Natl. Acad. Sci. U.S.A. 108, 4453–4458. Shankar, G.M., Lelic, N., Gill, C.M., et al., 2016. BRAF alteration status and the histone H3F3A gene K27M mutation segregate spinal cord astrocytoma histology. Acta Neuropathol. 131, 147–150. Taylor, K.R., Mackay, A., Truffaux, N., et al., 2014. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat. Genet. 46, 457–461. Wu, G., Broniscer, A., Mceachron, T.A., et al., 2012. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet. 44, 251–253. Wu, G., Diaz, A.K., Paugh, B.S., et al., 2014. The genomic landscape of diffuse intrinsic pontine glioma and pediatric nonbrainstem high-grade glioma. Nat. Genet. 46, 444–450.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 128-2 MRI imaging of pediatric pontine lesions that were not DIPG. Dysplasia seen on (A) axial T2 FLAIR and (B) axial T1 with contrast. Pilocytic astrocytoma on (C) axial T2 FLAIR and (D) sagittal T2. Ganglioglioma seen on (E) axial and (F) sagittal T1. Leukodystrophy secondary to metabolic disease seen on (G) axial T2 and (H) sagittal T2 FLAIR. (Courtesy of Kristen Yeom, MD, Assistant Professor of Radiology, Department of Radiology, Pediatric Radiology, Stanford University School of Medicine.)

129  Atypical Teratoid/Rhabdoid Tumors Alyssa T. Reddy, Susan N. Chi, and Jaclyn A. Biegel

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor that occurs predominantly in very young children. The tumor was first described in 1987 by Lucy Rorke and colleagues and officially recognized by the World Health Organization as a WHO grade IV neoplasm in 1993 (Rorke, et al., 1995). Before this distinct recognition, the tumor was often misdiagnosed as medulloblastoma or another embryonal tumor. AT/RT is the first pediatric brain tumor with a consistent known genetic alteration. In recent years, identification of AT/RT has been dramatically simplified with an immunohistochemical assay for the SMARCB1 (also referred to as INI1, hSNF5, BAF47) gene product, the aberrant tumor suppressor gene found in the majority of AT/RTs (Judkins, et al., 2004). Early accounts of the disease reported it to be rapidly fatal in all but a very small minority of patients. Recent prospective studies that incorporated intensified multimodal therapy have reported improved long-term survival rates approaching 50% (Chi, et al., 2009). Although these results are encouraging, much work remains to be done to understand why durable disease control is not obtained for roughly half of the patients with current therapies and to also identify therapies with less toxicity. A better understanding of the function of the SMARCB1 gene will hopefully improve our understanding of the disease and lead to specific targeted treatment.

HISTORICAL BACKGROUND AND INCIDENCE In the late 1980s, a distinctive brain neoplasm characterized by diverse histologic components was identified and termed atypical teratoid tumor of infancy. The tumor contained mixed elements and had a rapidly fatal course. It took careful inspection of multiple fields to separate this tumor from other embryonal tumors. As more cases were recognized, it was noted that the tumors contained areas of rhabdoid cells in addition to areas of primitive neuroectodermal, mesenchymal, or epithelial cells. The tumor was subsequently renamed atypical teratoid/rhabdoid tumor (AT/RT) in the mid-1990s (Rorke, et al., 1995) and given its own distinction by the World Health Organization as a Grade IV embryonal neoplasm in 1993. Before being recognized as a distinct tumor, AT/RT was often misdiagnosed as medulloblastoma, primitive neuroectodermal tumor, or choroid plexus carcinoma. A heightened awareness of AT/RT led neuropathologists to more extensively examine embryonal tumors in young patients to look for mixed cellular histology and common immunophenotypic patterns, even in the absence of a clear rhabdoid component. The first patients reported with AT/RT all died from their disease within a year of diagnosis despite surgery and chemotherapy. Most patients were initially treated either on or according to protocols that treated a variety of malignant brain tumors. It was not until the 2000s that prospective clinical trials specific to AT/RT were initiated. AT/RT was initially thought to be extraordinarily rare. With the increased clinical awareness of this tumor and the utility

of the immunohistochemistry assay for SMARCB1, it is now estimated that AT/RT accounts for at least 3% of brain tumors in children. All published series report a peak incidence in very young children, less than 3 years of age. Based on prior Pediatric Oncology Group and Pediatric Brain Tumor Consortium studies, approximately 15% of children less than 36 months with malignant brain tumors have AT/RT. In one series the ratio of AT/RT to primitive neuroectodermal tumors was found to be 1 to 3.8 (26%) among patients younger than 3 years of age. A recent Austrian study of 311 newly diagnosed patients demonstrated that AT/RT was the sixth most common entity (6.1%). The number of reported patients with AT/RT has increased 5.5-fold in an analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data from 1992 to 2008, likely reflecting greater awareness and improved diagnostic techniques (Buscariollo, et al., 2012). Although it is much less common in older children and adults, AT/RT has been reported with increasing frequency in these populations as well. There are several names given to the mutated gene in AT/ RT. It is referred to throughout this chapter as SMARCB1 as that is its official Human Genome Organization (HUGO) name (Kim and Roberts, 2014). Other names that have been used for the gene are SPF5, INI1, and BAF47.

CLINICAL PRESENTATION AND   RADIOGRAPHIC FINDINGS Due to the aggressive nature of AT/RT, the vast majority of patients present with very short histories of progressive symptoms that can be measured in days to weeks. Because AT/RT can arise anywhere in the nervous system, neurologic signs and symptoms are nonspecific and referable to the tumor location. About half the patients have tumors that arise in the posterior fossa, and they often present with symptoms related to hydrocephalus, particularly early morning headaches, vomiting, and lethargy. Ambulatory children may have ataxia and other cerebellar dysfunction. Nonspecific symptoms such as lethargy, regression of milestones, and seizures are often seen in very young children with cortical tumors. Focal weakness may also be seen especially in a child who is old enough to cooperate with the examination. Because infants have open sutures and fairly pliable skulls, a rapidly enlarging head size should alert the clinician to evaluate the patient for a brain tumor as this may be the only sign at presentation. Rarely, AT/ RT can arise primarily in the spinal cord, and those patients can present with back pain, diplegia, or bowel and bladder dysfunction. Imaging characteristics are helpful but also nonspecific for AT/RT. All patients with suspected AT/RT should undergo MRI imaging of brain and spine before surgery unless emergent resection is medically necessary. On T1-weighted MRI, the tumor mass is typically isointense with frequent hyperintense foci secondary to intratumoral hemorrhage. On postgadolinium images, AT/RT does vividly take up contrast but in a heterogeneous pattern (Fig. 129-1). On T2-weighted and flair MRI, the tumor appears heterogeneous as a result of the

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Figure 129-1.  Axial gadolinium enhanced T1 brain MRI of a 12-yearold patient with bifrontal AT/RT. The mass has a heterogeneous pattern with more enhancement around the margins and central hypovascularity suggesting necrosis. The patient presented with 1-month history of progressive headaches, morning vomiting, and personality changes.

Figure 129-4.  Axial diffusion-weighted image (DWI) of an 18-monthold patient with posterior fossa AT/RT. The image demonstrates increased signal intensity (restricted diffusion) within the tumor, related to increased cell density of the AT/RT.

mixture of tumor cellularity, hemorrhage, necrosis, and cysts (Fig. 129-2). There is often significant peritumoral edema due to rapid growth and high cellular turnover. The tumors often invade into brain parenchyma. The CT appearance is typically that of a large hyperdense mass that enhances intensely with contrast. Dissemination throughout the neuraxis at diagnosis is not uncommon and occurs in approximately 25% of cases (Fig. 129-3) (Packer, et al., 2002). MR spectroscopy is similar to primitive neuroectodermal tumors with marked elevation of choline and low or absent N-acetyl-aspartate and creatine. Other MR sequences such as diffusion weighted imaging (DWI) may augment the suspicion that a tumor is highly cellular. Densely cellular neoplasms have a greater restriction of water diffusion than less dense tissues and therefore give rise to increased signal on DWI (Fig. 129-4).

HISTOPATHOLOGY As previously mentioned, the pathologic diagnosis of AT/RT requires careful histologic examination of multiple fields of tumor and application of a panel of immunohistochemical markers. Whereas some tumors are composed almost entirely of rhabdoid cells, the more typical finding is that of sheets of rhabdoid cells adjacent to areas of primitive neuroectodermal cells, mesenchymal cells, and/or epithelial cells, as shown in the hematoxylin and eosin (H and E) stained section in Figure 129-5. Immunohistochemical features can help to identify the disease but vary depending on the cellular composition of the tumor. Rhabdoid cells express vimentin, epithelial membrane antigen (EMA), and smooth muscle actin (SMA). The primitive neuroectodermal cells variably express neurofilament protein (NFP), glial fibrillary acidic protein (GFAP), keratin, or desmin. MIB-1 is a marker of cellular proliferation. Not surprisingly, MIB-1 is extremely high in AT/RT with labeling

Figure 129-5.  Hematoxylin and eosin (H and E) stain of AT/RT demonstrates densely packed rhabdoid cells intermixed with areas of primitive neuroectodermal cells. There is a clump of primitive neuroectodermal cells, so called “small blue cells” in the middle of the picture (arrow).

indices of 50% to 100% (Fig. 129-6). Development of an immunohistochemical stain with a SMARCB1 (BAF47) antibody has greatly assisted the identification of AT/RT (Judkins, et al., 2004). There should be no staining with the antibody in the nuclei of tumor cells due to homozygous inactivation of the gene product (Fig. 129-7).

GENETICS OF AT/RT Cytogenetic studies of AT/RT demonstrate simple karyotypes, with loss of all or part of chromosome 22 as the primary and often solitary finding. The deletions target the SMARCB1 gene



Figure 129-7.  Immunohistochemical staining for the SMARCB1 protein is absent in AT/RT tumor nuclei. Nonneoplastic tissue including blood vessels and inflammatory cells serve as positive internal control (dark brown) with retained nuclear reactivity. (Photo courtesy of Rong Li, MD.)

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other members of the SWI/SNF complex, may also predispose carriers to schwannomatosis, and in fact two-thirds of patients with familial schwannomatosis have germline mutations in SMARCB1. Of note, whole gene deletions of SMARCB1, or 22q11.2 deletions that include SMARCB1, appear to be restricted to patients with rhabdoid tumors. There are families in which a carrier parent had one or more schwannomas, but the offspring had AT/RT, suggesting that there is a window in development in which the risk of rhabdoid tumor is high, which diminishes with age. Long-term survivors of AT/RT may therefore be at risk for additional primary rhabdoid tumors, as well as schwannomas and other malignant tumors. The latency for second tumors may be as long as 15 or more years. SMARCB1 is a member of the SWI/SNF chromatin-remodeling complex, which acts in an ATP-dependent manner to remodel nucleosomes, thus allowing or restricting transcription factor and other protein complexes to bind to the regulatory regions of target genes. The specific function of SMARCB1 as it relates to malignant transformation, however, is still unknown. Numerous cell-signaling pathways are altered in primary rhabdoid tumors, thus providing a variety of potential biologic targets for therapy (Kim and Roberts, 2014).

STAGING AND THERAPEUTIC INTERVENTIONS in chromosome band 22q11.2, which demonstrates biallelic mutations, deletions, or intragenic duplications in up to 98% of AT/RTs (Biegel, et al., 1999). The homozygous inactivation of the gene leads to loss of expression of the protein, which is the basis for the diagnostic immunohistochemistry assay noted previously, showing loss of nuclear expression of SMARCB1 in the tumor cells. Loss of SMARCB1 expression has now been reported in a variety of CNS malignancies, such as cribriform neuroepithelial tumor; therefore the assay must be performed in the setting of careful histologic evaluation and assessment of other clinical presenting features. The most common alterations of SMARCB1 are homozygous losses, due to monosomy 22 and/or partial 22q deletions; loss of one copy of SMARCB1 and a mutation in the remaining allele; and deletion or mutation followed by a copy number loss of heterozygosity event such as loss of the normal chromosome 22 and duplication of the remaining homologue. Biallelic mutations, however, are very uncommon. Whole exome sequencing studies of primary rhabdoid tumors have shown that this group of tumors has the lowest total number of mutations among all tumors examined to date. Based on the genomic analyses, loss of SMARCB1 alone appears to be sufficient for tumorigenesis. SMARCB1 functions as a classic tumor suppressor gene in AT/RT. A germline mutation or copy number alteration is present in up to 35% of patients, which predisposes individuals to rhabdoid tumors of the kidney or soft tissues, as well as AT/RT. Loss of the remaining SMARCB1 allele is a somatic, or acquired, event. Patients may present with multiple primary tumors at diagnosis, strongly implicating the presence of a germline alteration. Careful staging workups for all patients with newly diagnosed AT/RT must therefore include abdominal ultrasound or whole body imaging. Germline mutations, as well as intragenic gains or losses of one or more exons of the gene, may be inherited, often from an unaffected carrier, whereas whole gene deletions are typically de novo, thus reducing the risk to other family members. Germline mutations may be mosaic, affecting only certain cells in the body, and gonadal mosaicism may lead to the development of rhabdoid tumors in siblings even when neither parent appears to be a carrier. Genetic counseling for all families in which a child has presented with a rhabdoid tumor is therefore highly recommended. Germline mutations in SMARCB1, as well as

The initial staging evaluation for all patients should include an MRI of the brain unless emergent surgery is necessary. Preoperative MRI with and without contrast is important to assess the extent of disease both at primary and distant sites. A postoperative MRI should be done within 48 hours of surgery to confirm extent of resection. MRI of the whole spine should also be done preoperatively or within 48 hours of surgical resection. These scans will help the neurooncologist and radiation oncologist formulate treatment plans and are critically important to the care of the patient. A lumbar puncture to obtain cerebrospinal fluid should be obtained 7 to 10 days after surgery to look for disease dissemination, unless medically contraindicated. Molecular genetic analysis of the primary tumor and blood to look for a germline SMARCB1 alteration and abdominal ultrasound or full body imaging are recommended at diagnosis given the risk of concurrent rhabdoid tumors in patients with germline mutations. There is general consensus that aggressive multimodal therapy is necessary to treat AT/RT, but standard-of-care guidelines have not been established. Published series and casereports include a variety of multifaceted approaches that include combinations of surgery, conventional and high-dose chemotherapy, and radiation. Neurosurgical tumor resection is usually the first intervention for patients and is necessary to establish the diagnosis. In some cases, the tumor may be so vascular or located in a very eloquent area of brain that only a biopsy is feasible. A prospective clinical trial and retrospective data available from the AT/RT registry demonstrate that patients who have had a gross total resection (GTR) have a longer disease-free and overall survival (Chi, et al., 2009; Hilden, et al., 2004). The Canadian Pediatric Brain Tumor Consortium reported in their population-based registry that patients who achieved a GTR had a better survival with a 2-year overall survival of 60% compared with 21.7% for patients who underwent less than GTR (p = 0.03) (LafayCousins, et al., 2012). However, only a third of these patients had a GTR. Due to the invasive nature of AT/RT, complete resection may not be possible, as it may present unacceptable risk to the patient. It has been estimated that less than onethird of patients have tumors that are amenable to complete resection. A less invasive tumor may be biologically different and influence outcome. The goal of surgery should be to

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remove as much tumor as is deemed safely possible by the surgeon. In the case of a highly vascular tumor that cannot be safely resected at diagnosis, treatment with chemotherapy may decrease vascularity and improve the surgeon’s ability to safely resect the tumor. Consideration of “second look surgery” should be given in cases in which complete resection is not possible at the time of diagnosis. Surgery also provides tumor tissue for diagnostic and research purposes. It is highly recommended that fresh frozen tissue be obtained as evolving sequencing of tumors is likely to yield both prognostic and therapeutic information in the future.

CHEMOTHERAPY Given the very young age of most patients with AT/RT, chemotherapy has been a mainstay of postsurgical therapy. Because of the historical misdiagnosis of AT/RT, in the earliest reports, treatment regimens designed for other CNS neoplasms were utilized in patients with AT/RT. Most commonly, these were regimens designed for embryonal tumors (e.g., medulloblastoma, supratentorial primitive neuroectodermal tumor). Even once AT/RT was more readily recognized, the regimens employed were designed with chemotherapy to delay or exclude radiotherapy altogether (i.e., “baby brain” protocols) because of the young age at which most children with AT/RT were diagnosed. The overall results of many “baby brain” chemotherapy protocols, however, were generally disappointing, although the ability to defer radiation therapy in subsets of patients was an important advance. Consequently, the generally accepted outcome for patients with AT/RT treated with standard chemotherapy regimens is dismal with median survival time reported between 6 to 11 months. Information presented at a National Cancer Institute Workshop in 2002 incorporating data from a national rhabdoid tumor registry demonstrated a median survival of approximately 8.5 months (Packer, et al., 2002). In a review of 32 infants and children treated for CNS AT/RT, treatment was highly variable but typically included multimodality treatment, including surgery, radiation, and chemotherapy (Hilden, et al., 2004). Median survival in this analysis was 6.5 months. A similar retrospective study of 31 children treated at St. Jude Children’s Research Hospital reported equally dismal outcomes for children under the age of 3 years, with 2-year eventfree (EFS) and overall survival (OS) of 11% and 17%, respectively (Tekautz, et al., 2005). For children older than 3 years, survival outcomes were much more encouraging, likely due to the inclusion of radiation therapy and high-dose alkylator chemotherapy agents. In two case series, several patients with newly diagnosed AT/RT achieved prolonged remission after surgery, radiation therapy, and chemotherapy based upon a protocol for children with rhabdomyosarcoma with parameningeal extension (Intergroup Rhabdomyosarcoma Study-III or IRS-III, Regimen 36). Since these initial reports, several investigators have shown that multiagent chemotherapy containing the anthracycline doxorubicin, the backbone chemotherapeutic agent for IRS-III, can be efficacious. Because AT/RT often shows leptomeningeal dissemination, intrathecal chemotherapy has been employed as a method of delivering local treatment to these areas. The first prospective clinical trial for children with newly diagnosed AT/RT using an intensive multimodality approach, systemic and intrathecal chemotherapy, and age-adapted radiation therapy, based on the IRS-III regimen, demonstrated the highest event-free and overall survivals to date, with 2-year progression-free survival (PFS) and overall survival (OS) at 53% and 70%, respectively (Chi, et al., 2009). Long-term survival outcomes have remained encouraging.

High-dose chemotherapy (HDC) with stem cell rescue is a strategy that allows higher doses of cytotoxic agents to be given, and this approach has also shown efficacy in treating AT/RT. The “head start” chemotherapy protocols used highdose methotrexate as a key component to its chemotherapy backbone before its consolidative stem-cell rescue. Several investigators have shown that long-term survival is achievable using this approach. The Canadian Pediatric Brain Tumor Consortium reported that 9 of the 18 patients who received various HDC regimens were alive at a median follow up time of 40.8  months (10 to 90) from diagnosis (Lafay-Cousin, et  al., 2012). HDC was associated with a significant survival benefit with a 2-year overall survival of 47.9% (plus or minus 12.1) versus 27.3% (plus or minus 9.5) for the conventional chemotherapy group (p  =  0.036). The Children’s Oncology Group (COG) conducted a pilot study, 99703, to treat a variety of malignant brain tumors, including AT/RT, which incorporated three cycles of conventional chemotherapy with cyclophosphamide, etoposide, vincristine, and cisplatin, followed by three high dose cycles of carboplatin and dose escalation of thiotepa with stem cell transplants (Cohen et al., 2015). This study demonstrated feasibility of this approach and improved survival. The current national Children’s Oncology Group phase III study (ACNS0333) utilizes the chemotherapeutic backbone of 99703 with the additional of high-dose methotrexate during induction and conformal field radiation therapy. The study accrued 70 patients and is currently in analysis. For 55 patients treated on the study who were younger than 36 months at diagnosis, the 2 year event free and overall survival are 39% and 48% respectively. For 11 patients greater than 3 years of age, the 2 year event free and overall survival are 60% and 80% (Reddy et al., 2016). Given the very young age of these patients, these results are also very encouraging.

RADIATION The vast majority of AT/RT survivors in the literature have received some form of radiation therapy as a component of their treatment and its positive effect on long-term survival has been reported in several series (Hilden, et  al., 2004; Tekautz, et  al., 2005; Chi, et  al., 2009). The most recent compelling evidence comes from analysis of the National Cancer Institute’s SEER database, which identified 144 patients with AT/RT from 1973 to 2008 (Buscariollo, et  al., 2012). As expected, the majority of patients (82%) were less than age 3 years and approximately one-third of patients received radiation. The median overall survival (OS) of patients who did not receive radiation therapy was 6 months. For those who had received some form of radiation as part of their primary therapy, the mean overall survival had not been reached at the time patients were reported. There was an increased use of radiation in young children after 2005. Both the IRSIII and COG trials, ACNS0333, mentioned in the previous section, both included conformal radiation for all patients. There are some long-term survivors of AT/RT reported in the literature who were treated with HDC but did not receive radiation. Until we are better able to risk-stratify patients, there is good evidence that focal radiation coupled with intensive chemotherapy provides the best chance at durable control of AT/RT.

TOXICITY OF THERAPY The intensive therapeutic regimens carry potential morbidity, and a few deaths due to treatment toxicity have been reported. It is very well established that craniospinal radiation has significant deleterious effects on the developing nervous system,



and its use in young children gives many clinicians great angst. Advanced radiation techniques, specifically 3D conformal therapy and the wider availability of proton beam radiation, are showing decreased long-term neurologic sequelae and less effect on cognitive function. Chemotherapy, surgery, and the tumor itself also contribute to the long-term neurologic sequelae. Intensive chemotherapy also has significant longterm systemic sequelae and the risk of major organ dysfunction. As more patients are long-term survivors of AT/RT, their long-term cognitive, neurologic, endocrine, and systemic function will need to be monitored. Early and ongoing intervention from psychologists, teachers, and therapists is highly important to help patients maximize their potential. Although treatment will likely continue to be refined, the importance of these posttreatment interventions cannot be overemphasized.

FUTURE DIRECTIONS As current treatment regimens are highly intensive and consequently highly toxic, further improvements in outcome will require improved understanding of the biology of this tumor and targeting of therapy to the tumor. Extensive laboratory investigations have been carried out to better understand the tumorigenesis of AT/RT as well as to identify potential therapeutic targets. Preclinical testing of rhabdoid cell lines and xenografts has shown data that are provocative with regard to the chemo-responsiveness of AT/RT. These have given biologic rationale to early experimental clinical trials with small molecule inhibitors, for example, targeting HDAC, Aurora a kinase, CDK, and EZH2. What remains a limitation, however, is the lack of genetically engineered or orthotopic CNS AT/ RT animal models that reflect the human condition. Current modern technologies, including whole exome and genome sequencing and epigenetic assays, have propelled our understanding of AT/RT but will require validation. Undoubtedly, future clinical studies will incorporate targeted approaches based on an improved biological understanding of these tumors.

CONCLUSIONS Since first being recognized as a distinct tumor in the late 1980s, significant strides have been made in understanding the biology and treatment of AT/RT. It is the first pediatric brain tumor for which a common genetic abnormality has been identified. Immunohistochemical antibody staining for the SMARCB1 gene product has simplified identification of the tumor. Although the function of SMARCB1 is not yet known, modern and evolving technologies will likely help identify targeted therapies. Once a disease that was considered to be universally fatal, recent intensive multimodal regimens have improved long-term overall survival for patients with AT/RT to approximately 50%. Genetic sequencing of tumors in recent trials may also help identify prognostic factors. There is optimism that targeted therapy can be combined with more traditional modalities to improve survival rates. Ideally, targeted therapies will also allow for reduction of more conventional therapies for at least some patients. Although much work remains to be done, continued multidisciplinary collaboration of preclinical and clinical researchers will likely continue to unravel this high aggressive tumor.

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REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Biegel, J.A., Zhou, J.Y., Rorke, L.B., et al., 1999. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59 (1), 74–79. Buscariollo, D.L., Park, H.S., Roberts, K.B., et al., 2012. Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a surveillance, epidemiology, and end results analysis. Cancer 118 (17), 4212–4219. Chi, S.N., Zimmerman, M.A., Yao, X., et al., 2009. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J. Clin. Oncol. 27 (3), 385–389. Cohen, B.H., Geyer, J.R., Miller, D.C., et al., 2015. Pilot Study of Intensive Chemotherapy With Peripheral Hematopoietic Cell Support for Children Less Than 3 Years of Age With Malignant Brain Tumors, the CCG-99703 Phase I/II Study. A Report From the Children’s Oncology Group. Pediatr. Neurol. 53 (1), 31–46. Hilden, J.M., Meerbaum, S., Burger, P., et al., 2004. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J. Clin. Oncol. 22 (14), 2877–2884. Judkins, A.R., Mauger, J., Ht, A., et al., 2004. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am. J. Surg. Pathol. 28 (5), 644–650. Kim, K.H., Roberts, C.W., 2014. Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth. Cancer Genet. 207 (9), 365–372. Lafay-Cousin, L., Hawkins, C., Carret, A.S., et al., 2012. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Pediatric Brain Tumor Consortium experience. Eur. J. Cancer 48 (3), 353–359. Packer, R.J., Biegel, J.A., Blaney, S., et al., 2002. Atypical teratoid/ rhabdoid tumor of the central nervous system: report on workshop. J. Pediatr. Hematol. Oncol 24 (5), 337–342. Reddy, A.T., Strother, D., Judkins, A., et al., 2016. Treatment of Atypical Teratoid Rhabdoid Tumors (ATRT) of the Central Nervous System with Surgery, Intensive Chemotherapy, and 3-D Conformal Radiation (ACNS0333). A Report from the Children’s Oncology Group. Abstracts from the 17th International Symposium on Pediatric Neuro-Oncology, Liverpool, UK. Neuro. Oncol. Rorke, L.B., Packer, R., Biegel, J., 1995. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J. Neurooncol. 24 (1), 21–28. Tekautz, T.M., Fuller, C.E., Blaney, S., et al., 2005. Atypical teratoid/ rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J. Clin. Oncol. 23 (7), 1491–1499.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 129-2 Axial T2 MRI of a 4-month-old patient with right cortical AT/RT. Fig. 129-3 Sagittal gadolinium enhanced T1 cervical and thoracic spine MRI of a 2-year-old patient recently diagnosed with cortical AT/RT. Fig. 129-6 MIB-1, a marker of cellular proliferation, stains actively proliferating tumor cells dark brown. The MIB-1 labeling index is very high in AT/RT. It is approximately 70% in this case. (Photo courtesy of Rong Li, MD.)

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Nervous System Germinoma and Other Germ 130  Central Cell Tumors Jeffrey C. Allen and Ute K. Bartels An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Germ cell tumors (GCTs) of the central nervous system (CNS) are a heterogeneous group of benign and malignant tumors currently classified as germinoma, teratoma (mature, immature, and teratoma with malignant transformation), and nongerminomatous germ cell tumors (NGGCTs). NGGCTs can include either a single tumor type or combinations of embryonal carcinoma, yolk sac tumors (or endodermal sinus tumors), choriocarcinoma, teratoma, and Germinoma. The term NGGCT is considered inaccurate, and efforts are ongoing to seek consensus for a new terminology (Finlay et al., 2008). The management of this group of rare CNS tumors has been the recent focus of prospective clinical trials throughout Asia, the Americas, and Europe, and the clinical approach to these tumors is undergoing continuous modification. Because of their rarity, most of the research is conducted in large cooperative groups. Most encouraging is the recent exploration of the biologic basis of CNS GCTs, an effort that will likely lead to more targeted, safer therapies. Insight into the biology and management of CNS GCTs has been obtained from experience with these tumors outside the CNS, where they are of highest incidence in the gonads, mediastinum, and retroperitoneum. From a biologic perspective, unusual features of CNS GCTs include their demographics (males > females, especially in the pineal region; higher incidence in people from Asia); onset primarily during adolescence and early adulthood; midline, extraaxial location in the CNS (pineal region, suprasellar region/neurohypophyseal); unique patterns of presentation in particular locations (bifocal pineal/suprasellar, basal ganglia); histologic distinctions by age and location (germinoma in pineal and bifocal locations; NGGCTs more common in females in suprasellar location; immature teratoma more common in infants); the ability to use tumor markers (alpha fetoprotein and human chorionic gonadotropin) in serum and cerebrospinal fluid (CSF) to diagnose and monitor response to treatment; and association with various genetic syndromes such as trisomy 21, Klinefelter syndrome, and Noonan syndrome. Pure germinomas may produce very low levels of human chorionic gonadotropin (hCG), but never alpha fetoprotein (AFP), in either CSF or serum, whereas NGGCT can produce any combination of both tumor markers. In general, CNS GCTs often require multimodality therapy for optimum care. With the exception of low-grade variants such as mature or immature teratoma, where a gross total resection may be curative, combinations of chemotherapy and radiation therapy are necessary for most patients. Germinomas are very responsive to chemotherapy, and radiation and current clinical research is aimed at minimizing treatment and its consequences while preserving a high cure rate (5year overall survival [OS] > 85%). For NGGCTs, more intensive preradiation chemotherapy combined with maximum surgical debulking of the tumor followed by radiation

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therapy appears to have dramatically improved survival (5year OS > 70%).

EPIDEMIOLOGY In a population-based study in Canada using data from a tumor registry, the mean annual incidence of CNS GCT was reported to be 1.06 per million children (0–18 years of age). In this study, the annual incidence of germinoma was approximately twice that of NGGCT. Whereas other Western countries estimate similar incidence rates, with CNS GCTs accounting for up to 3.6% of all pediatric intracranial CNS tumors, the rates appear higher in Japan and the Far East, accounting for up to 15.3% of all pediatric intracranial CNS tumors (Report of Brain Tumor Registry of Japan, 2003). The reasons for these variations in incidence remain elusive, but genetic predisposition and geographic or environmental factors may contribute. The peak incidence of CNS GCT is in the second decade of life, and male gender increases the likelihood of this diagnosis. The male predominance is striking in GCTs arising in the pineal area, with a male : female ratio as high as 15 : 1. In contrast, girls are slightly more affected by GCTs arising in the suprasellar region.

PATHOLOGY AND ETIOLOGY OF   GERM CELL TUMORS CNS GCTs are immunophenotypic and morphologic homologues of GCTs arising in extracranial locations, but the distribution of histologic subtypes appears to differ by site of origin. Mature and immature teratomas mimic elements of all three embryonic germ layers: endoderm, mesoderm, and ectoderm. Uncertainty remains regarding the cells of origin of other subtypes, such as choriocarcinoma, germinoma, yolk sac tumors, and embryonal carcinoma. The primordial stem cells that give rise to normal and abnormal germ cell components are totipotent and capable of differentiation along several pathways. As such, the primary occurrence of GCTs in gonadal tissue is not surprising, but they also arise in several unique “midline” locations in the body and CNS, related to either aberrant migratory behavior and eventual neoplastic transformation or the failure of migratory stem cells in the embryo to undergo spontaneous apoptosis. That this aberrant ontogeny is under genetic control is suggested by the occurrence of multiple firstdegree relatives affected by primary GCTs, both in the body and CNS, and the occurrence of GCTs in certain genetic syndromes such as Noonan syndrome and trisomy 21. Gonadotropins may also have a role in the etiology of GCTs, as suggested by their midline location, the “neighborhood” of diencephalic centers that regulate gonadotropins, and the increased prevalence in children of peripubertal age and in boys affected by Klinefelter syndrome (47 XXY).



Central Nervous System Germinoma and Other Germ Cell Tumors

GERMINOMA The predominant type of CNS GCT is a germinoma, accounting for approximately 60% to 70% of intracranial GCTs (Report of Brain Tumor Registry of Japan, 2003; Calaminus et al., 2013). This section focuses primarily on its clinical management. Most germinomas develop in the suprasellar/ neurohypophyseal and pineal regions. Occurrences outside the midline and in the basal ganglia are rare. Progression-free survival (PFS) in germinomas is excellent, with 5-year OS exceeding 90% in retrospective and prospective series.

Clinical Presentation The clinical presentation is determined by the location of the germinoma. Protracted courses, up to years, of symptoms before diagnosis are not uncommon. Diabetes insipidus, a symptom of the vast majority of patients with suprasellar and bifocal germinoma, can remain clinically compensated for a prolonged time period. Hence diligent history taking and review for polyuria and polydipsia are important. Symptoms of increased fluid intake, nocturia, weight loss, and personality changes are common. New onset of diabetes insipidus should prompt a diagnostic workup, including a referral to a pediatric endocrinologist and brain magnetic resonance imaging (MRI) without and with contrast and with attention to the suprasellar region. Sometimes the initial MRI is nondiagnostic or may show slight infundibular thickening. In the case of documented pituitary stalk thickening, a careful clinical and imaging follow up is recommended because about 15% to 25% of affected individuals may eventually develop germinoma. Other symptoms associated with suprasellar germinoma location are visual disturbances, as a result of the close proximity to the optic chiasm and optic nerves, and endocrinopathies. The most common symptoms of a pineal germinoma are those related to increased intracranial pressure resulting from obstruction of the aqueduct and, if the mass is large enough, Parinaud syndrome. This syndrome consists of vertical gaze impairment, convergence nystagmus, and pupils that respond to accommodation but not to light. It is a classical sign of tectal compression. Rare off-midline germinomas, arising in the basal ganglia, thalamus, or internal capsule, are often characterized by insidious (i.e., over 1–4.5 years) onset of cognitive or motor symptoms. They can occur in isolation or synchronously in multiple locations. Affected patients may present with symptoms related to corticospinal tract or extrapyramidal dysfunction, such as hemiparesis and/or choreoathetotic movements, personality changes, and speech disturbances.

Radiology Classical imaging characteristics of suprasellar and pineal (or bifocal) germinoma are homogenous isointense or hypointense lesions on T1-weighted MRI and isointense or hyperintense lesions on T2-weighted MRI (isodense or hyperdense on computed tomography [CT]), with avid enhancement after contrast administration. However, the tumor may also heterogeneously enhance and include cystic components and intratumoral calcifications. Subependymal ventricular dissemination is common and usually characterized by linear or nodular enhancement along the ependymal ventricular lining of the lateral or third ventricles, especially in the frontal horns. Large tumors may be surrounded by a 2- to 3-cm penumbra of FLAIR signal abnormality suggestive of either edema or infiltration. Basal ganglia germinomas may lack this avid enhancement and sometimes

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show little or no mass effect, especially in the early stages of the disease. Ipsilateral cerebral and/or brainstem atrophy (Wallerian degeneration) is present in one third of patients with basal ganglia germinoma. Infiltrative disease appears to exert an anatomic and, most likely, physiologic “toxic” effect on brain parenchyma. After treatment, the tumor bed and surrounding tissue usually become atrophic, with calcium deposition.

Tumor Markers Intracranial GCTs can secrete tumor markers into the bloodstream and/or CSF. For some tumor markers, such as hCG, there appears to be a CNS/systemic gradient, and lumbar assay values are usually higher. For others, such as AFP, the serum and CSF values are often similar. Germinomas do not secrete AFP but may secrete low levels of hCG and hCGβ either into serum and/or into CSF, possibly as a result of the presence of a small component of syncytiotrophoblastic giant cells (STGCs). Retrospective and prospective analyses found elevated hCG levels in serum and/or CSF in up to 42% of germinoma patients (Allen et al., 2012). The majority of cases have mild elevations of hCG levels solely in CSF; however, the presence of both or an elevated concentration in serum with a normal concentration in CSF have been described. Different timing of the sampling of hCG in serum and CSF (because of the short half-life of hCG [1.5 days]) and different units and kits may contribute to some of the variability in these findings. Some authors have suggested a different prognosis for germinoma with elevated levels of hCG, but many studies do not specify the site of hCG measurement, and a recent publication suggests that serum hCG is an insensitive screening tool and that lumbar, but not ventricular, CSF is much more sensitive. Nonetheless, tumor marker analysis is currently being used in lieu of biopsy to diagnose germinoma and to distinguish germinoma from NGGCT. Patients with typical midline tumors and modest elevations of hCG are treated as cases of germinoma, and patients with any elevation of AFP are treated as cases of NGGCT in the Children’s Oncology Group (COG) Germ Cell Tumor study (ACNS1123) protocol. For patients with normal tumor markers, biopsy is required.

S-Kit in Germinoma Immunohistochemical studies have shown that c-kit, a protooncogene and transmembrane tyrosine receptor, is highly expressed in germinoma cells. S-kit is its soluble equivalent and can be measured in CSF. S-kit values in CSF are usually higher in germinoma compared with NGGCT patients, and levels correlate with treatment response and relapse (Miyanohara et al., 2002). These data suggest that CSF s-kit may represent a valuable tumor marker of germinomatous components, but currently the assay is used mostly for research purposes in Japan.

Staging As with malignant childhood brain tumors in general, MRI of the entire CNS at the time of initial diagnosis is essential for staging. Should surgery be required as a result of obstructive hydrocephalus, MRI of the brain and spine should be obtained within a 48- to 72-hour window after the surgical intervention. This minimizes misinterpretation of the contrast enhancement that occurs between 72 hours and 6 weeks after surgery as a result of disruption of the blood–brain barrier. Tumor marker determinations in serum and CSF should be

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included in the staging. In the case of uncontrolled raised intracranial pressure or a lesion with mass effect, performance of a lumbar puncture is contraindicated. In most cases, however, lumbar CSF for cytology and marker analysis can safely be obtained following either an endoscopic third ventriculostomy (ETV) or placement of a ventriculoperitoneal (VP) shunt. To date, there are insufficient data on the significance and reliability of ventricular CSF tumor or cytology assays. The International Society of Pediatric Oncology (SIOPCNS-GCT) trial allowed enrollment of patients if CSF cytology was undertaken via either the ventricular route or lumbar puncture. Interestingly, the Japanese working group dismisses CSF cytology because it is not taken into consideration for treatment decisions. Data from prospective studies suggest that 15% to 20% of germinoma patients have disseminated disease at diagnosis either on imaging (M+) or on CSF investigation (M1). Although bifocal involvement is considered metasynchronous but not metastatic disease, there is some controversy about whether observed studding on endoscopic inspection, which is invisible on MRI, or diffuse basal ganglia involvement are should be classified as M0 or M+.

Treatment Role of Radiation and Chemotherapy Historically, craniospinal irradiation has been the gold standard of treatment for CNS germinoma. Because of concerns about the long-term sequelae of both large-volume and highdose radiation, there has been a concerted effort to either completely substitute intensive chemotherapy for radiation therapy or reduce both volume and dose in select cohorts of patients based on response to preradiotherapy chemotherapy. The outcome measures by which success will be gauged include maintenance of high survival rates with decreased long-term negative effects on cognitive and endocrine function and quality of life. Given the rarity of this disease and paucity of cooperative group phase III clinical trials, documentation of the achievement of these goals may be difficult. The current state-of-the-art treatment therapies are reviewed here, with the expectation that changes may emerge as clinical trials progress. Radiation Therapy.  Although reduction of craniospinal irradiation to whole-ventricular (WV) or whole-brain (WB) irradiation in completely staged, M0, primary germinoma appears relatively safe from the standpoint of tumor eradication and has evolved as an accepted practice throughout the world, the safety of elimination of WV irradiation and substitution with involved field (IF) irradiation has been questioned since the observation of increased numbers of ventricular relapses. Currently WV radiation is utilized by the Japanese, French, SIOP, and COG working groups in combination with chemotherapy as the standard of care for nonmetastatic suprasellar and pineal-region germinoma. The relative contributions of chemotherapy and irradiation remain a topic of debate. Rogers, Mosleh-Shirazi, and Saran (2005) conducted a meta-analysis of radiation therapy for germinoma patients and found a recurrence rate of 7.6% after WB or WV radiation and a rate of 3.8% after craniospinal irradiation (CSI). No predilection for isolated spinal metastasis was found when CSI was omitted (2.9% versus 1.2%). The authors concluded that reduced-volume irradiation should replace craniospinal irradiation (Rogers et al., 2005). Ogawa et al.’s (2004) retrospective review of the Japanese experience concurs with a low risk of spinal relapse, reporting an incidence of 4% (2/56) for patients treated with CSI and 3% (2/70) for patients treated without spinal radiation. Excellent PFS rates for localized

germinomas with the use of either WB or WV irradiation have been reported by several institutions. Nevertheless, the volume of radiation should cover all areas of measurable disease identified at the initial MRI staging. In addition to the controversies surrounding the optimum volume of radiation therapy, there has also been controversy about the optimum dose to both the primary tumor and any prophylactic field. Small retrospective experiences suggest that radiation doses can be reduced to 36 and 30 Gy WV irradiation, respectively, without preirradiation chemotherapy. However, the use of radiation therapy alone has been associated with the risk of extra-CNS relapses. Several clinical trials have proposed that preradiation chemotherapy may be used to triage patients who can more safely be treated with both volume and dose reductions of radiation, thereby reducing radiation-related long-term sequelae. Chemotherapy.  Germinomas are highly sensitive to radiation therapy and chemotherapy. Platinum compounds and cyclophosphamide are particularly efficacious chemotherapeutic agents in treating germinomas. The largest “chemotherapy-only” experience in newly diagnosed patients is reported in the First, Second, and Third International CNS Germ Cell Tumor Studies. In the first study, chemotherapy consisted of four cycles of carboplatin (500 mg/m2/day, days 1 and 2), etoposide (150 mg/m2/day, day 3), and bleomycin (15 mg/m2/day, day 3). Patients with complete radiologic and tumor marker response proceeded to two more identical cycles, whereas cyclophosphamide (65 mg/kg) was added to the three-drug regimen for those with incomplete response. Of the CNS germinoma patients, 22 of 45 eventually relapsed. Although most relapsed patients were salvageable with high doses and volumes of radiation therapy, the 2-year OS in this study was only 84%. Nineteen germinoma patients were enrolled in the second study using an intensified cisplatinand cyclophosphamide-based chemotherapy induction. Despite proof of effectiveness with a high rate of complete remission, the 5-year event-free survival (EFS) and OS rates were unsatisfactory at 47% ± 2.3% and 68% ± 2.2%, respectively. Moreover, chemotherapy was associated with unacceptable morbidity and mortality (4 deaths), predominantly in patients with diabetes insipidus. The third study included 25 patients and confirmed the inferior outcome of this strategy, with a 6-year EFS of 45.6% when avoiding radiation. In conclusion, “chemotherapy-only” strategies have not matched the long-term survival rates obtained with either radiation therapy alone or combined chemotherapy and radiation therapy. Chemotherapy should therefore not be used in isolation in patients with germinoma unless new targeted agents or new molecular markers for tumor responsiveness afford the hope of better outcomes. Combined Chemotherapy and Radiation Therapy.  One of the first trials of single-agent, neoadjuvant chemotherapy with carboplatin followed by response-dependent reductions in radiation volume and fields in biopsy-proven CNS germinoma observed a high complete response rate (7/11) and favorable outcome, with 10 of 11 patients experiencing longterm survival (Allen, Kim, and Packer, 1987). Preirradiation chemotherapy with carboplatin, etoposide, and ifosfamide followed by focal irradiation (40 Gy) has been studied in the SIOP-CNS-GCT-96 protocol for patients with nonmetastatic germinomas. Physicians had the option to use this approach or craniospinal irradiation without chemotherapy. This prospective multinational study included 190 patients with localized germinoma. The 5-year EFS and OS rates for patients treated with preirradiation chemotherapy (n = 65) were 88% ± 0.4% and 96% ± 0.3%, respectively, whereas the 5-year EFS and OS rates of patients treated with craniospinal radiation



Central Nervous System Germinoma and Other Germ Cell Tumors

(n = 125) were 94% ± 0.2% and 95% ± 0.2%. Whereas relapses (4/125) only occurred locally in the CSI group, six of seven relapses occurred in the ventricular area in the chemotherapy/ focal radiation treatment group. As a consequence, the current open SIOP trial combines preirradiation chemotherapy with ventricular irradiation (24 Gy) with an additional boost of 16 Gy to the primary tumor bed in patients with localized disease. Metastatic germinoma patients will continue to be treated with CSI only at the doses outlined previously without chemotherapy, as the 45 metastatic patients included in the aforementioned study showed an excellent 5-year EFS and OS of 98% ± 0.2%. The risk of ventricular recurrence in patients treated with chemotherapy and focal radiation has also been well documented by the French and Japanese working groups. Alapetite et al. (2010) reported the SFOP (Societé Française d’Oncologie Pédiatrique) experience, which included 60 patients treated for CNS germinoma with a combination of carboplatin, etoposide, and ifosfamide followed by focal radiation (40 Gy). The 5-year EFS and OS rates were 84.2% and 98.2%, respectively. Ten of 60 patients relapsed at a median time of 32 months (range: 10–121 months), with the majority (n = 8) of relapses occurring within the ventricular system (Alapetite et al., 2010). The second trial of the Japanese GCT study group consisted of three cycles of carboplatin (450 mg/m2/day, day 1) and etoposide (150 mg/m2/day, days 1–3) chemotherapy followed by local irradiation (24 Gy). The 5-year OS rate was 98%. However, 13% of the patients (16/123) developed recurrence. In an interim analysis, a high incidence of ventricular/ locoregional relapses was reported. As a consequence, current treatment in Japan, Europe, and North America combines chemotherapy with WV irradiation. Although the dose of WV irradiation is 24 Gy in Europe and Japan, the current Children’s Oncology Group GCT trial evaluates the efficacy of a reduced dose of 18-Gy WV irradiation (plus boost to tumor bed to a total of 30 Gy) in chemotherapy-responsive germinoma patients with localized disease. The vast majority of patients with suprasellar germinoma suffer from diabetes insipidus. Cisplatin- or ifosfamide-based chemotherapy requires hyperhydration, which significantly increases the risk for electrolyte imbalances and subsequent complications such as seizures (Afzal et al., 2008). A combination of carboplatin and etoposide chemotherapy is currently employed by the Japanese and North American working groups. This offers the advantage of easier outpatient administration and reduced risk of hyperhydration associated metabolic complications. Interestingly, whereas carboplatin alone has been proven effective (Allen, DaRoso, Donahue, and Nirenberg, 1994), etoposide has never been evaluated as an active single agent in the treatment of germinoma.

Role of Surgery The Need for Biopsy and Second-Look Surgery Currently, it is not sufficient to treat patients with isolated pineal or suprasellar tumors as cases of germinoma without biopsy confirmation or demonstration of hCG elevation. There are several types of tumors that arise in these locations, including those with low-grade and malignant histologies. In the era when the risks of operating on a patient with a pinealregion tumor were high, the practice was to use a radiographic response to 2 weeks of radiation therapy to confirm the assumption that a germinoma was involved. However, this practice is no longer viable because tumor types such as pineoblastomas or ependymomas may also briefly respond but would require very different doses and volumes of radiation for potential cure. Second, low-grade tumors such as

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pineocytomas or teratomas would be irradiated needlessly when surgery could be curative. Currently, the risks of surgery in this area of the CNS are greatly reduced with the use of modern operating techniques and equipment and steroids. In addition, endoscopic procedures often provide very useful diagnostic information and serve to relieve intracranial hypertension via third ventriculostomy (ETV). Thus it is the gold standard to establish the histologic presence of a GCT by either open or endoscopic biopsy if the tumor markers are normal. The choice of technique (stereotactic, endoscopic, open craniotomy) and the goal of surgery (tissue diagnosis versus tumor resection) are complex and largely determined by the anatomy of the lesion (size, accessibility through the ventricle, etc.) and the presence and extent of ventriculomegaly. If the tumor is confirmed to be a germinoma, the general goal of surgical intervention (apart from hydrocephalus management) is tissue diagnosis rather than tumor resection, because germinoma is so responsive to medical therapy. Symptomatic obstructive hydrocephalus may necessitate an emergent intervention such as placement of an external ventricular drain (EVD) and/or an ETV. At the time of ETV, many groups favor attempted tumor biopsy to confirm the histology. The need for tissue biopsy in patients with a bifocal lesion, considered metasynchronous and not metastatic, is debatable. In accordance with the current SFOP, SIOP, and North American approach, a biopsy is not required if the clinical presentation, imaging characteristics, and tumor marker profile (AFP negative, no or mild elevation of hCG) are consistent with a bifocal germinoma. With very rare exceptions, bifocal lesions associated with negative serum and CSF tumor markers are almost always pure germinoma. However, some very rare cases of different pathologies have been reported. The current North American GCT trial does not mandate a biopsy for suprasellar, pineal, or unifocal ventricular lesions (radiologically consistent with germinoma) if AFP is negative and if serum and/or CSF hCG is elevated but is less than or equal to 50 IU/L. However, in this protocol, a biopsy is required for patients with hCG values above 50 IU/L to a maximum of 100 IU/L. The Japanese approach has been surgical removal of lesions whenever feasible, and subsequent treatment is based on the final pathology result. Germinomas are highly chemosensitive, and response to treatment is often obvious within days after the first cycle. At the Hospital for Sick Children in Toronto, a transient EVD is favored over a permanent shunt in patients with obstructive hydrocephalus likely caused by a germinoma in whom an ETV is not possible. After the diagnosis of a germinoma is confirmed, one cycle of chemotherapy is administered, and if the patient tolerates clamping of the drain, it is removed before the child becomes neutropenic. The presence of residual disease at the end of treatment is not predictive of worse outcome, and patients with residual MRI abnormality following chemotherapy and radiation therapy fare as well as those without, as long as the tumor markers remain normal in serum and CSF (Calaminus et al., 2013). Lack of responsiveness to chemotherapy in either an hCGpositive or a biopsy-proven germinoma raises concerns of a potential mixed GCT, especially if there is persistence of or increase in the tumor markers; hence the current Children’s Oncology Group GCT trial mandates second surgery at the end of chemotherapy in case of incomplete response if the residual suprasellar or pineal lesion is larger than 1 cm2 and 1.5 cm2, respectively, or the tumor markers do not normalize. The “growing teratoma” syndrome has been described primarily in patients with NGGCTs undergoing resection of a residual or enlarging primary tumor whose tumor markers are normal. The histology reflects a mature or immature teratoma.

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Prognosis and Summary The overall survival in germinoma exceeds 90%, with either radiation alone or with combinations of chemotherapy and radiation. Current treatment strategies include preradiation chemotherapy to reduce radiation doses and minimize longterm sequelae. Current evidence suggests that extent of resection does not contribute to superior outcome but may add morbidity. Hence, surgery should be limited to a biopsy or avoided where possible. There are many advances to be made, such as in the search for more specific and sensitive tumor markers, studies of whether responses to neoadjuvant chemotherapy justify radiation dose reductions, determination of the optimum dose and volume of radiation therapy, and determination of whether current efforts to further reduce radiation dose and volume justify the potential avoidance of late effects. Only through cooperative group trials and international collaboration around this rare disease can we make clinical progress. The exploration of the molecular basis of the origin and treatment sensitivity of GCTs deserves further effort, but currently the rate-limiting step is the paucity of tumor tissue given the small size of a biopsy specimen. With improvements in technology, more research will be possible and smaller amounts of tissue and CSF may be required, allowing some of these critical questions to be addressed. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Afzal, S., Wherrett, D., Bartels, U., et al., 2008. Challenges and difficulties in management of patients with intracranial germ cell tumor having diabetes insipidus treated with cisplatin- and/or ifosfamidebased chemotherapy. Neuro Oncol. 10 (3), 417.

Alapetite, C., Brisse, H., Patte, C., et al., 2010. Pattern of relapse and outcome of non-metastatic germinoma patients treated with chemotherapy and limited field radiation: the SFOP experience. Neuro Oncol. 12 (12), 1318–1325. Allen, J.C., Kim, J.H., Packer, R.J., 1987. Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system. J. Neurosurg. 67 (1), 65–70. Allen, J.C., DaRoso, R.C., Donahue, B., et al., 1994. Aphase II trial of preirradiation carboplatin in newly diagnose germinoma of the central nervous system. Cancer 74 (3), 940–944. Allen, J., Chacko, J., Donahue, B., et al., 2012. Diagnostic sensitivity of serum and lumbar CSF bHCG in newly diagnosed CNS germinoma. Pediatr. Blood Cancer 59 (7), 1180–1182. Calaminus, G., Kortmann, R., Worch, J., et al., 2013. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol. 15 (6), 788–796. Finlay, J., da Silva, N.S., Lavey, R., et al., 2008. The management of patients with primary central nervous system (CNS) germinoma: current controversies requiring resolutions. Pediatr. Blood Cancer 51 (2), 313–316. Miyanohara, O., Takeshima, H., Kaji, M., et al., 2002. Diagnostic significance of soluble c-kit in the cerebrospinal fluid of patients with germ cell tumors. J. Neurosurg. 97 (1), 177–183. Ogawa, K., Shikama, N., Toita, T., et al., 2004. Long-term results of radiotherapy for intracranial germinoma: a multi-institutional retrospective review of 126 patients. Int. J. Radiat. Oncol. Biol. Phys. 58 (3), 705–713. Report of Brain Tumor Registry of Japan (1969–1996). 2003. Neurol Med. Chir. (Tokyo) 43 (Suppl. (11th edition)), 1–111. Rogers, S.J., Mosleh-Shirazi, M.A., Saran, F.H., 2005. Radiotherapy of localised intracranial germinoma: time to sever historical ties? Lancet Oncol. 6 (7), 509–519.

131  Craniopharyngioma, Meningiomas, and Schwannomas Michelle Lauren Feinberg, Jeffrey H. Wisoff, and Robert Keating

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Craniopharyngiomas, meningiomas, and schwannomas are less common than other childhood brain tumors, frequently present insidiously over months to years, and often are amenable to successful surgical and medical intervention. The advent of improved neuroimaging has allowed earlier diagnosis, targeted treatment, and the ability to noninvasively and serially monitor patients. This chapter reviews the epidemiology, clinical presentation, neuroimaging findings, histology, genetics, surgical and medical management, and outcomes of these three tumors as they occur in the pediatric population.

CRANIOPHARYNGIOMAS Few topics in neurosurgery inspire more controversy than the optimal treatment of craniopharyngiomas. The benign histology of these tumors often belies their malignant clinical course, particularly in children. The location of craniopharyngiomas, and specifically their intimate association with the visual pathways, pituitary, hypothalamus, and limbic system, predisposes patients to severe visual, endocrine, and cognitive deficits, both at presentation and as a result of treatment. Although most children can compensate for neurologic deficits and endocrinologic deficiencies, the cognitive and psychosocial sequelae can be functionally devastating, interfering with education, limiting independence, and adversely affecting the quality of life as these children approach adulthood.

Epidemiology The Central Brain Tumor Registry found craniopharyngiomas to comprise 4.2% of all tumors in children aged 0 to 14 years (Ostrom et al., 2015). Craniopharyngiomas have a bimodal age distribution with a peak in the pediatric population between age 5 and 14 years and another peak in the adult population between age 50 and 74 years (McCrea et al., 2015). Thirty-three percent to 54% of all craniopharyngiomas occur in children, accounting for 6% to 9% of all pediatric brain tumors. These tumors are the most common nonglial tumors of childhood. Although there does not appear to be any racial or ethnic predilection for craniopharyngiomas, the influence of gender is not as clear. Considering the available data, craniopharyngiomas may occur slightly more often in males than in females.

Clinical Presentation The slow growth of craniopharyngiomas often results in a delay between onset of symptoms and diagnosis, with a typical prodrome of 1 to 2 years. The main presenting signs and symptoms of craniopharyngiomas are secondary to pressure upon adjacent neural structures. Headaches from raised intracranial pressure are the most common complaint, occurring in 60% to 75% of patients. Visual impairment, caused by compression of optic pathway structures, is the presenting complaint in approximately 50% of children. On preoperative neuroophthalmo-

logic testing, 70% to 80% of children have abnormal visual acuity or visual fields. The specific deficits are a reflection of the direction of tumor growth and its compression of various portions of the visual apparatus. Prechiasmatic extension will compress optic nerves with loss of visual acuity, whereas posterior tumors cause chiasmatic compression with complex visual field defects. Papilledema is present in approximately 20% of children (Fig. 131-1). Hypothalamic and endocrine dysfunction, including growth failure (short stature), delayed sexual maturation, excessive weight gain, and diabetes insipidus, is present in 20% to 50% of children at the time of diagnosis, but is less commonly the symptom that brings the child to medical attention. At the time of presentation, less than one third of children are endocrinologically normal, making preoperative endocrine assessment mandatory.

Neuroimaging The role of neuroimaging is to establish a preoperative diagnosis and then define the location and extent of the cystic, solid, and calcified portions of the tumor and its relation to the distorted normal anatomy. Radiographic evaluation includes computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and, where available, magnetic resonance spectroscopy (MRS). Vascular anatomy can be well demonstrated by MRI and MRA obviating the need for invasive cerebral angiography. The noncontrast CT usually demonstrates a suprasellar and often intrasellar mass with calcifications as well as hypodense solid and cystic components (Fig. 131-2). The low-density component usually has an attenuation greater than that of CSF. A small percentage of craniopharyngiomas may be of high density. CT shows secondary changes in the skull base such as enlargement of the sella turcica and/or erosion of the dorsum sella. MRI provides invaluable information regarding the relation of the tumor to the surrounding critical structures, including the visual pathway, hypothalamus, blood vessels of the circle of Willis, and ventricles (Fig. 131-3). The appearance of a normal pituitary gland helps to make the correct diagnosis. Administration of gadolinium demonstrates the avidly enhancing cystic capsule and solid tumor. The appearance of the cyst fluid is uniformly hyperintense on T2-weighted sequences, but can vary in intensity on T1-weighted sequences based on its biochemical composition (Fig. 131-4). Solid craniopharyngiomas without calcifications can be difficult to differentiate from other pediatric suprasellar tumors. In these instances, MR spectroscopy can provide additional findings that may help to establish a specific diagnosis. Craniopharyngiomas exhibit an elevated lactate peak and only trace amounts of other spectral metabolites. This is in contrast to gliomas that demonstrate an increased choline– to–N-acetylaspartate ratio compared with normal brain. Pituitary adenomas will exhibit either a choline peak or no abnormal metabolite peaks.

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surgical resection may be obtained more often in these tumors than in adamantinomatous or mixed craniopharyngiomas (Fig. 131-6). Microscopic islets or “fingers” of adamantinomatous tumor embedded in densely gliotic parenchyma are frequently seen when this tumor arises in the region of the tuber cinereum, hypothalamus, and floor of the third ventricle. The gliotic reaction of Rosenthal fibers and fibrillary astrocytes, varying between several hundred micrometers to millimeters in thickness, effectively separates the tumor from the brain, thus providing a safe plane for surgical dissection. The presence of this gliotic tissue on surgical pathology is associated with a decreased risk of recurrence after gross total tumor resection.

Treatment

Figure 131-3.  Craniopharyngioma. Magnetic resonance imaging (MRI)—Note the heterogeneous nature (solid > cystic) of this craniopharyngioma on MRI with significant suprasellar extension. Despite its location, potentially obstructing the foramen of Monro(s), there was no hydrocephalus.

Histopathology Craniopharyngiomas develop from epithelial nests that are embryonic remnants of Rathke’s pouch located along an axis extending from the sella turcica along the pituitary stalk to the hypothalamus and the floor of the third ventricle. The tumors gradually enlarge as partially calcified, heterogeneous solid, and cystic masses predominantly in the suprasellar region. They extend along the path of least resistance into the basal cisterns or invaginate into the third ventricle. Hydrocephalus can result from continued growth superiorly into the third ventricle. Craniopharyngiomas have two basic patterns of cellular growth—adamantinomatous and papillary. Mixed tumors with both adamantinomatous and squamous papillary components or combinations of craniopharyngioma and Rathke’s cleft cysts can occur. Adamantinomatous tumors are the more common variant. They resemble the epithelium of tooth-forming tumors containing three distinct components: a basal layer of small cells; an intermediate layer of variable thickness with loose, stellate cells; and a top layer facing the cystic lumen where the cells are abruptly enlarged, flattened, and keratinized. At the cyst surface, desquamated epithelial cells are present either singly or in characteristic stacked clusters (keratin nodules). These nodules may undergo mineralization with accumulation of calcium salts, which, in rare instances, progress to metaplastic bone formation. The cysts in these tumors usually contain an oily liquid composed of this desquamated epithelium, rich in cholesterol, keratin, and occasionally calcium (Fig. 131-5). Squamous papillary tumors occur nearly exclusively in adults and often involve the third ventricle. They consist of solid epithelium, without loose stellate zones, in a papillary architecture that resembles metaplastic respiratory epithelium. They are predominantly solid and rarely undergo mineralization. When cysts occur, the fluid is less oily and dark than in adamantinomatous tumors. As a result of the absence of calcification and minimal cyst formation, complete curative

The treatment goal for craniopharyngiomas in the pediatric population is permanent tumor control or cure. However, the optimal treatment strategy remains controversial, with the debate centered on the extent of tumor resection, the role of radiation therapy, and the utilization of intracystic therapies, including radionuclides, baclofen, and interferon. The philosophy of curative treatment of craniopharyngiomas is predicated on children and their families having unimpeded access to long-term medical care and the personal or societal financial resources for the costs of lifetime hormone replacement therapy. A multidisciplinary team including pediatric endocrinology, neuropsychology, pediatric neurosurgery, pediatric oncology, radiation oncology, and pediatric neurology is essential. Primary irradiation without resection, intracystic therapies, and palliative strategies may be more appropriate in those settings in which resources are limited or multidisciplinary expertise is lacking. Although partial resection without adjuvant radiation or cyst aspiration alone may provide temporary relief from symptoms, progressive solid and cystic tumor growth is inevitable. The management of craniopharyngiomas that have failed primary therapy is associated with significantly increased morbidity and mortality.

Radical Surgical Resection Many pediatric neurosurgeons in North America and Europe favor complete microsurgical resection as the treatment of choice for newly diagnosed craniopharyngiomas (Fig. 131-7). The feasibility and success of such radical resection is dependent on the size and extent of the tumor, whether the tumor is primary or recurrent, the availability of surgical expertise and postoperative endocrinologic support, as well as the presence of societal resources to cope with potential postoperative deficits. If the socioeconomic conditions applicable to an individual patient do not provide appropriate long-term neurologic care and endocrinologic support, functional morbidity may overshadow the merits of curative resection. Proponents of radical surgical resection argue that the advances of microsurgical techniques have facilitated treatment of these tumors and substitutive therapy can ameliorate endocrinologic sequelae secondary to hypothalamic injury. The greater immediate morbidity of this approach may be mitigated by the fact that radiation therapy carries the risk of unpredictable late neurologic, vascular, and oncogenic side effects as well as long-term development of neuropsychologic deficits in children. Radiographically confirmed total resection can be accomplished in 60% to 100% of primary tumors in children with mortality rates of 0% to 4%. Recurrence rates after total resection range from 0% to 20%, and most recurrences occur within 2 to 3 years after surgery.



The philosophy and experience of the surgeon significantly affect the likelihood of achieving a curative total resection with a low mortality and without disabling morbidity. Centers performing fewer than 2 radical resections per year had a good outcome in only 52% of patients, whereas institutions that performed radical resections more often had a good outcome in 87% of patients. Factors such as tumor size, severity of preoperative deficits, and the presence of hydrocephalus all play a role in postoperative morbidity but not in disease control.

Subtotal Resection With Irradiation Craniopharyngiomas are radiosensitive tumors. To reduce the morbidity associated with radical surgery, particularly when there is significant involvement of the hypothalamus, subtotal resection with adjuvant irradiation may provide similar disease control and less endocrinologic morbidity compared with radical resection alone. The addition of postoperative radiotherapy in the setting of gross residual disease can decrease the recurrence rate to 15% to 20%, whereas subtotal resection alone results in progression rates of 55% to 85%. Although radiation therapy has significantly improved progression-free outcomes, it does carry its own set of risks. The adjacent critical structures surrounding the tumor bed can be injured as a result of radiation treatment, with risks of visual problems, endocrine derangements, or cognitive changes. Several radiation modalities have been used in treatment of craniopharyngiomas, including conventional external beam radiation, intensity-modulated radiation, single-fraction stereotactic radiosurgery, fractionated stereotactic radiotherapy, and proton beam radiotherapy. With improvements in neuroimaging and radiation modalities, radiation treatment has become more accurate, resulting in decreased complication rates and improved survival (Lee et al., 2014; Kim et al., 2015). At this time, there is no standard of care regarding radiation for craniopharyngiomas although fractionated external beam radiation with a dose of 54 to 55.8 Gy in 1.8 Gy fractions is commonly used. Recently a large case series of patients treated for residual tumor or tumor regrowth with single-dose gamma knife radiosurgery was published. In this series, progression-free survival was 70% at 5 years and 43.8% at 10 years, with an overall survival rate of 83.9% at 10-year follow-up. Most of the patients who developed new neurologic or endocrine disturbances demonstrated tumor regrowth; however, a total 10.9% of patients were thought to develop complications as a result of radiosurgery (Kim et al., 2015).

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described by Leksell and Liden in the 1950s. The procedure is performed by using a fine needle to puncture the cyst or cysts under stereotactic guidance. The amount of radionuclide to be delivered is calculated using a standard formula based on the cyst’s volume. This calculation can be difficult in very small cysts. An equivalent volume of cyst fluid is first aspirated before the radionuclide is injected into the cysts. It is important not to alter the size and shape of the cysts, as this ensures even distribution of the radioisotope over the entire internal cyst wall without wall collapse or “wrinkling.” Cyst regression after intracavitary irradiation occurs gradually over several months. It does not control solid tumor growth, nor does it prevent the development of new cysts. Intracystic irradiation is generally well tolerated. Cyst leakage can occur in up to 10% of patients, with no subsequent sequelae. It can often be used in combination with stereotactic radiosurgery in patients with tumors that have a larger cystic component and a smaller residual solid component (Kim et al., 2015). Intracystic Bleomycin.  Bleomycin inhibits DNA production and has shown clinical efficacy in the treatment of analogous epithelial tumors. The cell cycle kinetics and spatial distribution of S-phase proliferative cells in the squamous epithelium of craniopharyngioma cysts provide a rationale for the use of antineoplastic agents. An Ommaya catheter is placed into the cyst either stereotactically or at the time of craniotomy. Several days after placement, a contrast injection and CT are performed to verify no leakage of cyst contents. Between 1.5 and 10 mg of bleomycin is injected at 1- to 2-day intervals depending on the cyst volume. Repeat injections are performed over a 10- to 21-day period for average total dose of 60 to 80 mg. Similar to intracystic irradiation, involution of cysts occurs slowly over several months. Although the total number of patients treated remains small, the reported series demonstrate reduction in cyst volume in almost all patients, with up to 50% of patients showing complete disappearance of the cyst and indefinite remission. Despite proper positing of the catheter, bleomycin has been reported to leak into normal surrounding brain with significant complications of hypothalamic injury, seizures, hemiparesis, panhypopituitarism, blindness, and, rarely, death.

Intracystic Therapy

Intracystic Interferon.  Interferon-alpha has been advocated as a safer alternative to bleomycin. Interferon-alpha is a cytokine with established antitumoral activity with the advantage of not having any neurotoxicity. Interferon-alpha has been used as both systemic and intracavitary therapy for primary craniopharyngiomas. In one of the initial studies, all 19 patients receiving intracystic interferon-alpha showed reduction in tumor size with a mean initial volume 33.50 cm3 and mean final tumor volume of 3.10 cm3. Cavalheiro et al. reported an international multiinstitutional open-label trial of intracavitary interferon-alpha in 60 children. This study demonstrated a greater than 50% reduction in cyst size in 78% of children; however, with relatively short follow-up, 22% showed disease progression requiring repeat surgery. Three of the responders had previously experienced tumor progression after bleomycin but were salvaged with interferon. There was no information on long-term outcome or durability of disease control. Side effects in both studies included fatigue and headache with no development of new hormonal deficits or need to stop treatment because of side effects.

Intracystic therapy with bleomycin, interferon, or radionuclide can also be delivered through an Ommaya catheter.

Outcomes and Quality of Life

Intracavitary Irradiation.  Local treatment of cystic craniopharyngiomas with intracavitary beta irradiation was first

Hypothalamic dysfunction is a unique complication of craniopharyngiomas and can be life-threatening. Symptoms can

Aspiration Simple stereotactic aspiration of tumor cysts or placement of an Ommaya reservoir into the cyst for serial aspirations is never indicated as primary therapy in children and should be reserved for palliation when all other treatment modalities have failed. Frequent aspirations tend to stimulate cyst fluid production, leading to progressively shorter symptom-free intervals. Solid tumor growth is unimpeded and may extend into areas of the decompressed cysts. Aspiration may be required to control cyst volume while waiting for the therapeutic effects of intracavitary irradiation (Fig. 131-8).

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include obesity, hyperphagia, memory deficits, thermoregulatory abnormalities, labile behavior, and sleep-wake cycle abnormalities. Severe obesity with a body mass index defined as greater than three standard deviations above average has been reported in up to 44% of children after surgical resection (Müller, 2015).

TABLE 131-1  Presenting Symptoms and Signs of Pediatric Meningiomas

Overview Craniopharyngiomas are histologically benign epithelial neoplasms that arise in the sellar and suprasellar region. Their intimate relationship with the optic chiasm, pituitary, hypothalamus, and cerebral vasculature leads a unique set of challenges in both treatment and management. There is no current consensus on optimal management strategies with outcomes supporting similar survival rates between gross total resection and subtotal resection followed by radiation. After treatment, patients must be followed with frequent imaging studies for early detection of recurrent tumors.

MENINGIOMAS

Seizures

33%

Headache

13%

Ataxia

10%

Hemiparesis

10%

Scalp mass

3%

Surveillance

3%

Incidental

1%

(Data from Rushing et al. Central nervous system meningiomas in the first two decades of life: a clinicopathological analysis of 87 patients. J Neurosurg 2005;103:489–95.)

on published series, children present most commonly with headaches, followed by seizures, and least commonly with neurologic deficits (Table 131-1).

Meningiomas are benign tumors that arise from the arachnoid cap cells of the meninges. Although meningiomas are the most common primary brain tumor diagnosed in adults, they are rare in the pediatric population, comprising only 2.6% of pediatric brain tumors. Because of their relatively low frequency, there are little data published regarding pediatric meningiomas. Much of the treatment strategies and management options are based on extrapolations from the adult literature despite significant differences being found between the two groups. In general, pediatric meningiomas are most often related to a preexisting genetic condition (e.g., neurofibromatosis-2, NF-2), a history of radiation, or arise de novo.

Molecular Genetics

Epidemiology

In the pediatric population, meningiomas are commonly associated with several disorders, including NF-2, Gorlin syndrome, Rubenstein-Taybi syndrome, and Castleman disease. Pediatric meningiomas are most frequently seen in patients with NF-2. It is estimated that 20% to 40% of all pediatric meningiomas are in patients with NF-2 and 53% of patients with NF-2 will develop meningiomas (Stanuszek et al., 2014). The Wishart variant of NF-2 has meningioma rates as high as 83% (Stanuszek et al., 2014). Patients with NF-2 have a much higher risk of being diagnosed with multifocal meningiomas. Children presenting with an isolated meningioma have a 20% risk of developing NF-2 and evaluation for the disease should be undertaken at diagnosis (Stanuszek et al., 2014). The disease course of NF-2 meningiomas can vary greatly from that of sporadic meningiomas. The location of NF-2– associated meningiomas are different from that in the general population, with higher rates in the spinal canal and optic nerve sheath. Although sporadic meningiomas tend to invade brain tissue causing a poorer short-term prognosis, NF-2 meningiomas have less of a tendency for brain invasion, offering a more favorable short-term prognosis. However, because of multiple tumors that tend to develop in NF-2, the overall long-term prognosis is less favorable than that seen for the general population (Stanuszek et al., 2014). NF-2–associated meningiomas also have been calculated to grow at faster rates than sporadic meningiomas with growth rates of 0.01 to 6.7 cm3/year and 0.2 to 2.5 cm3/year, respectively. Treatment of patients with NF-2 meningiomas differs compared with the regular pediatric population. Because of the frequency of meningiomas and other associated tumors, management of NF-2 focuses on quality of life and conservation of neurologic function (Stanuszek et al., 2014). For

The central brain tumor registry of the United States reported that meningiomas comprise 2.6% of all pediatric brain tumors with a similar rate of 2.4% reported in a recent meta-analysis of all published cases of pediatric meningiomas. A previous diagnosis of NF-2 was found in 10.2% of patients. In contrast to the female predilection seen in adult meningiomas, differing series in children have reported equal gender distributions or a slight male predominance (Stanuszek et al., 2014). Being derived from arachnoid cells, meningiomas can develop in any location where meninges are present. In approximately 90% of patients, meningiomas are supratentorial and are usually found at the convexity. However, atypical lesions such as intraventricular or locations without obvious dural attachments can be seen in children at higher rates than seen in adults (Stanuszek et al., 2014). For example, intraventricular meningiomas comprise only 0.5% to 2% of tumors in adults, in contrast to 11% in children (Stanuszek et al., 2014). Additionally, tumors that lack dural attachment have been reported to be as high as 30% in children (Stanuszek et al., 2014).

Clinical Presentation As with any intracranial lesion, the presenting signs and symptoms depend on the size and location of the lesion. Compared with adults, pediatric meningiomas tend to be larger at the time of presentation and thus children often present with signs of increased intracranial pressure such as headache, nausea, vomiting, increased head circumference, or frontal bossing. Seizures have been the presenting symptom in up to 30% of pediatric patients with meningiomas. Based

Much of the knowledge regarding molecular genetics of meningiomas is due to studies in the adult meningioma population but which has not been further extended to assessment of children. The precipitating cytogenetic event resulting in meningioma development is thought to be caused by a deletion on chromosome 22, close to the NF-2 gene. Deletions in both 1p and 14q have also been found in pediatric meningiomas and are associated with higher rates of tumor recurrence.

Meningiomas and Genetic Conditions



Craniopharyngioma, Meningiomas, and Schwannomas

these reasons, it is recommended to operate only on lesions that are causing progressive symptoms and not necessarily for radiographic progression alone (Stanuszek et al., 2014). NF-2 meningiomas have been reported to be less sensitive to stereotactic radiosurgery compared with sporadic tumors (Stanuszek et al., 2014).

Radiation-Induced Meningiomas Radiation therapy for treatment of other malignancies is a well-documented cause for meningioma development. The interval between initial radiation exposure and development of meningiomas is dependent on the intensity of radiation received, with the earliest reports of meningioma occurrence at 2 years after treatment to as late as 63 years after radiation therapy. Meningiomas caused by radiation damage often will show complex structural chromosomal abnormalities as a result of DNA damage. Because of the increased risk of meningioma development, all children who received prior cranial radiation should be followed with serial surveillance MRI screenings into adulthood.

Neuroimaging Imaging characteristics of meningiomas are similar in both pediatric and adult tumors. Typical findings on CT are isodense or hypodense lesions with surrounding edema. Additionally, hyperostosis of the surrounding bone is a common finding. On MRI, meningiomas appear as hypointense on T1weighted imaging and hyperintense on T2-weighted imaging (Fig. 131-9). With contrast administration, meningiomas show avid and homogenous enhancement. A dural tail is characteristic of meningiomas but not pathognomonic. Calcifications and cystic transformation can be seen more commonly in children. As opposed to adults, any patient with a newly diagnosed meningioma should undergo imaging of the complete neuroaxis to evaluate for either multiple lesions or metastatic lesions.

Histopathology The revised WHO classification divides meningiomas into grade I (benign), grade II (atypical), and, grade III (anaplastic). Based on histopathologic characteristics, meningiomas can be further subdivided into 13 variants. Although this classification scheme is based on adult meningiomas, all variants have been described in pediatric meningiomas as well (Fig. 131-10). As with adults, WHO grade I meningiomas are most common, with transitional, meningiothelial, and fibrous histopathologic types occurring most frequently (Stanuszek et al., 2014) (Table 131-2). However, in contrast to adults, there are higher rates of atypical histopathology in children, TABLE 131-2  Pathologic Classification of Pediatric Meningiomas Grade I

Typical (20 mit/10hpf)

Papillary, rhabdoid

(Adapted from Louis et al. World Health Organization classification of tumors. Pathology and genetics of tumors. Lyon: IARC Press; 2000. p. 176–84.)

1009

especially with the clear cell and papillary variants. In the adult population, the incidence of WHO grade II and III meningiomas is 1 to 2.8% whereas in children the incidence reaches 4.7% to 7.2% (Stanuszek et al., 2014). Although histologic grade usually does influence treatment, 15-year survival was not influenced in children and adolescents (Stanuszek et al., 2014). Unlike adults, the behavior of childhood meningiomas can be very difficult to predict based on the WHO grade. There is, however, a tendency for WHO grade III meningiomas to behave in a more aggressive manner, as seen in smaller case series. The risk of developing recurrent disease in pediatric patients has been shown to be linked to the WHO grade. WHO grade I tumors have a 92% 10-year event-free survival, whereas 10-year event-free survival for WHO grade II and III tumors is 70% and 33%, respectively.

Treatment Because of the largely benign nature of the disease, treatment options for meningiomas can be either conservative (observation) or via surgical intervention. Because of the rare nature of the disease and often atypical imaging findings, the need for a tissue diagnosis may necessitate operative intervention. Radiation therapy has been shown to be an effective adjuvant treatment, although the risks of radiation in the pediatric brain must be considered, especially with the possibility of malignant transformation. To date, chemotherapy has not been found to be efficacious in the management of meningiomas and is not a reasonable treatment option.

Observation Conservative management via observation is a potential option in the pediatric population; however, the potential for long-term complications must be taken into account. Characteristics of the lesion, such as size, location, and symptomology, should be evaluated before deciding on conservative management. Observation is a common strategy in incidentally found meningiomas in adults. Studies of the adult population have shown that over 90% of meningiomas managed with observation grew over time with tumors larger than 2.5 cm tending to grow at more significant rates. With the long life expectancy of children, patients and parents should appropriately be counseled on the likely need for future surgical intervention. If conservative management is chosen, patients should be closely monitored with serial MRI every 6 to 12 months. If at any point there is radiographic evidence of tumor growth or if tumor-related symptoms develop, surgical intervention is strongly recommended.

Surgery The definitive treatment for meningiomas is complete surgical resection, and the extent of surgical resection has been shown to be the most important prognostic factor for survival across all WHO tumor grades. Subtotal resection is associated with disease progression and the potential for malignant transformation. Surgical planning, including patient positioning, approach, and technique, is specifically dependent on tumor location, vascular supply, and patient-related factors. In the pediatric population, where blood loss is a major concern, staged procedures may also be an option in order to achieve gross total resection. Because of the large size of tumors at presentation and small blood volumes in pediatric patients, surgical mortality is estimated to be as high as 3% with a postoperative morbidity of as high as 40%. As meningiomas tend to be vascular tumors, preoperative angiograms for tumor embolization are commonly employed

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in adults (Stanuszek et al., 2014). Evidence has shown that selective embolization of feeding vessels has reduced operative blood loss and the length of surgery. However, because of the small-caliber vessels in children, there may be a significant risk of procedural complications, and treatment decisions must be made on an individual basis (Stanuszek et al., 2014). If preoperative embolization is not undertaken, attempts should be made to access and disrupt the major vascular supply (usually extradural) of the tumor early during surgery. This technique reduces intraoperative blood loss and also may make the tumor softer and more amenable to resection (Fig. 131-11). For the most part, low-grade meningiomas maintain an arachnoid plane between the tumor and surrounding brain. In cases of atypical or malignant meningiomas, tumors are more likely to violate the arachnoid barrier and invade brain tissue, dura, and vessels. For these reasons, compete resection becomes considerably more difficult. If dura or bone appears to be invaded by tumor, it should be resected as much as possible. Small tumors may be able to be removed en bloc; however, larger tumors may require piecemeal resection. The greatest difficulties arise when a patent’s venous sinus is invaded by the tumor. In such cases, it may be prudent to leave a small portion of the tumor behind, rather than sacrificing an open dural sinus. Even in the anterior third of the sagittal sinus, sacrifice of this portion of the vessel cannot always be done with impunity. Close observation, even allowing the affected dural sinus to occlude slowly over time, will often permit an additional attempt at total tumor extirpation. Stereotactic radiosurgery may also be considered a therapeutic option, although the risk of malignant transformation cannot be discounted. Recurrence rates of meningiomas are largely based on data obtained from the adult literature. With complete resection, recurrence rates of up to 20% within 25 years have been reported. In patients with subtotal resections, recurrence rates may be as high as 80% to 90%. These data necessitate long-term follow-up of children with meningiomas into adulthood.

Radiation Data regarding adjuvant radiation to childhood meningiomas are limited; however, radiation therapy has been proven to be effective as an adjuvant to surgery in adults. The National Institute for Health and Clinical Excellence recommends radiation treatment for adult patients with WHO grade 2/3 tumors, presence of adjacent brain or local invasion, tumor relapse, or if there is a contraindication to initial surgical resection. With conventional fractionated radiotherapy, doses of 50 to 55 Gy with dose increases to 60 Gy only considered in exceptional circumstances. Progression-free survival was shown to improve from 50% to 80% in adults with subtotal resection after radiation. In the pediatric population, the longterm neurocognitive sequelae must also be taken into account before delivering radiation.

Overview Meningiomas in the pediatric population manifest significant differences from their adult counterparts with a much lower incidence. Tumors in children are highly associated with genetic syndromes, especially NF-2, and evaluation for such conditions should be done at the time of diagnosis. Although conservative management with close observation is an option, complete surgical resection portends the best long-term outcome of patients.

SCHWANNOMAS Although intracranial schwannomas are the most common tumor of the cerebellopontine angle in adults, they are exceedingly rare in children. Only 0.7% of all schwannomas develop in the pediatric population and account for 2% of posterior fossa tumors in children. Schwannomas can arise from any cranial nerve and have been reported to grown from nerves III, V, VII, VIII, IX, X, XI, and XII. As in adults, vestibular schwannomas are the most common form and are typically associated with NF-2. Although these are benign lesions, their size and location can make these tumors particularly challenging to treat (Fig. 131-12).

Clinical Presentation The clinical presentation of intracranial schwannomas is quite varied. As with all mass lesions, common presentation includes signs of increased intracranial pressure with accelerations in head growth, developmental delay, papilledema, headaches, or vomiting. Tumors arising in the cerebellopontine angle can result in obstructive hydrocephalus from mass effect on the fourth ventricle, cerebral aqueduct, or fourth ventricular outflow pathways. As the tumors enlarge, cerebellar symptoms may also develop. Schwannomas are tumors of the nerve sheath rather than the nerves themselves. For this reason, tumors will grow centripetally outward from the nerve. Cranial nerve palsies will occur only if tumor growth is restricted, usually by local bony anatomy.

Schwannomas and Genetic Conditions The development of intracranial schwannomas is associated with both NF2 and schwannomatosis. These conditions are a result of genetic mutations in the merlin gene on chromosome 22q12 (Hilton and Hanemann, 2014). In cases of sporadic schwannomas, the majority have also shown loss of the chromosome 22q as well. Bilateral vestibular schwannomas are pathognomonic for the diagnosis of NF-2, and the presence of a unilateral vestibular schwannoma in patients aged under 30 years should prompt an evaluation for NF-2. Schwannomatosis is a relatively newly reported clinically distinct form of neurofibromatosis. It is characterized by the development of multiple spinal peripheral, and cranial nerve schwannomas as well as rhabdoid tumors. However, these patients lack vestibular schwannomas and the other diagnostic criteria of NF-2 (Hilton and Hanemann, 2014). In 2007, it was first identified that a mutation in the SMARCB1 tumor suppressor gene is responsible for this condition.

Neuroimaging Intracranial schwannomas are typically found in the cerebellopontine angle. Noncontrast CT imaging shows isodense lesions to normal brain. On cranial bone imaging, tumors may have expansion of the porus acusticus, jugular foramen, or any other bony foramina. MRI generally shows a T1-weighted isointense lesion to gray matter and homogenous enhancement with contrast delivery.

Histopathology Schwannomas are benign tumors of Schwann cell origin and are classified by the World Health Organization as a grade I benign nerve sheath tumor. They can originate from any peripheral, cranial, or autonomic nerve (Agarwal, 2015).



Classically, schwannomas are composed of two distinct cellular patterns. Antoni A fibers are compact cellular structures with spindle-shaped cells. These cells can palisade to form Verocay bodies. Contrarily, Antoni B fibers are less compact with a loose microcystic matrix. They are relatively hypocellular but rich in collagen fibers and macrophages. Often pediatric schwannomas lack the biphasic histology of adult schwannomas. Rather, they are more uniformly hypercellular with the presence of Verocay bodies. Other features unique to pediatric schwannomas include hemosiderin deposits and reactive vascular changes. Although mitotic figures are not seen in adult schwannomas, they may be present in their pediatric counterparts.

Treatment Because of the rare nature of pediatric schwannomas, treatment options are extrapolated from the adult literature. Management includes three strategies: observation, radiosurgery, or microsurgery (Zygourakis et al., 2014). Tumor size and symptomatology as well as patient and family preferences dictate the best course of treatment. Complete surgical resection is curative for schwannomas, and symptomatic lesions should be surgically resected when possible. Surgical approaches vary based on tumor location, with the retrosigmoid approach being commonly used. If tumors appear to be highly vascular, preoperative embolization is an option to reduce blood loss.

Overview Schwannomas are rare in childhood. They occur more frequently in patients with NF-2 but, even then, are seen more commonly in adults than in children. When possible, complete surgical resection is indicated and curative. SELECTED REFERENCES Agarwal, A., 2015. Intracranial trigeminal schwannoma. Neuroradiol. J. 28, 36–41. Hilton, D.A., Hanemann, C.O., 2014. Schwannomas and their pathogenesis. Brain Pathol. 24, 205–220. Kim, I., Shekhtman, E., Wisoff, J.H., et al., 2015. Stereotactic radiosurgery as part of multimodality craniopharyngioma management. In: Evans, J.J., Kenning, T.J. (Eds.), Craniopharyngiomas: Comprehensive Diagnosis, Treatment and Outcome. Elsevier, New York, pp. 327–334. Lee, C.C., Yang, H.C., Chen, C.J., et al., 2014. Gamma knife surgery for craniopharyngioma: report on a 20-year experience. J. Neurosurg. 121 (Suppl.), 167–178.

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McCrea, H.J., George, E., Settler, A., et al., 2015. Pediatric suprasellar tumors. J. Child Neurol. 2015. [Epub ahead of print]. Müller, H.L., 2015. Craniopharyngioma: long-term consequences of a chronic disease. Expert Rev. Neurother. 15, 1241–1244. Ostrom, Q.T., Gittleman, H., Fulop, J., et al., 2015. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 17 (Suppl. 4), iv1–iv62. Stanuszek, A., Piatek, P., Kwiatkowski, S., et al., 2014. Multiple faces of children and juvenile meningiomas: a report of single-center experience and review of literature. Clin. Neurol. Neurosurg. 118, 69–75. Zygourakis, C., Oh, T., Sun, M., et al., 2014. Surgery is cost effective treatment of young patients with vestibular schwannomas: decision tree modeling of surgery, radiation, and observation. Neurosurg. Focus 37, E8.

E-BOOK FIGURES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 131-1 Craniopharyngioma distorting the optic chiasm (arrow). Fig. 131-2 Computed tomography scan in patient with craniopharyngioma demonstrating a suprasellar and intrasellar mass with calcifications as well as hypodense solid and cyst components. Fig. 131-4 Craniopharyngioma. Magnetic resonance imaging with gadolinium demonstrates the enhancing cystic capsule and the solid tumor. Fig. 131-5 Craniopharyngioma demonstrating histology of the adamantinomatous tumor subtype with multistratified squamous epithelium with peripheral palisading (dark nuclei). Fig. 131-6 Craniopharyngioma demonstrating histology of the squamous papillary tumor subtype. Fig. 131-7 Microsurgical resection. Fig. 131-8 Stereotactic localization of trajectory for aspiration of craniopharyngioma cyst as well as placement of intracyst catheter/reservoir for subsequent repeated aspirations of tumor cyst. Fig. 131-9 Meningioma. Fig. 131-10 Meningioma. Histology of a grade 1 meningioma. Fig. 131-11 Meningioma—the tumor arises in the extraaxial plane and distorts the surrounding brain. Fig. 131-12 NF-2 schwannoma.

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132  Pediatric Intradural Spinal Cord Tumors

Ben Shofty, Ori Barzilai, Zvi Lidar, Eugene Hwang, and Shlomi Constantini

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Intradural spinal cord tumors (SCTs) are composed of a heterogeneous group of neoplasms, accounting for approximately 10% of pediatric central nervous system tumors (Russell & Rubinstein 1989). Over the past five decades, the overall mortality and morbidity caused by these tumors has been reduced dramatically. The advantages of early diagnosis via modern imaging and modern neurosurgical tools such as intraoperative electrophysiological monitoring, the surgical microscope, and the ultrasonic aspirator have led to improvements in surgical morbidity and in general prognosis. Today, the standard of care of SCTs is complete surgical resection when possible, although adjuvant therapy provides benefit in selected cases. This chapter focuses on the diagnosis and management of common intradural (extramedullary and intramedullary) primary pediatric SCTs.

EPIDEMIOLOGY There is little population-based data available on pediatric primary SCTs. Many of the existing statistics are not current, having often been obtained from outdated surgical series. Intradural spinal tumors as a whole are believed to occur with an incidence that ranges from 0.7 to 1.1 cases per 100,000 persons. Intramedullary spinal cord tumors (IMSCTs) account for approximately 2% to 4% of all CNS tumors in the general population. It has been estimated that approximately 30% of SCTs in the pediatric population are intramedullary, 24% are extramedullary, 35% are extradural (and not included in this chapter), and 10% are of other types. Astroglial tumors are the most common type of intramedullary tumors, accounting for around 90% of all pediatric IMSCTs, with a mean presentation age of 5 to 10 years and 60% in adolescence. Neurofibromatosis (NF) 1 and 2 are associated with IMSCTs, with as many as 19% of patients suffering from such tumors. Among NF1 patients, astrocytomas are more common. In NF2, ependymomas are more frequent. NF1 and NF2 are also known for their hallmark extramedullary nerve-sheath tumors (NSTs): neurofibromas and schwannomas, respectively.

PRESENTATION Reported clinical manifestations of SCTs have changed since the beginning of the magnetic resonance imaging (MRI era), potentially due to earlier diagnosis. Yet even today the primary physician, neurologist, and orthopedist must have a high index of suspicion of primary sensory complaints such as dysesthesia and localized back pain to make an early diagnosis before permanent damage occurs. In the pediatric age group, it is common for parents to become aware of a problem before any objective signs are apparent on the neurologic examination. In many of these patients the onset of symptoms is attributed to an apparently trivial injury. Occasionally, parents describe symptomatic exacerbations and remissions. For both children and adults,

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the most common early symptom is local pain along the spinal axis that is usually most acute in the bony segment directly over the tumor. Typically pain is worse in the recumbent position because venous congestion further distends the dural tube, resulting in characteristic night pain. Other symptoms include motor disturbances, radicular pain (occurring in about 10% of patients, usually limited to one or two dermatomes), paresthesias, painful dysesthesia (hot or cold painful sensations), and rarely, sphincter dysfunction. Weakness of the lower limbs is usually first manifested as an alteration in normal gait. This is often very subtle and may only be evident initially to a watchful parent who notes more frequent falling and/or walking on heels or toes. In young children there is often a history of being a “late walker,” and in very young children (under 3 years) there is often a history of motor regression. IMSCTs usually present with myelopathic symptoms of insidious onset. Localized pain and upper extremity paresthesias are the initial symptoms in 50% to 90% of patients with cervical lesions. Thoracic lesions may present with lower limb sensory losses and with upper motor neuron signs. Sphincter dysfunction is present in up to 40% of patients. In the pediatric population, pain is less often a presenting symptom, but is present in approximately 50% of patients. Symptoms usually last for months or even years before diagnosis. Different SCT subtypes may present with slightly different clinical pictures. For rare malignant astrocytomas, the clinical presentation will include a more rapid decline in gait and pain of increasing intensity. Cervical ependymomas characteristically present with bilateral, symmetric dysesthesias. The anatomic location of the tumor usually correlates with the clinical presentation. Cervical tumors may present with torticollis. Scoliosis is the most common early sign of an intramedullary thoracic cord tumor. Sphincter laxity is considered a late sign except in tumors that originate in the conus/ cauda equina area. Higher tumors present less commonly with sphincter abnormalities, even with cystic components extending into the conus, Spinal cord compression is more common at presentation of EMSCTs than IMSCTs. Hydrocephalus due to protein secretion into the cerebrospinal fluid is a common presentation of IMSCTs in infants. Torticollis and progressive kyphoscoliosis are also common (Box 132-1).

DIAGNOSIS Once an SCT is suspected, spinal MRI (preferably of the entire neuroaxis) is the imaging method of choice. The MRI protocol should always be carefully planned according to the clinical symptoms and neurologic signs in conjunction with a neuroradiologist. It should consist of unenhanced T1- and T2weighted images and contrast-enhanced T1-weighted images. Gadolinium may enhance the solid component of the tumor and help delineate it from surrounding edema. Ependymomas, meningiomas, and NSTs typically contrast-enhance brightly after gadolinium injection. Astrocytomas have a



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TABLE 132-1  Tumor Characteristics, Treatment Recommendations, and Average Prognosis Tumor EXTRAMEDULLARY Meningioma Schwannoma and Neurofibroma Ependymoma of cauda equina (Myxopapillary) INTRAMEDULLARY Astrocytoma

Malignant Glioma Hemangioblastoma

Ependymoma

MR Appearance

Typical Location

Treatment

Prognosis

T1-hypo T2-hyper Contrast enhancing Solid T1-iso T2-hyper Contrast enhancing Expansile T2-hyper Contrast enhancing

Thoracic region Dural based

CR

Sometimes dumbbell shaped Extending toward the foramen

Resection

Generally good Beware of anteriorly located tumors Generally good

Filum/Conus/Cauda

Resection RT

Good Beware of infiltration into the conus

Expansile T2-hyper Heterogeneous enhancement Cyst and/or syrinx T2-hyper Contrast enhancing Syringobulbia Syringomyelia Highly vascular Cord edema Expansile T2-hyper Contrast enhancing Cyst and/or syrinx

Cervical/thoracic

Aggressive resection RT/CT

Good

Cervical/thoracic

Resection RT/CT

Poor

Cervical/thoracic

Resection

Good

Cervical

Resection RT reserved for special cases

Very good

CR, Complete resection; CT, chemotherapy; MR, magnetic resonance; RT, radiotherapy T1-hypo, T1 hypointense; T2-hyper, T2 hyperintense.

BOX 132-1  When to Obtain an MRI on a Patient With Scoliosis 1. Documented rapid progression 2. Atypical curve 3. Age: early onset ( 10 years) 6 to 115x ULN

Normal to 2x ULN Normal to 7x ULN Normal to 125x ULN 4 to 260x ULN 4 to 28x ULN Normal to 15x ULN

Limb-girdle muscular dystrophy type 1 (autosomal dominant) 1.6 to 9x ULN   LGMD1A (MYOT) Normal to moderately elevated   LGMD1B (LMNA) 4 to 25x ULN   LGMD1C (CAV3) Normal to 10x ULN   LGMD1D (DNAJB6) Normal to 2x ULN   LGMD1E (DES) Normal to 20x ULN   LGMD1F (TNPO3)

Limb-girdle muscular dystrophy type 2 (autosomal recessive) 6 to 84x ULN   LGMD2A (CAPN3) 2 to 150x ULN   LGMD2B (DYSF) 8 to 150x ULN   LGMD2C (SGCG) 4 to 100x ULN   LGMD2D (SGCA) 3 to 209x ULN   LGMD2E (SGCB) 5 to 60x ULN   LGMD2F (SGCD) 1.2 to 17.5x ULN   LGMD2G (TCAP) 1.4 to 24.5x ULN   LGMD2H (TRIM32) 3 to 60x ULN   LGMD2I (FKRP) 1.5 to 17x ULN   LGMD2J (TTN) 20 to 40x ULN   LGMD2K (POMT1) 6 to 57x ULN   LGMD2L (ANO5) 6.7 to 343x ULN   LGMD2M (FKTN) 8.6 to 22x ULN   LGMD2N (POMT2) 28 to 68x ULN   LGMD2O (POMGNT1) 19 to 29x ULN   LGMD2Q (PLEC) FSHD1

Normal to 3.8x ULN

FSHD2

3 to 4x ULN

Congenital myopathy

Values typically normal (see following entries) Normal to 9x ULN Normal to moderately elevated Normal to mildly elevated Normal to 8x ULN Normal to mildly elevated

         

Myotubular myopathy Centronuclear myopathy (DNM2) Nemaline myopathy Central core disease Congenital fiber type disproportion

Pompe disease

Normal to 15x ULN

Myotonic dystrophy type 1 (DM1)

Normal to 4x ULN

Juvenile dermatomyositis

Normal to 100x ULN

Juvenile polymyositis

Normal to 35x ULN

Viral myositis

Normal to 59x ULN

CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CMD, congenital muscular dystrophy; FSHD, facioscapulohumeral muscular dystrophy; LGMD, limb-girdle muscular dystrophy; ULN, upper limit of normal.

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Drug Administration (FDA) in 2016. The potential falsepositive rate and difficulties interpreting mild serum CK levels should be considered as newborn screening programs are rolled out because pediatric neurologists will begin seeing infants with positive screening results. A pilot study of newborn screening in DMD demonstrated high sensitivity and low false-positive rates when the serum CK was over 2000  U/L (Mendell et  al., 2012). Screening serum and urine tests are also available for some metabolic muscle diseases. These include lactate and pyruvate for mitochondrial disease and the serum carnitine panel, serum acylcarnitine panel, and urine acylglycine panel for other metabolic myopathies. The measurement and interpretation of lactate and pyruvate are often difficult. Serum lactate levels may be artifactually elevated if a child is upset during phlebotomy or if a tourniquet is used, and thus mild to moderate elevations do not necessarily indicate the presence of a mitochondrial disorder. Lactate and pyruvate levels measured in cerebrospinal fluid tend to be more reliable but are more invasive to obtain. A third means of quantifying lactate levels is magnetic resonance spectroscopy (MRS), which can detect elevated lactate in selected regions of the brain. Serum chemistries and serologies may be useful in several acquired neuromuscular disorders, including inflammatory myopathies. If a child is suspected of having dermatomyositis or polymyositis, serum testing for general inflammatory markers and more specific antibody titers may contribute to the diagnostic evaluation. A serum antibody that is specific for dermatomyositis is Jo-1. This topic is discussed in more detail in Chapter 150. Antibody titers can be very helpful in the diagnostic evaluation of a child with suspected neonatal or juvenile myasthenia gravis (Chiang, Darras, and Kang, 2009). The classic and most commonly elevated antibody titers for myasthenia gravis in both children and adults are the acetylcholine binding, blocking, and modulating antibodies, which are found in about half of children with ocular myasthenia and the majority of children with generalized myasthenia (Liew et al., 2014). Binding antibodies attach to portions of the receptor aside from the acetylcholine binding site, blocking antibodies prevent attachment of acetylcholine to the receptor, and modulating antibodies cross-link acetylcholine receptors with subsequent degradation. Because acetylcholine receptor antibodies were the first to be identified in association with myasthenia and are so commonly found, patients without these laboratory abnormalities are referred to as having “seronegative” myasthenia gravis. This is to some extent a misnomer because this patient subpopulation is also likely to harbor elevated antibody titers of various types. The most well known of these is the muscle-specific kinase (MuSK) antibody, which is often detected in seronegative adult myasthenia gravis and less frequently in seronegative juvenile myasthenia gravis (Liew et al., 2014). Important therapeutic considerations in MuSK antibody–positive myasthenia gravis are that this subtype of disease tends to be less responsive to cholinesterase inhibitors, which are often first-line therapies for myasthenia gravis, and that the literature regarding the efficacy of thymectomy, although to some extent supportive, is somewhat more conflicted than for acetylcholine receptor antibody–positive cases. A third category of antibody for myasthenia gravis is the antistriated muscle or antititin antibody. In adults, elevations of this antibody are usually seen in conjunction with elevations of acetylcholine receptor antibodies and are associated with a higher incidence of thymoma. In children, elevated antistriated muscle/antititin antibody titers may be found in isolation and do not seem to be associated as consistently with thymoma (Liew et al., 2014). This topic is discussed further in Chapter 145.

With respect to inflammatory neuropathies, serum antiganglioside antibodies are useful for selected subtypes. Anti-GQ1b antibodies may be elevated in the Miller-Fisher variant of Guillain-Barré syndrome, whereas anti-GM1 antibodies are sometimes elevated in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, antibody elevations are less consistently recorded in affected children, especially those with CIDP. Cerebrospinal fluid analysis is useful in selected situations, most prominently for the evaluation of suspected inflammatory neuropathies such as Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The classic finding of cytoalbuminologic dissociation (elevated protein without pleocytosis) supports the diagnosis of an inflammatory neuropathy and is likely caused by the radicular involvement that is often seen in these disorders. However, it is important to remember that cytoalbuminologic dissociation may also be seen in inherited neuropathies, which may be an important consideration for more chronic and indolent presentations.

NERVE CONDUCTION STUDIES AND ELECTROMYOGRAPHY Peripheral electrodiagnostic testing, consisting of nerve conduction studies and electromyography, was first developed in the 1940s. It continues to be an important test modality for the diagnosis of certain types of peripheral nervous system disorders in the pediatric population (Karakis, Liew, Darras, Jones, and Kang, 2014). Diagnostic categories that may be characterized in this manner include anterior horn cell diseases (spinal muscular atrophy, polio), neuropathies (CharcotMarie-Tooth disease, inflammatory neuropathies), disorders of the neuromuscular junction (myasthenia gravis, congenital myasthenic syndrome, botulism), and myopathies (congenital myopathies, dystrophies, myotonias and myositis). The one major neuromuscular disease category for which electrodiagnostic testing is typically no longer useful is muscular dystrophy because significantly elevated serum CK levels, especially if associated with abnormal results on muscle ultrasound, will nowadays justify immediate genetic testing. However, electrodiagnostic testing remains useful even in some cases of muscular dystrophy because some subtypes do not yield dramatic elevations of serum CK levels and present differently than other forms. Facioscapulohumeral muscular dystrophy is one example. Technical considerations abound in the conduct of pediatric nerve conduction studies and electromyography, ranging from potential distress to the patient to electrode placement to differences in normal values. When performed by an electromyographer who is experienced and comfortable with children, these studies are often surprisingly well tolerated by the majority of children without the use of analgesia, conscious sedation, or general anesthesia. Toddlers are typically the most challenging and are more likely than infants or older children to require conscious sedation or general anesthesia. One important practical consideration when general anesthesia is used is that certain drugs, especially propofol, obliterate F-wave responses, and thus these factors should be taken into account when planning and interpreting electrodiagnostic testing in such settings. Electrode placement may be more challenging in infants and younger children because of the smaller extremity sizes. Surface electrodes may need to be trimmed in certain situations, and smaller-sized ring electrodes may be helpful for some sensory studies. Standard distances are impractical for infants and younger children. One specific consideration is that sural sensory responses are



Laboratory Assessment of the Child with Suspected Neuromuscular Disorders

typically difficult to record in infants; the medial plantar response is more consistently obtainable in this age group. Normal ranges for latencies, amplitudes, and conduction velocities vary by age. Two general rules are helpful to remember: newborn nerve conduction velocities are typically half the values of those found in older children and adults, and nerve conduction study parameters reach adult values by the age of 3 to 5 years. The electrodiagnostic approach to disorders of the neuromuscular junction merits particular attention. Repetitive stimulation testing, a variant of a motor nerve conduction study, is as useful in children as in adults, but it is often more difficult for young children to remain still for this delicate test than adults. If there is a high index of suspicion for a disorder of the neuromuscular junction and the child has difficulty with this testing modality, conscious sedation or general anesthesia may be justified depending on what other supportive data are available. Single-fiber electromyography is a specialized form of electromyography that is especially useful in diagnosing disorders of the neuromuscular junction. The core measurement in single-fiber electromyography is the difference in latencies between the potentials generated by two different muscle fibers from the same motor unit. In disorders of the neuromuscular junction, the latencies are more volatile, leading to increased “jitter.” Traditional single-fiber electromyography requires that the patient be extremely compliant with the gentle activation of the muscle being tested; ideally, only a single motor unit would be activated at a time. As one can imagine, this degree of subtle motor control cannot realistically be expected of many children. Thus a variant of this test, called stimulated single-fiber electromyography, was developed, and it is especially useful in children (Tidswell and Pitt, 2007; Pitt, 2008). Instead of requiring voluntary motor activation, this variant makes use of a monopolar stimulating electrode to activate individual motor units with small electrical currents. Accurate recordings are possible with ordinary concentric electrodes. In skilled hands, this test has a high degree of accuracy.

MOTOR UNIT NUMBER ESTIMATION One of the great difficulties in assessing motor neuron disease is the impracticality of sampling motor neurons, either via biopsy or imaging techniques, to measure the progression of these disease processes in clinical and research settings. Functional motor testing is a key component of such assessments, but there is a need for complementary neurophysiological measures. The motor unit number estimate is an approach developed in the 1970s that makes use of a variant of nerve conduction studies to stimulate and estimate the size and number of individual motor units in a given peripheral nerve. The currents used are much lower than in traditional motor nerve conduction studies, and the motor unit amplitudes are measured in µV rather than mV, on the same scale as sensory nerve action potentials. Several specific techniques have been developed to collect relevant data and calculate the motor unit size. Motor unit number estimation was initially applied to the study of amyotrophic lateral sclerosis, polio, and Duchenne muscular dystrophy. In recent years, it has gained increased attention as a potential outcome measure for spinal muscular atrophy in children. Several clinical studies have validated its longitudinal reliability in this setting, and intriguing observations were made in a natural history study that involved this modality. Motor unit number estimation is currently used primarily as a biomarker to track outcomes in longitudinal clinical studies, but it may have future diagnostic applications.

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ELECTRICAL IMPEDANCE MYOGRAPHY Electrical impedance myography is an emerging technique that shows a great deal of promise as a tool to assess the severity of various neuromuscular disorders. It is likely to play a role as an outcome measure for human clinical trials and may eventually have diagnostic applications as well. Its chief virtues are that it is noninvasive and painless, making use of high-frequency, low-intensity electrical currents that are not perceptible by humans; thus, this approach could be especially useful in the pediatric population. As in traditional nerve conduction studies, current is administered, and voltage is measured using surface electrodes. One study demonstrated that electrical impedance myography could distinguish between spinal muscular atrophy types 2 and 3 and between individuals affected and unaffected by spinal muscular atrophy in general, indicating that this tool has a high potential to serve as an outcome measure for spinal muscular atrophy clinical trials. Electrical impedance myography and skeletal muscle ultrasound also appear to be complementary measures that could be used in clinical trial settings.

IMAGING STUDIES Skeletal muscle imaging via ultrasonography and magnetic resonance imaging (MRI) techniques has become increasingly sophisticated over the years. Both technologies have advantages in various circumstances. Ultrasound technology was first applied to monitoring for cardiac complications in Duchenne muscular dystrophy in the 1970s. The possibility of using sonographic studies of skeletal muscle for primary diagnostic purposes in muscular dystrophy, congenital myopathy, myotonic dystrophy, and spinal muscular atrophy was subsequently examined in the 1980s. Muscle ultrasound was also explored as a means of carrier detection for Duchenne muscular dystrophy and Becker muscular dystrophy. One of the great advantages of muscle ultrasound is that it is a noninvasive technique that can be easily used in infants and children, providing evidence for muscle disease, seen as increased echogenicity with scarce or no visualization of the underlying bone structures. This information can be very useful at the time of deciding on further diagnostic evaluations in children with minimal clinical signs or mildly elevated CK levels without any weakness. The increased echogenicity pattern differs from the one observed in spinal muscular atrophy, which displays a denervation pattern characterized by an increased ratio between subcutaneous tissue and the muscle belly and often a granular pattern in the muscle. As investigators and clinicians gained greater experience with this testing modality, they were able to associate different ultrasound patterns with specific neuromuscular diseases, including congenital muscular dystrophy. During much of the 1990s, as causative genes for various type of neuromuscular diseases were discovered in rapid succession, skeletal muscle ultrasound was given less attention as a diagnostic modality. However, in the 2000s, it became clear that genetic analysis in isolation would often not be sufficient to clarify the diagnosis for various neuromuscular disorders, especially as genotype–phenotype correlations became more complicated than initially expected. As a result, ultrasonography of skeletal muscles as a diagnostic tool underwent a renaissance, and reference ranges for children were established in greater detail. Currently, skeletal muscle ultrasound is used in a number of centers as a diagnostic tool that helps narrow the differential diagnosis for neuromuscular disorders in children. By examining several muscles, one can assess which are involved and those that are relatively spared. Collectively, this montage can suggest a specific disorder, for example, sparing of the rectus femoris in RYR1-related central core

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myopathy. This technique can be implemented with minimal training. Some studies suggest that skeletal muscle ultrasound may hold promise as a longitudinal outcome measure for human clinical trials. The potential of applying MRI techniques to the study of skeletal muscle began to be explored in the 1980s, initially for Duchenne muscular dystrophy, followed by other diseases. As in other tissues, this testing modality has the capacity to show even greater morphologic detail than ultrasound in skeletal muscle, allowing for an analysis of the extent and type of involvement of individual muscles. Thus with skeletal muscle MRI studies, detailed portfolios of patterns of muscle involvement may be constructed. A number of disease-specific patterns have been identified in neuromuscular disorders such as myotonic dystrophy, Emery-Dreifuss muscular dystrophy, Ullrich congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, Miyoshi myopathy, and Becker and limbgirdle muscular dystrophies. This has proven to be important to guide genetic testing, especially for muscle disorders with overlapping clinical phenotypes, such as muscular dystrophies with rigidity of the spine (Mercuri et al., 2010) and congenital myopathy subtypes that are associated with mutations in several genes. Short scanner protocols help make this testing modality more accessible to children. MRI findings correlate well with muscle histologic abnormalities. Skeletal muscle MRI is showing increasing promise as a noninvasive outcome measure in clinical trials of new therapies for muscular dystrophy. Longitudinal changes in fat content, for example, are correlated with muscle function changes in boys with DMD. The use of nerve imaging to aid in the diagnosis of neuropathies has gained more attention recently. Nerve ultrasound data and magnetic resonance neurography can help with the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and aid in the detection of nerve entrapment. Brain imaging does not typically contribute to the diagnostic evaluation of many neuromuscular disorders. The most prominent exceptions to this rule lie among several subtypes of congenital muscular dystrophy. Merosin-deficient congenital muscular dystrophy is classically accompanied by diffuse, symmetric white-matter lesions on MRI. The classic dystroglycanopathies are usually accompanied by striking structural brain abnormalities that overlap among subtypes. These range from isolated cerebellar structural abnormalities that often include hypoplasia or cysts to prominent supratentorial abnormalities that include cortical pachygyria, polymicrogyria, and hypoplasia of the corpus callosum, as observed in Fukuyama congenital muscular dystrophy or muscle–eye– brain disease. One of the most severe cortical malformations, lissencephaly, is a classic finding in Walker-Warburg syndrome.

for clinical applications currently is targeted sequence capture, in which a selection of genes is sequenced based on the putative disease phenotype. Next-generation sequencing can be especially helpful in diagnosing disease categories in which the number of causative genes is especially abundant, such as limb-girdle muscular dystrophy, congenital muscular dystrophy, and congenital myopathy. This technique has also helped with the identification of novel muscle disease genes such as MEGF10 and its newly identified phenotype, EMARDD, and the identification of novel genotype–phenotype correlations for previously described disease genes. Whole-exome sequencing is offered by some test facilities for clinical use; whole-genome sequencing currently is primarily used in research settings, but it may have greater clinical applicability in the future. However, the proliferation of causative genes and genetic test modalities has generated increasing confusion among physicians and other health-care providers regarding the best approach to genetic diagnosis in children with neuromuscular diseases. It is important to remember that newer technologies such as next-generation sequencing are currently most accurate with respect to detecting single-nucleotide changes and small insertions and deletions (called “indels”) up to about 10 nucleotides in length. Larger mutations may sometimes be detected but not with the consistency that is seen with some of the older genetic technologies. Some of the most common inherited neuromuscular disorders may be missed by nextgeneration sequencing in its current forms because of the nature of the mutations involved. Examples of such diseases include Charcot-Marie-Tooth disease type 1A (duplication of the PMP22 gene), Duchenne muscular dystrophy and Becker muscular dystrophy (frequently caused by single- or multipleexon deletions), facioscapulohumeral muscular dystrophy type 1 (caused in part by contraction of the D4Z4 macrosatellite region on 4q35), and myotonic dystrophy types 1 and 2 (caused by trinucleotide repeat expansions in DMPK and quadruplet repeat expansions in ZNF9, respectively). All of these neuromuscular diseases are caused by large genetic mutations. Many of the older genetic test modalities will retain pockets of applicability for some time to come. The delivery and accessibility of genetic testing are also changing rapidly. For example, 23andMe has gained a great deal of attention with its efforts to market its genetic testing products directly to consumers. After extensive discussions and what turned out to be a temporary cease and desist order, the U.S. Food and Drug Administration recently approved the use of 23andMe’s product to screen for Bloom syndrome. This is certainly a harbinger of a time to come when many individuals will obtain genetic testing of various types and then come to the physician with a report in hand, requesting an interpretation.

GENETIC TESTING

CONCLUSIONS

The inherited basis of many neuromuscular diseases was strongly suspected for many years, but the tools to investigate such connections did not exist until the late twentieth century. The invention of DNA sequencing in 1970s and the polymerase chain reaction in the 1980s paved the way for the landmark cloning of the dystrophin gene in 1986 and the identification of the dystrophin protein in 1987. Since then, dozens of causative genes for muscular dystrophy and other inherited neuromuscular diseases have been identified. The potential for improved diagnosis is vast, and has been augmented further by the sequencing of the complete human genome at the turn of the millennium and the subsequent development of high-throughput next-generation sequencing technologies. The most widely used next-generation sequencing technique

Major advances in the diagnosis of neuromuscular disease were separated by long intervals in the nineteenth century and the first half of the twentieth century. The pace of discovery has accelerated since then and shows no signs of slowing down. The early years of the 21st century have brought a wealth of diagnostic tools that are being applied to neuromuscular disorders, including increasingly sophisticated genetic testing and noninvasive muscle imaging and electrophysiological techniques. These complement an array of established diagnostic test modalities that still play an important role in the diagnostic evaluation of children with suspected neuromuscular disease. As a result, the test options available have become abundant and sometimes confusing. There is, unfortunately, no single diagnostic test that can provide subtype- and



Laboratory Assessment of the Child with Suspected Neuromuscular Disorders

mutation-specific information for all, or even the majority, of such patients. Thus a good history and physical examination remain central to the evaluation of these children, and a basic working knowledge of the information provided by old and new diagnostic tests will be critical to navigating the diagnostic odyssey in the future. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Chiang, L.M., Darras, B.T., Kang, P.B., 2009. Juvenile myasthenia gravis. Muscle Nerve 39, 423–431. Karakis, I., Liew, W., Darras, B.T., et al., 2014. Referral and diagnostic trends in pediatric electromyography in the molecular era. Muscle Nerve 50, 244–249. Liew, W.K., Powell, C.A., Sloan, S.R., et al., 2014. Comparison of plasmapheresis and intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis. JAMA Neurol. 71, 575–580. McMillan, H.J., Gregas, M., Darras, B.T., et al., 2011. Serum transaminase levels in boys with Duchenne and Becker muscular dystrophy. Pediatrics 127, e132–e136.

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Mendell, J.R., Shilling, C., Leslie, N.D., et al., 2012. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann. Neurol. 71, 304–313. Mercuri, E., Clements, E., Offiah, A., et al., 2010. Muscle magnetic resonance imaging involvement in muscular dystrophies with rigidity of the spine. Ann. Neurol. 67, 201–208. Monaco, A.P., Neve, R.L., Colletti-Feener, C., et al., 1986. Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 323, 646–650. Pitt, M., 2008. Neurophysiological strategies for the diagnosis of disorders of the neuromuscular junction in children. Dev. Med. Child Neurol. 50, 328–333. Tidswell, T., Pitt, M.C., 2007. A new analytical method to diagnose congenital myasthenia with stimulated single-fiber electromyography. Muscle Nerve 35, 107–110.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Box 136-1. Useful Neuromuscular Websites with Genetic Information

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Assessment of Pediatric 137  Clinical Neuromuscular Disorders Richard S. Finkel An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Pediatric neuromuscular disorders are common and present significant diagnostic and therapeutic challenges for physicians responsible for their care. In addition, the families of affected children are confronted with much uncertainty about their child’s condition and how to optimize their child’s potential. The combined efforts of multiple specialists are often required to evaluate and manage such children to optimize their potential and quality of life. This chapter presents an overview of the clinical assessment of the neonate, infant, child, and adolescent with a suspected or known neuromuscular disorder. Other chapters review the general principles of the neurologic examination (Chapters 1 to 5), muscle and nerve development (Chapter 135), laboratory assessment of neuromuscular disorders (Chapter 136), diseasespecific information (Chapters 138 to 151), and management of children with neuromuscular disorders (Chapter 153).

DEFINITION, CLASSIFICATION, AND EPIDEMIOLOGY OF PEDIATRIC NEUROMUSCULAR DISORDERS Definition. Neuromuscular disorders are characterized by the anatomic localization of the pathology within the motor unit, which consists of the motor neuron within the ventral horn of the spinal cord and brainstem motor nuclei, peripheral nerve, neuromuscular junction and muscle. Peripheral neuropathies are further characterized as involving the motor, sensory, and/or autonomic modalities, and by their distribution into focal, multifocal or generalized disorders. Muscle disorders are subdivided into six categories based upon histopathology: 1. Dystrophies (degenerative disorders of the muscle fiber) 2. Congenital myopathies (structural abnormality of the muscle fiber or extracellular collagen matrix) 3. Metabolic disorders affecting muscle (storage diseases, energy processing disorders) 4. Mitochondrial diseases (disordered energy generation or utilization) 5. Inflammatory myopathies (idiopathic) 6. Infectious myositis (bacterial, viral, protozoan) Myopathies and dystrophies are genetically based disorders that can be further characterized by the subcellular localization of a mutant protein within the contractile apparatus, dystrophin-associated complex in the sarcolemmal membrane, nuclear envelope, or the extracellular matrix. Myotonic disorders are characterized by clinical features and the related abnormal ion channel. Table 137-1 lists the more common pediatric neuromuscular disorders and is organized based upon these anatomic, pathophysiologic, and genetic principles. A more comprehensive compendium, Gene Table of Neuromuscular Disorders, can be accessed online at http://www .musclegenetable.fr.

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Epidemiology. The combined prevalence of neuromuscular disorders among children and adults was initially estimated in 1991 at 1 in 3500 individuals and 1 in 3000 in children. See the Table 137-2 for additional information. The most commonly encountered pediatric neuromuscular disorders, in descending order of prevalence, are Duchenne muscular dystrophy, Charcot-Marie-Tooth disease (i.e., hereditary motor and sensory neuropathies), congenital myopathies, myotonic dystrophy, other myopathies, spinal muscular atrophies, mitochondrial encephalomyopathies, congenital muscular dystrophies, nondystrophic myotonias, unclassifiable disorders, Becker muscular dystrophy, and metabolic myopathies. Remaining disorders all have much lower prevalence.

EVALUATION OF THE CHILD WITH A SUSPECTED NEUROMUSCULAR DISORDER As clinicians, we endeavor to establish a diagnosis in the neuromuscular patient similar to how we approach other neurologic patients. Sometimes, the diagnosis is obvious and needs only confirmation with a definitive test—for example, the classic infant with spinal muscular atrophy or the boy with Duchenne muscular dystrophy. More often a structured approach is needed to work through the diagnostic process. One such approach is described here and focuses specifically on the more common neuromuscular disorders in the pediatric population. The clinician needs to address several aspects based upon the history and physical examination findings: presenting symptoms, age at symptom onset, gender, rate of progression, other organ system involvement, and family history. Collectively, these clinical features will enable the clinician to localize the lesion within the neuraxis, develop a differential diagnosis, and strategize a plan for further evaluation. Figure 137-1 presents an algorithmic approach to diagnosing pediatric patients with a suspected neuromuscular disorder. Details on laboratory diagnostic testing can be found in Chapter 136. The www.genetests.org website is a compendium of genetic testing laboratories where testing for specific disorders or gene panels can be obtained.

Localization and Classification Neuromuscular disorders in each of the four domains of the motor unit can result from genetic or acquired etiologies. The differential diagnosis is often extensive. Having a structured approach sharpens the focus and reduces the diagnostic odyssey for the patient and family. A fundamental goal of the history and physical examination in the neuromuscular patient is to localize the primary site of dysfunction within the motor unit. Table 137-3 summarizes aspects of the examination that help localize the lesion. This, along with the age of onset, rate of progression, and relevant



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TABLE 137-1  Classification of Pediatric Neuromuscular Disorders This schema is based upon localization within the motor unit with consideration of salient clinical features, electrophysiological findings (for peripheral nerve and neuromuscular junction disorders), muscle biopsy features, and genetic aspects for heritable disorders. The more commonly encountered pediatric disorders are listed here. A full listing of genetic neuromuscular disorders can be accessed on the http://www.musclegenetable.fr. Abbreviations used here are listed at the end of the chapter. Disorder

Features

Gene

Protein

Genetic Etiology

Acquired Etiology Motor Neuron SMA SMA with respiratory distress (SMARD) SMA, X-linked SMA, lower extremity predominant

SMN1 IGHMBP2 UBA1 TRPV4

AIDP (Guillain-Barre syndrome)

CMT type 1, AD, demyelinating

6 main types e.g. CMT1A

13 genes e.g. PMP22

Peripheral myelin protein 22

CIDP

CMT type 2, AD, axonal

22 subtypes e.g. CMT 2A

22 genes e.g. MFN2

Mitofusin 2

CMT type 4, AR CMT, X-linked

6 types e.g. CMTX1

13 genes GJB1

Gap junction protein beta 1

4 subtypes 3 subtypes

4 genes 3 genes

Infection: Polio West Nile virus Enterovirus

Survival of motor neuron 1 Immunoglobulin mu binding protein 2 Ubiquitin-activating enzyme 1 Transient receptor potential cation channel, subfamily V, member 4

Peripheral Nerve

Infection: Tick paralysis Lyme disease

Neuromuscular Junction Infantile botulism

CMS, slow channel

Myasthenia gravis

CMS, fast channel

Neonatal myasthenia gravis

CMS, acetylcholine receptor deficiency Other specific phenotypes

3 subtypes

3 genes

17 subtypes

RAPSYN, CHAT, CHRNE, DOK7, COLQ, MUSK, AGRN, others

Muscular Dystrophy

DMD/BMD EDD

DMD EMD FHL1 LMNA DUX4 22AR and 8 AD forms LAMA2 COL6A1, A2 and A3 SEPN1 ACTA1 18 genes

Muscle

Congenital Muscular Dystrophy

Congenital Myopathy

Myotonic Disorders

FSHD LGMDs Merosin deficient Ullrich/Bethlem Rigid spine Defective glycosylation disorders Nemaline Congenital fiber type disproportion Myotubular Centronuclear Central core Distal Myopathy e.g. Miyoshi Myotonic dystrophy type 1 Myotonic dystrophy type 2 Myotonia congenita Paramyotonia congenita Schwartz-Jampel syndrome

Dystrophin Emerin 4 12 LIM domain 1 lamin A/C Double homeobox 4 Laminin alpha 2 chain of merosin Collagen type VI A1, A2, A3 Selenoprotein N1 Alpha actin e.g. FKRP

10 genes 5 genes MTM1 5 genes RYR1 (also malignant hyperthermia gene)

Myotubularin

DYSF DMPK

Dysferlin Myotonic dystrophy protein kinase

CNBP

Cellular nucleic acid binding protein

CLCN1 (Thompson = AD, Becker = AR) SCN4A (also periodic paralysis) HSPG2

Chloride channel 1

Ryanodine receptor 1

Sodium channel, voltage-gated, type IV, alpha Perlecan Continued on following page

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TABLE 137-1  Classification of Pediatric Neuromuscular Disorders (Continued) Disorder

Features

Metabolic Myopathy

Glycogen storage e.g. GSD type II (Pompe disease) Glycolytic pathway e.g. GSD type V (McArdle disease) Lipid metabolism e.g. CPT type 2

Acquired Etiology

Gene

Protein

Genetic Etiology 10 genes GAA

Alpha-glucosidase

4 genes PYGM

Muscle phosphorylase

12 genes CPT2

Carnitine palmitoyl-transferase II

Idiopathic Inflammatory Myopathy Dermatomyositis Polymyositis Infectious Myositis Viral Bacterial Protozoal

medical and family history, aids in generating a differential diagnosis and plan for further assessment. Neuromuscular disorders present with distinctive and agerelated developmental features. Weakness is the cardinal feature of most neuromuscular disorders but may not be the initial or predominant symptom. Fixed weakness and related impairment need to be distinguished from fluctuating or intermittent weakness. Age at onset varies and may help to limit possible diagnoses. Acquired disorders generally present with an acute or subacute onset and may progress rapidly, with loss of strength and decline in motor function, although genetically based disorders tend to present with a more indolent onset and subtle influence. Exceptions certainly occur; for example, spinal muscular atrophy (SMA) type 1 can present acutely similar to infantile botulism and chronic inflammatory demyelinating polyneuropathy (CIDP) may present in a chronic manner similar to Charcot-Marie-Tooth (CMT) inherited neuropathies. Motor impairment may be complicated by respiratory, cardiac, musculoskeletal, and nutritional compromise, with resultant morbidity, impaired independent functioning, and effect on survival.

History The history needs to capture aspects of the patient’s onset of symptoms and signs, tempo of progression, effect on motor development, presence or absence of muscle pain or cramps, increased or decreased sensory symptoms, and coordination and balance issues. Related respiratory, cardiac, feeding/ growth, and musculoskeletal issues need to be assessed carefully. It is important to inquire about the effect on the patient’s independent functioning at home, at school, and in the community. A careful family history should always be explored. The review of systems should search for features of a systemic or genetic disease (Table 137-4 and Box 137-1). Abnormal laboratory chemistry findings (AST and ALT) may incidentally lead to a neuromuscular diagnosis. Measuring the gammaglutamyl transferase (GGT) helps in eliminating a hepatic component. Findings in the neonate that indicate prenatal onset include congenital torticollis, scoliosis, or multiple joint contractures. These findings are not specific for a neuromuscular disorder and may be seen in many conditions, including genetic syndromes and skeletal dysplasias. Some neonates

with congenital myopathies may have characteristic facies and ophthalmoplegia. Signs and symptoms in the infant include hypotonia (“floppy baby”; see Chapter 138), delayed acquisition of motor milestones, dysphagia, failure to thrive, hypoventilation, and cardiomyopathy. The child with a neuromuscular disorder typically presents with a plateau or slowing of progression in motor development. For example, the boy with Duchenne muscular dystrophy (DMD) may walk at a normal age or be slightly delayed but does not typically come to attention until abnormal running, difficulty climbing stairs, and poor jumping are recognized at age 3 to 4 years. Similarly, the child with SMA type 2 achieves sitting at a normal age and may achieve standing but fails to ambulate independently. An alert parent with CMT may identify the early signs of foot drop or cavus deformity in their similarly affected child. Initial symptoms in the adolescent often include muscle fatigue and activity-related myalgias rather than weakness or a decline in motor function. Muscle stiffness or cramping should prompt consideration of a myotonic disorder or a metabolic disease. Although aching discomfort is common, frank pain is not typical in most neuromuscular disorders. Exceptions include myotonic dystrophy type 2 and the acute sensory presentation of Guillain-Barre syndrome. Fluctuating or intermittent weakness is characteristic of disorders of neuromuscular transmission (e.g., myasthenia gravis), the congenital myasthenic syndromes, and different subtypes of periodic paralysis. Patients with primary orthopedic, arthritic, or chronic pain syndromes may present with intermittent deficits in motor function, especially impaired gait.

Examination The examination can be done in a structured manner to provide maximum information. It includes the following components and is discussed in depth in the online chapter. Inspection. Assess posture, spontaneous motor activity, respiratory effort, and feeding, Muscle bulk and quality. Examine for atrophy, hypertrophy, and fasciculation. Joint mobility and tone. Examine for hypotonia or hypertonia and joint contractures. Joint hyperlaxity can be characterized using the Beighton score (Table 137-5A).



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PRESENTATION Evaluate the history and examination for the following; refer to Table 137-4 and Box 137-1 for additional details Age of onset: congenital, infancy, childhood, adolescence Gender: male/female Clinical symptoms: hypotonia, weakness, motor delay, fasiculations, myotonia, cramping, pain, sensory loss, etc Rate of progression: acute, subacute, chronic, chronic with acute presentation Other organ involvement: cardiac, pulmonary, gastrointestinal, hepatic, renal, musculoskeletal, brain Localization: motor neuron, peripheral nerve, neuromuscular junction, muscle Personal and family history: Do they suggest a genetic disorder?

ESTABLISH INITIAL DIFFERENTIAL DIAGNOSIS Genetic or acquired conditions to consider. See glossary for abbreviations

Motor Neuron Congenital Infancy Childhood Adolescence

SMA type 0 In utero toxin, HIE SMA types 1 and 2 Enterovirus/polio, WNV SMA type 3 Enterovirus/polio, WNV Juvenile ALS Enterovirus/polio, WNV

Peripheral nerve

NM junction

CMT variants In utero toxin CMT variants GBS, toxic, MN

CMS Neonatal MG CMS Botulism, MG

CMT variants GBS/CIDP,tick, toxic, IN, MN CMT variants GBS/CIDP, tick, toxic, IN, MN

CMS MG, toxin CMS MG, toxin

Muscle Congenital DM1, CM, CMD CM, DM1, CMD, MM, MiM, DMD, LGMD EM, IM DMD/BMD, CM, LGMD, DM1, CMD, MM, MiM DM/PM, IM, EM BMD, LGMD, DM1, DM2, MM, MiM DM/PM, IM, EM

PERFORM NON-INVASIVE FIRST-TIER AND, IF NEEDED, INVASIVE SECOND-TIER TESTING TO DETERMINE IF:

1. 2.

Neuropathic (motor neuron or peripheral nerve), neuromuscular junction or muscle disorder Genetic or acquired condition Motor Neuron and Peripheral Neuropathy

Neuromuscular Junction

Myopathy

FIRST TIER Muscle Enzyme (Creatinine Kinase) Other blood tests

Normal or slightly elevated

Normal

*Viral and antiganglioside antibody studies for acquired neuropathy *Heavy metal screen

Acetylcholine receptor antibody titer

Normal to marked elevation Lactate/pyruvate, carnitine, acylcarnitine; K+ for periodic paralysis; aldolase, LDH, ESR and ANA for DM/PM

Muscle imaging

Muscle ultrasound

normal

*Ultrasound for CM and MD *MRI for MD, DM/PM

Brain or other organ imaging

MRI brain for leukodystrophy or mitochondrial features MRI for nerve root enhancement in GBS

Mediastinal MRI or CT for MG associated thymoma

MRI for CMD

Electrophysiology Nerve conduction velocity and electromyography

*NCV: for axonal and demyelinating motor/sensory neuropathy – genetic and acquired *EMG: for motor neuron and axonal motor neuropathy

Repetitive nerve stimulation testing for MG, botulism, or NMJ poisoning

EMG for myopathic features and to exclude a neuropathy

Muscle and Nerve pathology

Nerve biopsy for inflammation or storage, EM for mitochondrial changes

EM of NMJ

Define disease specific myopathology (Chapter 135)

Lumbar Puncture

CSF profile for GBS/CIDP or metabolic neuropathy

N/A

N/A

SECOND TIER

1. 2.

Create ‘final’ differential diagnosis and if acquired condition complete diagnostic evaluation. If genetic, do disease specific testing, gene panel for neuromuscular disorder subtype or whole genome or exome sequencing (Chapter 136 and elsewhere in this section). The www.genetests.org website provides current information on genetic testing laboratories worldwide that offer this testing.

Figure 137-1.  This algorithm presents a suggested pathway for the assessment of the pediatric patient with a suspected neuromuscular disorder. Please refer to Tables 137-1, 137-3, 137-4, Box 137-1 and Figure 137-2 for additional information.

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Assessment of muscle strength and weakness. Weakness can be identified by formal testing of strength and by indirect assessment of motor impairment on functional testing. Strength is a composite of several physiologic elements of motor function: the magnitude, duration, velocity, and torque of muscle contraction. Peak torque strength is most commonly evaluated using manual muscle testing (MMT). The British Medical Research Council (1941, revised 1943) developed the 0 to 5 “MRC” scale, which has since been expanded into a fuller 10-point version (1976) that is now commonly used by neurologists. Table 137-6 describes the MRC scale and two others in common use. It is generally agreed that grade 5− should not be used; the examiner should make a decision that the muscle is normally strong (5) or mildly weak (4+). Proper position is important for administering MMT correctly by assessing the patient in the following positions: Sitting: shoulder abduction, elbow flexion and extension, wrist flexion and extension, fingers and thumb, hip flexion, knee extension, ankle dorsiflexion Supine: neck flexion Prone: neck extension, hip extension, knee flexion, ankle plantar flexion Side-lying: hip abduction The MRC scale focuses upon muscle groups that perform a particular joint motion (e.g., elbow flexion). The MRC scale is nonlinear. For example, on the MRC scale, there is a significant difference in power between a grade 5 (normal; “against strong pressure”) and grade 4+ (mildest grade of weakness, “against moderate to strong pressure”); however, little change in power is noted among grades 3 “against gravity,” 3+ (“against slight pressure”), and grade 4− (“against slight to moderate pressure.)” None of the MMT methods specify the length of time required to achieve a particular grade. As such, only brief peak torque is typically measured. Testing in children requires more subjective judgment as to what is normal for age and gender and usually can be assessed reliably by age 5 years. Testing in DMD has been shown to be reliable but more recently has been largely replaced by myometry and motor function testing, particularly in clinical trials. Myometry testing of strength has the benefit of being a linear scale and is typically used in a research setting. The most commonly used method is hand-held dynamometry of isometric strength. After carefully examining the child for specific areas of weakness, it is important to consider the overall distribution in more general terms of proximal versus distal, and whether there is associated ptosis, ophthalmoparesis, facial, bulbar, neck, or trunk weakness (Fig. 137-2). Motor function testing. This provides insight into the degree of functional motor impairment in addition to indicating indirectly the extent of weakness and fatigue. These tests need to be developmentally appropriate and should be performed quickly and without requiring special equipment. (a) Neonates and infants: It is important to consider developmental features and distribution of hypotonia and weakness. A healthy premature infant will normally have low tone and limited strength, whereas similar findings in a 6-month-old infant are abnormal. It is useful to use a neonatal scoring scale such as the Hammersmith Infant Neurologic Examination, which can be serially administered. It is helpful to note the infant’s posture and degree of antigravity limb activity and breathing pattern in the supine position and to elicit further activity by stroking the limb or tickling the foot. Next, one should examine for torticollis and

A

B

C

D

E

F

Figure 137-2.  Distribution of predominant muscle weakness in different types of muscular dystrophy. A, Duchenne and Becker. B, Emery-Dreifuss. C, Limb-girdle. D, Facioscapulohumeral. E, Distal. F, Oculopharyngeal. Shaded = affected areas. (With permission from Emery, AEH. Fortnightly review: The muscular dystrophies. BMJ 1998; 317:991–5.)

limb contractures and palpate the muscles for bulk and consistency. It also is helpful to examine whether the patient is capable of performing the following postural and elicited responses and note if there is related weakness, asymmetry, or fatigue during the maneuver (Table 137-7). 1. Perform the traction test with a slow pull to sit while holding the infant’s hands; note neck flexion, shoulder fixation, elbow flexion, and hand grip. 2. Observe for the degree of head and neck control in sitting while supporting the infant at the upper thorax under the arms. The spine can also be examined for excessive kyphosis, scoliosis, or rigidity. 3. Next lift the infant upright and check for “slip-through” at the shoulder girdle. 4. Test for weight-bearing capacity in the lower extremities while the infant is held vertically in one hand by placing the other hand on the plantar surface of the feet and pushing up gently to elicit a hip and knee extension reflex.



Clinical Assessment of Pediatric Neuromuscular Disorders

5. This is followed by tipping the infant from a vertical to horizontal posture while holding the infant at the thorax and determining whether there is active neck extension. This can also be elicited by the Landau or Galant maneuvers (see online text). 6. In the infant over 9 months of age the parachute reflex should be performed—first to see if the arms extend and the open hands symmetrically extend and “plant” onto the examination table, followed by checking for the ability of the infant to support his/her full upper body weight, then to “wheelbarrow” along the examination table. A variety of developmental and motor function scales have been used in weak infants and are summarized in the online chapter. (b) Child and adolescent: In the older child and adolescent, clinical symptoms may develop more slowly and findings may be more subtle so a careful and systematic examination can be helpful in detecting motor or sensory abnormalities. 1. Standing: Can the child stand securely? Is there a widebased stance? Encourage the child to squat to pick up a toy and see if she/he can recover upright posture or needs to push off the thigh to do so (Gowers assist). Can a full squat and recovery then be accomplished? Ask the child to stand with feet together and with eyes closed (Romberg test). How well can the child jump? 2. Gait: Using the hallway is often useful. The toddler who recently achieved ambulation will walk with a flat-footed stance phase gait but, within a few months, should develop into a more mature heel strike-stancetoe push-off cadence. Watch for toe walking and, if present, examine the Achilles tendons for tightness or knee for hyperextension, crouched gait, hip waddle, exaggerated lumbar lordosis, or if any asymmetries are present. Then encourage walking on toes and heels and running and making a turn. Finally, evaluate a brief jog and then full run. 3. Supine-to-stand test (Gowers maneuver): Have the child lay supine and then ask to him/her to stand up quickly. By age 3 to 4 years, the normal child will do a sit up, push off the floor with one hand, then pop upright quickly. A child with proximal lower extremity weakness will roll over into the prone position, push up onto both hands and knees (quadruped), spread the legs apart, and lift up the buttocks before thrusting the trunk upright to standing posture. With more advanced weakness of the trunk and hip extensors, the child will push off the anterior thigh with one or both hands to achieve an upright position. 4. Climbing stairs: Toddlers climb stairs initially marking time (both feet on one step) and use one or both handrails. A normally developing child will climb stairs with a handrail by age 20 months and will alternate feet without a handrail ascending by age 44 months and descending by 68 months. General Motor Function Scales. In patients with known weakness, upper limb function is often characterized using the Brooke scale and lower limb function with the Vignos scale (Table 137-9). Many neuromuscular physicians semiquantify how the child runs, arises from supine to stand, and climbs stairs (Table 137-10). This allows for comparison to determine subtle changes and adaptation over time. This can be done informally or in a more structured way that is part of the timed testing (e.g., the North Star Ambulatory Assessment functional scale as described later in this chapter).

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Timed testing of motor function is a practical and useful exercise that can be readily incorporated into the routine clinic evaluation of ambulatory children with neuromuscular disorder. The same three tests described previously are commonly employed: 10-meter run/walk, supine-to-stand time (Gowers maneuver), and the four-step climb. When performed serially at each clinic visit, timed tests provide a perspective that complements the patient’s, the parents’, the physical therapist’s, and the physician’s bedside assessment of strength. Changes in these timed tests are particularly useful in demonstrating a relative decline in function when no skill has actually been lost, referred to as the “plateau phase.” This phase is important to capture in DMD as it is commonly used as the time when initiation of glucocorticosteroid medication should be considered. These timed tests are also predictive of future loss of function. For example, greater than 7 seconds on the supine-to-stand test had an 80% predictive value for loss of ambulation within the next year. The 6-minute walk test distance (6MWT) was developed as a test for adults with cardiac and pulmonary disease. The 6MWT segued into the neuromuscular area initially in the study of adults with myotonic dystrophy and with late-onset Pompe disease, based upon the premise that it summates skeletal muscle, cardiac and respiratory aspects of motor disability. A 30-meter difference has been generally accepted to be clinically meaningful and has been used as the basis for determining a therapeutic response to an intervention in ambulant patients with neuromuscular disorders. As such, the 6MWT has been used as a primary outcome measure in several neuromuscular trials. Additional motor function scales. These scales for older children and adolescents focus largely on lower extremity function (Table 137-11). Muscle stretch reflexes. These “deep tendon reflexes” (DTRs) can be a challenge to obtain in infants and squirmy children. It is important to have the patient relaxed and to place the joint being testing under slight tension, to load the muscle spindles. This can be difficult in the child with hyperlaxity or who is resisting the examination. Distraction with toys or placing the child on the parent’s lap is often useful. It is usually helpful to delay testing reflexes until near the end of the examination, as the child may become upset with the testing and make additional assessment more problematic. Asymmetry in limb tone and reflexes may occur in an infant with an active tonic neck reflex. Thus assessment should be performed with the head midline. Reduced reflexes are typical of a neuromuscular disorder but are not a necessary finding early in the course of a myopathic or neuropathic disorder. In general, reflexes are reduced or absent in myopathies or dystrophies proportionate to the extent of weakness at that site. For example, the patellar reflex is reduced when there is quadriceps weakness. Similarly, acquired neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) will typically have a reduced Achilles tendon reflex when there is plantar flexion weakness. Generalized reduced or absent reflexes are typical of generalized myopathies/dystrophies or inherited neuropathies. Conditions such as myotonia congenita or periodic disorders without fixed weakness such as hypokalemic periodic paralysis will typically have normal reflexes. Increased reflexes are usually indicative of an upper motor neuron disorder. One notable exception is acute motor axonal neuropathy (AMAN), a subtype of CIDP, in which lower limb hyperreflexia is often noted. A few beats of ankle clonus is normal in infants; significant asymmetry, however, may prompt a brain or spinal cord imaging study. Sensory testing. This can be performed in the infant informally by tickle or gentle pinch to the toes. Applying a

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cool tuning fork to the foot and observing for withdrawal from the stimulus works as well as a pin, and the parents will be less alarmed. More detailed testing is sometimes necessary such as when mapping out any dermatomal loss of sensation in an infant with brachial plexus palsy. The sharp end of a wooden cotton tipped ear swab snapped in half works well. Large fiber modalities are important to check when a peripheral neuropathy is suspected—for example, inherited and inflammatory neuropathies. Joint position and vibration sense involve the same size sensory nerves and share the same central pathway in the dorsal columns. The sensory findings, however, may be divergent in these patients, and both modalities should be evaluated. In the child and adolescent, the Romberg test, standing with feet together and eyes closed, is more reliable, quicker, and more engaging than joint position testing. Semiquantitative testing of vibration sensitivity can be performed using a Rydel tuning fork. When sensory deficits are identified distally, it is then necessary to evaluate the lower extremity more proximally and then to compare to the upper extremity. It also is important to search for asymmetry. In this way a length-dependent neuropathy can be characterized.

Quality of Life and Disability Scales Patient reported outcome (PRO) and Quality of Life (QOL) instruments serve an important role in identifying the effect of a disease and, potentially, an intervention to treat that disease. Ideally this is from the direct perspective of the patients. For younger children the parents complete a proxy for their child. Age specific questionnaires have been validated and include the PedsQL, a generic QOL scale that has been incorporated into pediatric neuromuscular trials to address aspects particular to children with DMD and SMA. Abbreviations used in this chapter: AIDP: Acute inflammatory demyelinating polyneuropathy (Guillain-Barre syndrome) ALS: Amyotrophic lateral sclerosis BMD: Becker muscular dystrophy CIDP: Chronic inflammatory demyelinating polyneuropathy CM: Congenital myopathy CMD: Congenital muscular dystrophy CMT: Charcot-Marie-Tooth inherited neuropathies CMS: Congenital myasthenic syndrome DM: Dermatomyositis DM1: Myotonic dystrophy type 1 DM2: Myotonic dystrophy type 2 DMD: Duchenne muscular dystrophy EDD: Emery-Dreifuss muscular dystrophy EM: Endocrine-related myopathy, e.g., thyroid-related FSHD: Facioscapulohumeral muscular dystrophy GBS: Guillain-Barre Syndrome IN: Infection-related neuropathyp e.g., Lyme disease IM: Infection-related myopathy; e.g., influenza LGMD: Limb-girdle muscular dystrophy MiM: Mitochondrial myopathy MD: Muscular dystrophy MG: Myasthenia gravis MM: Metabolic myopathy, e.g. Pompe disease MN: Metabolic neuropathy, e.g. metachromatic leukodystrophy PM: Polymyositis SMA: Spinal muscular atrophy WNV: West Nile virus

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bushby, K., Finkel, R., Birnkrant, D.J., et al., 2010. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 9 (1), 77–93. Bushby, K., Finkel, R., Birnkrant, D.J., et al., 2010. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 9 (2), 177–189. Darras, B.T., Jones, H.R. Jr., Ryan, M.M., et al., 2015. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach, 2nd ed. Elsevier, London. Dubowitz, V., 1995. Muscle Disorders in Childhood, 2nd ed. W. B. Saunders, London. Engel, A.G., Franzini-Armstrong, C., 2004. Myology: Basic and Clinical, 3rd ed. McGraw-Hill, New York. England, J.D., Asbury, A.K., 2004. Peripheral neuropathy. Lancet 363 (9427), 2151–2161. McDonald, C.M., Henricson, E.K., Abresch, R.T., et al., 2013. The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve 48 (3), 357–368. Narayanaswami, P., Weiss, M., Selcen, D., et al., 2014. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular and Electrodiagnostic Medicine. Neurology 83 (16), 1453–1463. Saporta, A.S., Sottile, S.L., Miller, L.J., et al., 2011. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann. Neurol. 69 (1), 22–33. Wang, C.H., Finkel, R.S., Bertini, E.S., et al., 2007. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22 (8), 1027–1049.

E-BOOK BOX AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Box 137-1 Family History and Review of Systems Table 137-2 Prevalence of Chronic Neuromuscular Disorders Table 137-3 Localizing Clinical Features of Pediatric Neuromuscular Disorders Table 137-4 Common Presenting Symptoms and Signs Suggestive of a Pediatric Neuromuscular Disorder Table 137-5 Joint Tone Table 137-6 Scales of Strength Using Manual Muscle Testing Table 137-7 Testing Motor Strength and Function in the Infant Table 137-8 Developmental and Neuromuscular Scales Commonly Used for Evaluation of Infants in Clinical Trials Table 137-9 Global Upper and Lower Extremity Functional Grading Scales Table 137-10 Descriptive Scales for Gait, Arising From Supine and Climbing Stairs. Adapted From Michelle Eagle, Newcastle, UK Table 137-11 Motor Function Scales Commonly Used for Evaluation of Children and Adolescents in Clinical Trials

138  The Floppy Infant

Graeme A.M. Nimmo and Ronald D. Cohn

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

DEFINING HYPOTONIA “The floppy infant” is an informal term for generalized hypotonia and is a presenting feature for a wide range of both systemic and neurologic disease. The pediatric neurologist is regularly requested to evaluate an infant with hypotonia, and it poses a particular diagnostic challenge owing to the extensive differential diagnosis. The list of disorders with presenting features, including hypotonia, has expanded rapidly in the genomic era and continues to grow. Although at present most of the conditions have few disease modifying treatments, diagnosis is essential as it provides both families and physicians with prognostic information and screening strategies for associated pathologies. It may also expose certain risks associated with known diagnosis; for example, individuals with RYR1 mutations may be at increased risk for malignant hyperthermia (Brislin and Therous, 2013). Furthermore, many of the diagnoses are genetic and have implications for living family members or future family planning. Severe hypotonia usually presents in the neonatal period, but milder or slowly progressive pathologies may not come to a physician’s attention until the child fails to attain milestones in the latter part of the first or second years. In the neonatal period, the differential diagnosis must include hypoxicischemic injury, intraventricular hemorrhage, and systemic disease such as hypoglycemia, sepsis, and heart failure; these diagnoses are not discussed here. For the most part, the remaining conditions presenting in this period have an underlying genetic origin, but acquired causes that present in this age group are also discussed. Chapter 137 provides an approach to the older child with suspected neuromuscular disease.

Muscle Tone Muscle tone is defined as a skeletal muscle’s inherent resistance to passive movement. It is particularly important to differentiate this from muscle strength, which is a muscle’s maximum voluntary resistance to movement. Tone is controlled by the peripheral fusimotor system with input from the central nervous system (CNS). The afferent fibers detect muscle spindle stretch and subsequently direct the motor unit system to cause muscle contraction; this is reviewed in detail in Chapter 5. Failure of any component of the motor unit, from the anterior horn cell, motor neuron, neuromuscular junction, or the muscle itself, will result in hypotonia. Supraspinal input from the motor cortex, basal ganglia, striatum, red nucleus, and cerebellum is predominantly inhibitory in its interaction with fusimotor system. In older children and adults, disturbance of inhibitory pathways results in increased excitatory output with hypertonia and hyperreflexia. In contrast, disturbance to these pathways in infancy often presents with decreased muscle tone; but importantly, the reflex arc is the preserved. Hypotonia in infancy, therefore, may be caused by disorders affecting any level of the nervous system. Some diagnoses may be established directly from history and examination, and confirmation with further testing, often

in the form of genetic testing, can be carried out immediately. On the other hand, many of the neuromuscular diagnoses may be more difficult to distinguish based on the initial clinical evaluation alone and require preliminary investigations to better characterize the disease and define a group of diagnoses. The first step in the determination of the cause of hypotonia is to localize the pathology.

LOCALIZATION OF HYPOTONIA As with other types of neurologic presentation, the first step in the approach to diagnosis is to localize the clinical findings to the site of pathology. Conditions that affect the central nervous system, and therefore supraspinal pathways, cause a clinical picture referred to as central hypotonia. The term peripheral hypotonia is used to describe the clinical features of an infant that presents with pathology affecting the motor neuron unit. The key differentiating feature is the presence or absence of weakness (Dubowitz, 1980). Infants with a central cause for their hypotonia may present with other findings suggesting disorders involving the CNS: dysmorphic features, decreased level of consciousness, seizures, and may have evidence of brisk reflexes and clonus (Table 138-1). In an older child, there may be a history of developmental delay affecting both cognitive and motor domains. Infants with peripheral hypotonia, in contrast, have a paucity of antigravity movements and may have myopathic facies but are generally alert and reach cognitive milestones appropriately. Fasciculations, muscle atrophy, and diminished reflexes are characteristic of this group. There are some exceptions in these divisions. Infants with myotonic dystrophy and congenital myopathies often do not have profound weakness. Many of the findings thought to be present in central hypotonia such as seizures and dysmorphic features are found in considerable proportions in both divisions. Nevertheless, the constellation of findings generally allows correct classification an estimated 80% of the time. It is also useful to think of a third group of pathologies that have both central and peripheral features and are referred to here as combined hypotonia. A practical algorithm guiding the approach to a neonate or infant with hypotonia is shown in Figure 138-1.

HISTORY Key components of the clinical examination confirm the presence of hypotonia, localizes its origins, and narrows the differential diagnosis. A careful and complete history is essential. The pregnancy history should include corrected gestational age as infants may present with hypotonia secondary to premature gestational age alone. A history of maternal illnesses (particularly myasthenia gravis) and exposure to medications, drugs, and infection should be sought. Results of antenatal ultrasounds, specifically polyhydramnios and paucity of fetal movements, are characteristically seen in peripheral

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TABLE 138-1  Features Differentiating Central and Peripheral Hypotonia Central

Peripheral

Developmental delay

Weakness with paucity of spontaneous movement

Normal CKa

Raised (or normal) CK

Decreased LOC

Alert

Increased DTRs, clonus

Decreased DTRsc

b

Seizures

Muscle fasiculations

Dysmorphic facial features

Myopathic faciesd

Microcephaly

Ophthalmaplegia Ptosis Bulbar dysfunction

Apneas, irregular respiration

Prolonged breathing difficulties, ventilator dependence

High pitched/unusual cry

Fatigable or weak cry

Multiple congenital abnormalities

History of polyhydramnios

a

CK may be normally raised in the early neonatal period. bSeizures are common in patients with LAMA2-related congenital muscular dystrophy. cDTRs may be normal in patients with disorders affecting the neuromuscular junction. dTented upper lip, dolichocephaly, long face, and high arched palate. CK, creatinine kinase; DTRs, deep tendon reflexes.

hypotonia, whereas evidence of congenital malformations may be more in line with a multisystem syndrome and a cause of central hypotonia. Delivery history may uncover risk factors for hypoxicischemic injury (HIE), including maternal hypotension, breech extraction, cord prolapse, or placental abruption. HIE must be excluded as it is the most common cause for central hypotonia. Apgar scores and details surrounding resuscitation, if required, may be useful in order to further exclude birth asphyxia. Infants with HIE often present with an altered level of consciousness that gradually improves in the neonatal period. It is also not uncommon for the tone to improve over the first several months of life with evolution to hypertonia and spasticity within the first 2 to 3 months of life. Asphyxia has been observed in peripheral disorders. Details of resuscitation may be required to differentiate between these infants and those with severe diaphragmatic or bulbar muscle weakness of neuromuscular origin that may require early respiratory support. Onset and progression of the hypotonia should be elucidated. Central hypotonia tends to improve with time, whereas peripheral hypotonia remains stable or progresses gradually. Rapid progression after an uncomplicated pregnancy, delivery, and neonatal course suggests an inborn error of metabolism. Infantile botulism may also present with progressive weakness and history of constipation, after an otherwise unremarkable neonatal course. It is important to exclude the consumption of honey or corn syrup if this diagnosis is suspected. Fluctuation in symptoms may be seen with congenital myasthenia syndromes or in LAMA2-related muscular dystrophy. Many infants with hypotonia will require respiratory support owing to the more complicated delivery, presence of apneas, bulbar dysfunction, or respiratory muscle weakness. However, prolonged intubation, defined by a length greater than 5 days, is more commonly seen in infants with peripheral causes. A feeding history may also be reveal bulbar dysfunction, resulting in choking or aspiration often seen—although not

exclusively—with peripheral hypotonia. Fatigue with feeding may be observed with myasthenic syndromes. Seizures have been traditionally associated with central causes, although have been reported in peripheral disorders particularly in LAMA2-related muscular dystrophies. Developmental history should be obtained if the infant is of an appropriate age. Motor delay will often result secondary to the hypotonia, but cognitive delay is more common with central causes and myotonic dystrophy. A detailed family history is essential. Certain conditions are more common in particular ethnicities; Ashkenazi Jews have a high carrier rate for familial dysautonomia and Canavan disease. The presence of consanguinity increases the likelihood of any recessive disease and is commonly reported with inborn errors of metabolism. Familial or maternal history of recurrent miscarriages points to a multisystem, and perhaps syndromic, disorder. Positive family history and details of known skeletal muscle disease, congenital abnormalities, developmental delay, and intellectual disability may also narrow the differential considerably. History of malignant hyperthermia may suggest a congenital myopathy. Maternal features of myotonic dystrophy should also be elicited, as these stable symptoms commonly go unrecognized: distal muscle weakness, intellectual disability, insulin resistance, cataracts, cardiomyopathy, and arrhythmias (Thornton, 2014). If a diagnosis of mitochondrial disease is being considered a positive history of less severe manifestations of exercise intolerance, migraine headache, diabetes mellitus, retinitis pigmentosum, and sensorineural hearing loss may be elicited, and may demonstrate a maternal inheritance pattern (DiMauro, 2013).

EXAMINATION Identifying an infant as hypotonic is typically difficult for an inexperienced examiner, and a number of unaffected infant examinations may need to be performed before more subtle decrease in tone can be appreciated. Reliable determination of hypotonia, particularly in the NICU setting, is often complicated because tone may be influenced by systemic illness, medication, level of alertness, and gestational age. The examiner will often need to perform serial examinations or defer an examination to a time when the infant is not acutely unwell. The assumption of unusual postures by the hypotonic infant is often the first indication of decreased tone. Instead of the contracted posture of a healthy term infant, infants with hypotonia typically have flaccid extension of the arms and abduction of the legs of described as “frog-leg.” There are several maneuvers that are particularity useful for assessing tone in infants: 1. The pull-to-sit (or traction) test may be used to assess both axial tone and upper limb weakness. The supine infant is pulled by the hands to the sitting position with the examiner observing for head lag. Term neonates, until about 2 months, should have only mild head-lag. Infants usually resist this movement with flexion at the shoulder and elbow; this also gives the examiner an opportunity to assess strength in the upper limb. 2. The scarf-sign provides a measure of appendicular tone in the upper limb. To elicit this sign the supine infant’s hand is pulled toward the opposite shoulder and around the neck. The sign is positive for hypotonia if the elbow can be pulled across the midline. 3. Measurement of the popliteal angle is a more objective way to measure tone in the lower limb. In the supine position, the infant’s hip is flexed to the torso and the knee



The Floppy Infant

Features

Investigations to Consider

Diagnoses to consider

distinctive facial features failure to thrive multiple congenital anomalies

karyotype microarray

Down Syndrome chromosomal abnormalities

transferrin isoelectric focusing very long chain fatty acids Prader-Willi/Angleman methylation testing

congenital disorders of glycosylation peroxisomal disorders Prader-Willi/Angleman Syndrome

biochemical testing (lactate, PAA, ACP, UOA)

metabolic and mitochondrial disorders

CSF studies (lactate, NTs, AA) urine/plasma GAA genetic testing MeCP2 MRI brain (with MRS)

purine/pyrimidine metabolism disorders creatine deficiency disorders Rett/Rett-like Syndrome

Central

seizures

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structural brain abnormalities Canavan disease Pelizaeus-Merzbacher Disease Cerebellar atrophy - Marinesco-Sjogren Syndrome neuronal migration dystroglycanopathies abnormalities

Combined

congenital disorders of glycosylation

transferrin biochemical testing (lactate, PAA, ACP, UOA)

mitochondria encephalomyopathies muscle biopsy

congenital muscular dystrophies congenital myopathies muscle MRI

electromyography (EMG)

congenital muscular dystrophies congenital myasthenic syndromes

nerve conduction studies (NCS)

Peripheral joint hypermobility

COL genetic testing echocardiogram

peripheral neuropathies Ulrich congenital muscular dystrophy connective tissue disease (dilated aortic root) Pompe and Barth Syndromes (cardiomyopathy) carnitine palmitoyltransferase deficiency type II

absent reflexes +/- fasciculations respiratory difficulties

SMN1 genetic testing SMARD genetic testing

Spinal Muscular Atrophy Spinal Muscular Atrophy with Respiratory Distress

Legend: PAA, plasma amino acids ACP, acylcarnitine profile UOA, urine organic acids NTs, neurotransmitters AA, amino acids Figure 138-1.  Hypotonia algorithm (Adapted from Lisi, E.C., Cohn, R.D.,2011. Genetic evaluation of the pediatric patient with hypotonia: perspective from a hypotonia specialty clinic and review of the literature. Dev Med Child Neurol 53(7), 586–599.)

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extended as far as possible. The angle between the thigh and the leg is the popliteal angle and should be less than 90 degrees in the term infant. 4. Shoulder suspension or vertical suspension test in which the infant is held under the shoulders in the vertical position assesses appendicular tone. A term neonate resists falling through the hands of the examiner. 5. For the ventral suspension test, the examiner holds the infant by the torso in a supine position. An infant with adequate tone is able to maintain both upper and lower limbs in flexed posture and, at least transiently, be able to hold their head higher than the horizontal. The examiner should also get a subjective appreciation of appendicular tone as described in Chapter 5. Axial hypotonia with the relative preservation of peripheral tone should prompt consideration of metabolic disease. This particular pattern is also seen in the LMNA1 congenital muscular dystrophy and SPEN1-congenital myopathy (Bonnemann et al., 2014; North et al., 2014). The most common causes of severe hypotonia are Down syndrome, Prader-Willi syndrome, and centronuclear congenital myopathies. Once the determination of hypotonia is confirmed, most of the useful information for this age group can be gathered by observation alone. Severe weakness that impairs an infant’s spontaneous antigravity movement and appropriate withdrawal response is most likely secondary to a peripheral pathology. The presence or absence of weakness is the most reliable distinguishing feature between central and peripheral causes. Particular attention should be placed on examining the infant’s facial features. Distinctive features may point toward a specific syndromic diagnosis such as Down syndrome, Prader-Willi syndrome, Williams syndrome, or DiGeorge syndrome. Myopathic facies with marked facial weakness, open mouth, tended upper lip with additional dysmorphic features of dolichocephaly, long faces, and high arched palate suggest a severe form of congenital myopathy, myotonic dystrophy, or congenital myasthenic syndrome. Findings of ptosis and ophthalmoplegia should be noted as they are commonly seen in patients with congenital myopathies and congenital myasthenic syndromes. Isolated ophthalmoplegia is rare in neonates but may be associated with disorders of the mitochondrial respiratory chain. Diaphragmatic breathing is common in the neonatal period; however, respiratory distress with in-drawing of the sternum may indicate intercostal muscle weakness of neuromuscular origin. Weak cry is also a consequence of respiratory muscle weakness, although high pitched or unusual cries are more in keeping with central etiologies. A fatigable cry is associated with myasthenia. Joint contractures may also be observed in the context of weakness secondary to prolonged periods of decreased movement. Arthrogryposis may be present after fetal akinesia and are most commonly associated with congenital myopathies, congenital myasthenia, and spinal muscular atrophy (Wang et al., 2007). More localized contractures, including talipes equinovarus, may present with any of lower motor neuron etiologies but tend to be proximal in Collagen-VI-related congenital muscular dystrophy and distal in LAMA2-related congenital myopathy. Reflexes are often unreliable in the newborn period, as they are often brisk or may be normally absent. In older infants, reflexes may be brisk in upper motor neuron lesions and absent or reduced in lower motor neuron lesions. Clonus, if present, may indicate an upper motor neuron lesion, but it must be kept in mind that up to six beats of clonus may be normal in neonates.

Finally, full examination of all other systems should be performed in order to identify any additional congenital abnormalities that may indicate a syndromic diagnosis.

CENTRAL HYPOTONIA Hypotonia in the absence of weakness is suggestive of disorders affecting the central nervous system. This suspicion is often further supported with findings of altered level of consciousness, dysmorphic features, major congenital anomalies, and/or the presence of seizures. The creatine kinase (CK) is normal. The approach to an infant with central hypotonia should, as in all areas of medicine, be directed at identifying the most life-threatening and actionable diagnoses first with consideration of the most common etiologies next. It is therefore imperative that the general health of the infant be a part of the initial assessment. Both sepsis and severe congenital heart disease can cause a picture of central hypotonia. Hypoxicischemic injury accounts for approximately one-third of infants with hypotonia. Intraventricular hemorrhage accounts for a significant proportion of preterm neonates with hypotonia. All infants presenting with hypotonia should have a CK level measured. Creatine kinase is not raised with CNS disease, but care must be taken in interpreting this in the early neonatal period as CK may be normally raised in the first few days of life. Magnetic resonance imaging of the brain should be obtained to identify structural abnormalities. Importantly, a cranial ultrasound or MRI may also identify abnormalities characteristic of HIE or IVH as reviewed in Chapter 19. Additional investigations based on the history and examination should be considered in order to identify and characterize any congenital abnormalities that may be a part of a particular syndrome. Further testing may include echocardiogram, abdominal ultrasound, ophthalmology assessment, and/or hearing testing. Biochemical testing for inborn errors of metabolism should be considered and include plasma amino acids, urine organic acids, acylcarnitine profile, glycosylation patterns, and lactate/pyruvate. Additional biochemical testing may be warranted with specific clinical findings suggestive of peroxisomal disorders, Smith-Lemli-Opitz syndrome, or in the presence of seizures as outlined in Figure 138-1. The findings of multiple congenital abnormalities, dysmorphic facial features, or delay in cognitive milestones should prompt consideration of a syndromic diagnosis or chromosomal abnormalities, and involvement of a geneticist may be valuable. Depending on the clinical context, genetic tests may be indicated and include karyotype, microarray, fluorescence in situ hybridization (FISH), and/or methylation analysis (Watson et al., 2014). The more common diagnoses, including Down syndrome, Prader-Willi syndrome, and William syndrome, are listed in Table 138-2 with their distinguishing features.

PERIPHERAL HYPOTONIA Hypotonia with weakness suggests a disorder affecting the lower motor neuron. These infants are generally alert, and there are no signs of CNS involvement, although motor development may be delayed in older infants. Creatine kinase may or may not be raised. Peripheral hypotonia is less common than that of central origin, accounting for approximately 20% of diagnosis in infants with hypotonia in the NICU. The most common causes are spinal muscular atrophy, myotonic dystrophy, and the congenital myopathies. Table 138-3 lists the most common disorders causing peripheral hypotonia and the associated



The Floppy Infant

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TABLE 138-2  Distinguishing Features of Common Causes of Central Hypotonia

138

Diagnosis

Features Suggestive of Diagnosis

Chromosomal abnormalities

Dysmorphic facial features, multiple congenital abnormalities, microcephaly, macrocephaly, failure to thrive, delay in cognitive milestones, advanced maternal age, history of recurrent miscarriages, abnormal aneuploidy screening

Down syndrome

Flat facial profile, up slanting palpebral fissures, epicanthal folds, anomalous ears, transverse palmar crease, and fifth finger clinodactyly, endocardial cushion defects, duodenal atresia

Prader-Willi syndrome

Global developmental delay, distinctive facial features (bitemporal narrowing, almond shaped eyes, strabismus, thin upper lip, downturned upper lip), short stature, genital hypoplasia, failure to thrive in infancy with hyperphagia after 1 year if age

Angelman syndrome

Global developmental delay, acquired microcephaly, seizures, prognathism, skin hypopigmentation

MeCP2-Spectrum disorders

Acquired microcephaly, seizures, repetitive hand movements, regression, female predominant

Williams syndrome

Distinctive facial features (periorbital fullness, hypertelorism, long philtrum, wide mouth, think vermilion boarder, micrognathia), supravalvular aortic stenosis, hypercalcemia

Peroxisomal disorders

Liver dysfunction, seizures, cataracts, retinal dystrophy, hearing loss, chondrodysplasia punctata, large anterior fontanelle, flat facial profile

Smith-Lemli-Opitz

Growth delay, global developmental delay, Y-shaped 2–3 toe syndactyly, cleft palate, cataracts, cardiac abnormalities, downs plating palpebral fissures, prominent epicanthal folds, anteverted nares

Creatine Deficiency disorders

Global developmental delay, seizures, delayed myelination

TABLE 138-3  Distinguishing Features for Common Causes of Peripheral Hypotonia Diagnosis

Features Suggestive of Diagnosis

Spinal muscular atrophy

Predominantly proximal weakness with relative preservation of facial movements, contractures, absent deep tendon reflexes, tongue fasciculations. SMARD presents with diaphragmatic and intercostal muscle weakness

Congenital Myotonic dystrophy

Facial diplegia with inverted-V shaped upper lip, weak cry, poor suck, maternal history of weakness, cataracts, type 2 diabetes, and contraction myotonia

Congenital muscular dystrophies   LAMA2-CMD

Kyphoscoliosis, joint contractures, increased signal intensity of white matter with MRI

  Collagen VI-deficient CMD (Ullrich CMD)

Distal hypermobility, proximal contractures, scoliosis

  Dystroglycanopathies

Combined hypotonia, cobblestone lissencephaly, neuronal migration abnormalities, various ocular abnormalities

  SEPN1-related CMD

Axial hypotonia, progressive spinal rigidity, and scoliosis

  LMNA-related CMD

Weakness and contractures afecting the proximal upper limb and distal lower limb, cardiomyopathy

Congenital myopathies

Facial weakness with myopathic facies (ptosis, tented upper lip), dolichocephaly, long face, high arched palate, absent DTRs, family history of malignant hyperthermia, cardiomyopathy, orthopedic complications

  Centronuclear myopathy

X-linked, severe weakness (no spontaneous movement, respiratory insufficiency), joint contractures, macrocephaly, arachnodactyly, cryptorchidism

Congenital myasthenic syndromes

Weak cry, poor suck, ptosis, facial weakness, occasional arthrogryposis, fatigable weakness, exclude maternal history of myasthenia gravis

Carnitine palmitoyltransferase deficiency type II

Liver failure, cardiomyopathy, neuronal migration abnormalities, hypoketotic hypoglycemia

Pompe disease

Severe hypotonia, hypertrophic cardiomyopathy, hepatomegaly, shortened P-R interval on ECG

Barth syndrome

Cardiomyopathy, neutropenia, growth delay

Polyneuropathies

Distal weakness, sensory loss, decreased DTRs

  Guillain-Barré syndrome

Progressive weakness after antecedent illness, DTRs reduced, elevated CSF protein, nerve root enhancement on MRI Continued on following page

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TABLE 138-3  Distinguishing Features for Common Causes of Peripheral Hypotonia (Continued)   Hereditary motor and sensory neuropathies/ Charcot-Marie-Tooth disease spectrum

Wide range of presentation. Severe: arthrogryposis, respiratory distress, swallowing difficulties. slow nerve conduction velocities

  Familial dysautonomia

Distinguishing features present later, high carrier frequency in Ashkenazi and Eastern European Jewish population

  Infantile neuroaxonal dystrophy

Axial hypotonia, developmental regression, seizures, nystagmus, optic atrophy

  Infant botulism

Hyporeflexia, constipation, respiratory distress, eye movement abnormalities, history of pica or honey

Connective tissue disorders

Mild hypotonia, hypermobility, aortic root dilitation

  Marfan syndrome

scoliosis, pectus deformity, arachnodactyly, dolichostenomelia

  Loeys-Dietz syndrome

Craniosynostosis, hypertelorism, cleft palate or bifid uvula, tortuous blood vessels

Congenital disorders of glycosylation

Central hypotonia and weakness, global developmental delay, dysmorphic features, inverted nipples, abnormal fat distribution

Canavan disease

Global developmental delay, macrocephaly, optic atrophy, seizures, spongy appearance of white matter, Ashkenazi Jewish ethnicity

Marinesco-Sjögren syndrome

Global developmental delay, cerebellar atrophy, ataxia, cataracts

Mitochondrial respiratory chain diseases

Central hypotonia or myopathy, exercise intolerance, seizures, migraines, ataxia, cardiomyopathy, ophthalmaplegia, sensorineural hearing loss, optic atrophy, hypothyroidism, diabetes mellitus, maternal family history of above

Pelizaeus-Merzbacher disease

X-linked, progressive peripheral and central hypotonia with evolution to spasticity, ataxia

features. Given the large number of etiologies and overlapping pre­sentation, it may be impossible to make a diagnosis on clinical findings alone, and electromyography, nerve conduction studies, and/or muscle biopsy are often required. In the case in which maternal history of myotonic dystrophy or family history of specific neuromuscular disorder is present, it may be possible to avoid specific neuromuscular investigations and arrange for genetic testing in order to confirm the diagnosis. Certainly, some features, when present, are highly suggestive of specific diagnoses: tongue fasciculations in anterior horn cell disease, joint hypermobility in connective tissue disease or collagen VI-related CMD, and cardiac involvement in metabolic myopathies. Raised serum creatine kinase (CK) suggests hypotonia of a peripheral origin; further supports hypotonia of peripheral origin; the most marked CK elevations are observed in patients with congenital muscular dystrophies. It is important to note that in all forms of peripheral pathologies, CK may be normal; therefore it is not possible to rule out peripheral hypotonia based on CK results alone. EMG and NCS may identify slowed conduction velocities seen in peripheral nerve pathologies, characteristic response to repetitive stimulation in congenital myasthenic syndromes, denervation consistent with an anterior horn cell disorder, myopathic features with muscle irritability suggesting Pompe disease, or myopathic changes with primary muscle disease. Muscle imaging by ultrasound or MRI, particularly of the thigh muscle, is an emerging modality for identification of specific patterns of muscle involvement observed in the congenital myopathies and congenital muscular dystrophies. Finally, biopsy is often required in order to demonstrate the characteristic histologic findings of congenital myopathies or dystrophic changes in the muscular dystrophies. When selecting a biopsy site, It is important to target muscles that are affected by weakness; information from EMG, ultrasound, and MRI are often useful for selecting a biopsy site involving affected muscle. Information from the clinical presentation, family history, and investigations allows prioritization of genetic testing to

confirm a specific diagnosis. Because there is generally greater accessibility to genetic testing that is less invasive, muscle biopsy is sometimes bypassed, particularly if features of specific myopathy are present from the clinical examination or MRI findings. The route to direct genetic diagnosis with genetic testing does have some drawbacks. The first is the prolonged time required for the result to become available, which can be particularly problematic for families with a severe and unexpected presentation. Second, interpretation of genetic test results may be more complicated if precise diagnosis is unknown, particularly if the pathogenicity of the variant is not obvious or not consistent with the expected pattern of inheritance. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bonnemann, C.G., et al., 2014. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul. Disord. 24 (4), 289–311. Brislin, R.P., Theroux, M.C., 2013. Core myopathies and malignant hyperthermia susceptibility: a review. Paediatr. Anaesth. 23 (9), 834–841. DiMauro, S., et al., 2013. The clinical maze of mitochondrial neurology. Nat. Rev. Neurol. 9 (8), 429–444. Dubowitz, V., 1980. The Floppy Infant. JB Lippincott, Philadelphia, PA. North, K.N., et al., 2014. Approach to the diagnosis of congenital myopathies. Neuromuscul. Disord. 24 (2), 97–116. Thornton, C.A., 2014. Myotonic dystrophy. Neurol. Clin. 32 (3), 705–719, viii. Wang, C.H., et al., 2007. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22 (8), 1027–1049. Watson, C.T., et al., 2014. The genetics of microdeletion and microduplication syndromes: an update. Annu. Rev. Genomics Hum. Genet. 15, 215–244.

Disorders Affecting the Motor Neuron: 139  Genetic Spinal Muscular Atrophy Basil T. Darras, Umrao R. Monani, and Darryl C. De Vivo An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. In the early 1890s, the Austrian clinician Guido Werdnig at the University of Graz, Austria, and the German physician Johann Hoffmann in Heidelberg, Germany, described a neuromuscular disorder causing progressive muscular weakness associated with the loss of anterior horn cells in the spinal cord, with onset in infancy and early death. Together, their reports provide the first complete description of the severe form of spinal muscular atrophy (SMA), originally named Werdnig-Hoffmann disease. The SMAs have since been defined as a group of genetic disorders characterized by progressive muscle weakness and atrophy, associated with degeneration of spinal and, in the most severely affected patients, lower bulbar motor neurons. The most common of these forms, as well as the leading cause of infant mortality, is classic proximal SMA, which seems to be found in practically all populations but is diagnosed more frequently in infants and children, rather than in adults. Genetic studies have found that classic SMA results from homozygous deletions or mutations involving the “survival of motor neuron” (SMN) gene. Two copies of the SMN gene, designated SMN1 and SMN2, are present on each chromosome 5, forming an inverted duplication at locus 5q13 (Figure 139-1). The duplicated SMN2 gene is differentiated from SMN1 by 5 nucleotide changes that do not change amino acids. A single-nucleotide change in SMN2 creates an exonic splicing suppressor in exon 7, leading to exclusion of exon 7 in most transcripts (Monani et al., 1999) and thus diminished production of the functional SMN protein. Patients with 5q proximal SMA harbor homozygous deletions or mutations involving exon 7 of the SMN1 gene, but maintain at least 1 copy of SMN2.

EPIDEMIOLOGY The incidence of SMA has been estimated at 1 in 6000 to 11,000 live births or about 7.8 to 10 per 100,000 live births and at 4.1 per 100,000 live births for SMA type I. The estimated pan-ethnic disease frequency is approximately 1 in 11,000. The carrier frequency for mutations in the SMN1 gene has been estimated from 1 : 38 to 1 : 70. It should be noted that, despite the high carrier frequency, the incidence of SMA is lower than expected. It has been postulated that this may reflect that some fetuses have a 0/0 SMN1/SMN2 genotype (i.e., no SMN protein is present at all), which is known in other species to be embryonically lethal.

CLINICAL CHARACTERISTICS Though most patients with SMA have deletions or mutations involving the SMN1 gene, a range of phenotypic severity permits division into four broad clinical subtypes. It is recognized that the subtypes represent a phenotypic continuum extending from the very severe, with onset in utero, to the very mild, with onset during adulthood; there is also a spectrum of severity within each of these groups (Table 139-1). For the

purposes of clinical classification, or of guidelines developed for standards of care, the “maximal functional status achieved” approach, which classifies type I patients as “nonsitters,” type II patients as “sitters,” and type III patients as “walkers,” has been used (Wang et al., 2007). Patients with a mild phenotype and onset during middle or late age are classified as type IV. The age at onset is also considered in the classification but because of potential overlap between subtypes and the difficulty in accurately determining the onset of symptoms, it has not been considered as the sole determinant of disease subtype.

Type I SMA After the initial description of infantile SMA by Werdnig and Hoffmann in the early 1890s and further descriptions made by Sylvestre in 1899 and Beevor in 1903, infantile or type I SMA was described again in detail, both clinically and pathologically, by Randolph Byers and Betty Banker at Boston Children’s Hospital in 1961. Patients with type I SMA, also known as Werdnig-Hoffmann disease, present between birth and 6 months of age. SMA type I has been further subdivided into 3 groups: type IA (or type 0 in certain reports) with onset in utero and presentation at birth, type IB with onset of symptoms before 3 months of age, and type IC with onset between 3 and 6 months of age. Infants with SMA type I have progressive proximal weakness that affects the legs more than the arms. They have poor head control, hypotonia that causes them to assume a “frog-leg” posture when lying and to “slip through” on vertical suspension, and areflexia. They are never able to sit (“nonsitters”) or roll over independently (see Table 139-1). There is also weakness of the intercostal muscles with relative sparing of the diaphragm, producing a bell-shaped chest and a pattern of paradoxical or “belly”-breathing. Infants with type I SMA also classically exhibit tongue fasciculations and eventually have difficulty swallowing, with failure to thrive and a risk for aspiration. Other cranial nerves are not as affected, although facial weakness does occur at later stages of the disease. Cognition is apparently normal, and they are often noted at diagnosis to have a bright, alert expression that contrasts with their generalized weakness. Infants with type I SMA usually develop respiratory failure by age 2 years, or much earlier, and in the past most did not survive past 2 years; however, there has been some increase in survival in recent years with the use of assisted ventilation (to be described in more detail in later sections) and other interventions (Darras et al., 2015). Prior natural history studies have reported shortened life span, with 68% mortality within 2 years and 82% by 4 years of age. The application of nutritional and respiratory interventions has reduced the mortality to approximately 30% at 2 years, but about half of the survivors are fully dependent on noninvasive ventilation. In a recent observational study, the median age at reaching the combined endpoint of requiring at least 16 hours/day of noninvasive ventilation or death was 13.5 months. Infants with two SMN2 copies had

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q23 q24 q25.1 q25.2 q25.3

q22

q21

q12

q11.2

q11.1

p11.1

p11.2

p12

p15 p14 p13

Chromosome 5

c840 C>T transition Creation of ESS

SMN2

Exon 7

7 ~90%

100%

~10%

Full length SMN protein (294 AA)

Truncated protein SMN∆7

SMN1

Full length SMN protein (294 AA)

Figure 139-1.  Schematic diagram of human SMN1 and SMN2 genes on chromosome 5. Patients with spinal muscular atrophy have deletions or mutations in both copies of SMN1. A C-to-T transition at position 840 of SMN2 creates an exonic splicing suppressor (ESS) that leads to skipping of exon 7 during transcription and production of the truncated, nonfunctional SMN protein. However, a small amount (~10%) of full-length messenger RNA is produced from the SMN2 gene, resulting in the functional, full-length SMN protein. AA, amino acids. (With permission of Elsevier: Darras BT et al., editors. Neuromuscular disorders of infancy, childhood, and adolescence: a clinician’s approach, 2nd edition. San Diego: Academic Press; 2015.) TABLE 139-1  Clinical Classification of Spinal Muscular Atrophy Highest Motor Milestone Achieved

Other Names

Age at Onset

Life Span

Type IA

Prenatal (type 0), congenital SMA, Werdnig-Hoffmann disease

Prenatal

18 months Type IIIA (before 3 years) Type IIIB (after 3 years)

Almost normal

Stands and walks

• May have hand tremor • Resembles muscular dystrophy • CK often elevated 2-5X

12

Type IV

Adult SMA

>21 years

Normal

Normal

Type IC

Other Features

Proportion of Total SMA (%)

SMA Type

*Spinal muscular atrophy (SMA) types I, IA, IB, and IC all have a 60% proportion of total SMA. (Modified with permission of Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol 2012;46:1–12.)

1



Genetic Disorders Affecting the Motor Neuron: Spinal Muscular Atrophy

greater morbidity and mortality than those with three copies. The need for nutritional support preceded that for ventilation support (Finkel et al., 2014). It was previously believed that SMA is a purely motor neuron disorder. However, recent studies have shown that severe type I SMA can result in various organ manifestations, apart from spinal cord motor neurons such as brain, cardiac, vascular, and even sensory nerve involvement. Recent autopsy studies have shown increasing evidence of congenital heart disorders in severe SMA, with the most common association being hypoplastic left heart syndrome; however, this finding has not been confirmed and a chance of association has not been firmly excluded. Studies done on various mouse models have also found that severe SMN protein deficiency might present as vasculopathy. This was also noted in the case reports of two unrelated patients with severe SMA type I. Both these infants developed ulcerations and necroses of the fingers and toes. Autonomic dysfunction is thought to be the primary cause of this vasculopathy.

Type II SMA This intermediate form of SMA was first reported in 1893 at the University of Edinburgh, United Kingdom, and described again by Byers and Banker in 1961 and in detail by Dubowitz in 1964. Patients with type II SMA, also known as intermediate SMA or Dubowitz disease, are able to sit unsupported at some point (“sitters”), but are never able to stand alone or walk independently (see Table 139-1). The onset of symptoms is typically between 6 and 18 months of age. They have progressive proximal weakness affecting legs more than arms, hypotonia, and areflexia. They also develop progressive scoliosis, which, in combination with intercostal muscle weakness, results in significant restrictive lung disease as they grow older. They develop joint contractures and can have ankylosis of the mandible. They exhibit tremor, or polyminimyoclonus, of the hands (Darras et al., 2015). Although their body mass index may be low (at the third percentile or less compared with normal children), this likely represents reduced muscle mass as the high-functioning, nonambulatory patients have a higher relative fat mass index and are at risk of becoming overweight. Cognition is normal and verbal intelligence may be above average. In a study done on 240 type II patients, survival rates were found to be 98.5% at 5 years and 68.5% at 25 years. Patients may live into the third decade, but life expectancy is shortened because of the risk of respiratory compromise (Darras et al., 2015).

Type III SMA In 1956, Kugelberg and Welander described a much milder form of SMA characterized by prolonged ambulation. Patients with type III SMA, also known as Kugelberg-Welander disease, are able to stand alone and walk at some point (“walkers”). The onset of symptoms occurs after the age of 18 months; it has further been subdivided into type IIIA (onset between 18 months and 3 years) and type IIIB (onset after 3 years). They have progressive proximal weakness affecting legs more than arms and may ultimately need to use a wheelchair, especially the IIIA group, but they generally develop little to no respiratory muscle weakness or severe scoliosis. Loss of ambulation increases the risk of these complications. They may have tremor or polyminimyoclonus of the hands. Sometimes, the calves of these patients can be prominent and hence type III SMA can be confused with Becker muscular dystrophy. Creatine kinase levels are often elevated, usually no more than fivefold, and may lead to an erroneous evaluation for myopathy. EMG and nerve conduction testing is useful in this setting to indicate a neurogenic versus myopathic disorder and focus

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appropriate further testing. Life expectancy is not significantly different compared with the normal population (see Table 139-1) (Darras et al., 2015). There has been much debate about the appropriate classification of patients into these three types of SMA because, as mentioned, there are patients who within these categories exhibit phenotypes of differing severities. A classification system based on a continuous rather than discrete variable (e.g., SMA “Type 1.8” in the case of a less severely affected type I patient) has been proposed to better capture the clinical spectrum of these patients.

Outliers There are also patients who are outliers on either end of the phenotypic spectrum. As discussed above, an SMA “type IA” has been used to describe neonates who present with severe weakness and profound hypotonia, probably of prenatal onset, as well as with a history of decreased fetal movements. At the severe end of the type 1A subgroup are infants born with severe contractures and no movements. Patients with this severe presentation, known as type 0, require ventilation support and do not attain any motor milestones. Other findings include areflexia, facial diplegia, atrial septal defects, and joint contractures. In SMA type IA, respiratory failure forms an important cause of morbidity and mortality, requiring noninvasive ventilation and endotracheal intubation at birth. Life expectancy is reduced and most of them are unable to survive beyond 6 months of age (see Table 139-1). Furthermore, arthrogryposis multiplex congenita (congenital joint contractures involving at least two regions of body) has been noted in SMA patients with SMN1 gene deletions, and congenital axonal neuropathy involving motor and sensory nerves in conjunction with facial weakness, joint contractures, ophthalmoplegia, and respiratory failure at birth has been reported in three newborn siblings with deletions in the SMA chromosomal region. A milder adult-onset SMA, or type IV SMA, has also been described with onset of symptoms after age 21 years and essentially normal life span. Most patients with the SMA type IA and IV phenotypes have homozygous deletions of exon 7 in SMN1, but as it will be discussed in the Genetics section, the SMN2 copy number is usually only 1 in SMA type IA and 4 to 5 in SMA type IV.

Other “Spinal Muscular Atrophies” The non-5q13–associated spinal muscular atrophies are a heterogeneous group of motor neuron diseases associated with mutations in a variety of different genes (e.g., X-linked and autosomal-dominant or autosomal-recessive spinal muscular atrophies), distal or segmental spinal muscular atrophies or distal hereditary motor neuropathies. Patients with these disorders generally have some clinical characteristics that can help differentiate them from those with 5q13-associated or classic SMA.

GENETICS The SMN Gene Linkage analysis studies showed that all three forms of SMA map to chromosome 5q11.1-13.3. In 1995 Lefebvre et al. identified the SMN (survival of motor neuron) gene within this region, which was absent or interrupted in 98.6% of the patients in their group. The structure of this region is complex, with a large inverted duplication of a 500-kb element. This contains the SMN1 gene, which is deleted or interrupted in patients with SMA and is evolutionarily older, in the telomeric portion of the region, and the SMN2 gene, a duplication of

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SMN1 that differs from it by only five nucleotides, in the centromeric portion (see Figure 139-1). The critical difference between SMN1 and SMN2 is a C-to-T transition that creates an exon splicing suppressor in exon 7 of SMN2. Although this splice modulator change is translationally silent (i.e., it does not change the amino acid sequence), it affects the alternative splicing of the gene, so that exon 7 is spliced out of or excluded from most SMN2 mRNA transcripts. This altered mRNA results in production of a truncated version of the SMN protein, which does not oligomerize efficiently and is degraded. Because exon 7 is not always spliced out of all SMN2 mRNA, a small amount of full-length transcript and hence functional protein is produced by SMN2, but it yields only on average about 10% as much as that produced by SMN1. In patients with SMA both copies of the SMN1 gene are deleted or disrupted, so the individual is left with only the small amount of SMN protein produced by the remaining copies of SMN2. The amount of the SMN protein is inversely correlated with the severity of disease. About 95% to 98% of patients with SMA harbor deletions of the telomeric SMN1 gene. The remainder have small intragenic mutations or have undergone gene conversions from SMN1 to SMN2. De novo mutations occur at a rate of about 2%, which is relatively high, and explained by the fact that this region of chromosome 5 is unstable, containing not only the inverted repeat of SMN1 and SMN2, but other surrounding low-copy-number repeats. The number of copies of SMN2 per chromosome 5 varies among normal individuals, and 10% to 15% of the population possess no copies of SMN2. Among patients with SMA, a clear correlation has been established between SMN2 copy number and phenotypic severity. Feldkotter et al. in 2002 found that in their series 80% of patients with type I SMA had 1 or 2 copies of SMN2, 82% of patients with type II had 3 copies of SMN2, and 96% of patients with type III had 3 or 4 SMN2 copies (Figure 139-2). Studies by Mailman et al. in 2002 and Arkblad et al. in 2009 found similar results (95% to 100% of type I patients had 1 or 2 copies of SMN2, and all type III patients had at least 3 copies of SMN2). However, this correlation is not so perfect as to permit the absolute prediction of clinical severity based on SMN2 copy number, especially in the intermediate forms of the disease where there is some overlap (patients with three copies of SMN2 have been described with all three phenotypes). One reason for the overlap is that not all copies of SMN2 gene are equal; in terms of full-length SMN protein production, some copies probably

produce less and some more than 10% functional protein. In general, though, it can be said that a patient with 1 or 2 copies of SMN2 is highly likely to present with SMA type IA, IB, or IC. Interestingly, unaffected family members with homozygous SMN1 deletions and five copies of SMN2 have been described, which suggests that SMN2 copy number alone cannot be the sole modifying factor in disease severity, because there are patients with type III SMA who also have five copies of SMN2.

Genetic Diagnosis Genetic testing for SMA can be performed with PCR-based targeted mutation analysis using a restriction enzyme that digests exon 7. However, multiplex ligation probe amplification (MLPA) methodology is currently applied in most DNA diagnostic laboratories for deletion analysis of exon 7 of the SMN1 gene in potential probands and carriers. This type of targeted mutation testing in conjunction with sequence analysis can also detect individuals who are compound heterozygotes with a deletion of exon 7 in 1 SMN1 allele and an intragenic point mutation in the other allele. In such a case (approximately 2% to 5% of individuals with clinical diagnosis of SMA), sequence analysis of the SMN gene will detect the mutation; this sequence testing, however, will not detect exonic deletions or duplications (Prior and Russman, 1993). and will not determine whether the point mutation is in the SMN1 gene or SMN2 gene (if one of these genes is not deleted). Fortunately, certain point mutations have been described in more than 1 SMA patient already, and thus the detection of a previously reported mutation supports its pathogenicity and its location in the SMN1 gene. Carrier testing is feasible and accurate in the parents of patients with homozygous deletions of exon 7 or compound heterozygosity using a PCR-based dosage assay, known as “SMN gene dosage analysis.” It can also be performed using other techniques such as long-range PCR, MLPA, and chromosomal microarray (CMA) that includes this gene segment. Sequencing of the SMN gene will detect point mutations in nondeletion carriers. Rarely, carriers may have two copies of SMN1 on one chromosome (both copies in cis orientation on one allele, a so-called “2 + 0 carrier”); the incidence of this genotype is about 4% of the general population. In the “2 + 0 carriers,” the SMA dosage carrier test will be falsely normal and thus one may need to pursue other methods such as family linkage analysis to identify the disease-associated

90 80 70

Percentage

60 1 SMN2 copy

50

2 SMN2 copies 3 SMN2 copies

40

4 SMN2 copies

30 20 10 0

SMA I (N = 188)

SMA II (N = 110)

SMA III (N = 77)

Figure 139-2.  Frequency of patients with SMA types I, II, and III and SMN2 copy numbers. In SMA type I, 80% of patients had 1 or 2 copies of SMN2, 82% of patients with type II had 3 copies of SMN2, and 96% of patients with type III carried 3 or 4 SMN2 copies. (Modified with permission. This image was published in American Journal of Human Genetics, Volume 70, Feldkotter M et al., Quantitative analyses of SMN1 and SMN2 based on based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy, pages 358–368, copyright Elsevier [2002].)



Genetic Disorders Affecting the Motor Neuron: Spinal Muscular Atrophy

genotype in families in which a deletion mutation has been transmitted more than once from a parent with two copies of the SMN1 gene on gene dosage testing. Because of the occurrence of de novo mutations in 2% of patients with SMA, one of the parents may not be a carrier (Prior and Russman, 1993). So, in approximately 6% of parents of a child with SMA secondary to a homozygous SMN1 deletion, SMN1 gene dosage testing will be normal. As mentioned in the introduction, a general correlation has been found between SMN2 copy number and disease severity, and it is relatively straightforward to determine SMN2 copy number in individual patients using various methodologies. However, this correlation is not so strict that the severity or type of disease can be reliably predicted based on copy number, and it is hence not advisable to offer families prognostic information based on SMN2 copy number assays.

Newborn Screening The potential for newborn screening for SMA has been of great interest because the ideal time to initiate therapy would be before the initial degeneration of motor neurons, and newborn screening may help to identify presymptomatic individuals before the period of greatest motor neuron loss. A few pilot programs have been initiated in the United States.

OTHER DIAGNOSTIC TESTS In patients with SMA the serum creatine kinase may be 2- to 4-fold elevated, but not more than 10 times normal (Darras et al., 2015). Nerve conduction studies demonstrate normal sensory potentials, but may show diminished compound motor action potential amplitudes. Needle EMG in type II/III patients demonstrates a neurogenic pattern with highamplitude, long-duration motor unit potentials with reduced recruitment pattern, indicating chronic partial reinnervation. Needle EMG in type I patients shows denervation changes but may not show evidence of reinnervation, as there may not have been enough SMN protein and/or time for this to occur yet. As will be discussed in more detail in the Pathology section, muscle biopsy in all types of SMA demonstrates a neurogenic pattern, with grouped atrophy; the small atrophic fibers are of both types (type 1 and type 2), whereas the large ones are always type 1 fibers. Although EMG continues to be used in the diagnosis of SMA in selected atypical cases, the use of muscle biopsy has become essentially obsolete.

MOLECULAR FUNCTION OF SMN SMN is a 38-kDa protein found in all cells, located in both the cytoplasm and in the nucleus, where it localizes to structures known as Gemini of Cajal bodies, or simply “gems”; therefore, its expression is ubiquitous. In patient fibroblasts, the number of gems correlates with SMA severity. SMN is also localized in motor neuron axons. The SMN protein in conjunction with several Gemin proteins forms an SMN complex whose chaperone function facilitates the assembly of spliceosomal small nuclear ribonucleoprotein particles (snRNPs), essential components of the spliceosome complex, and hence plays a critical role in pre-mRNA splicing. The SMN protein may also be essential in assisting arginine methylation of some splicing-related proteins, transporting axonal mRNAs in motor neurons and perhaps in other processes in muscle and neuromuscular junction. The role of the SMN protein in axonal mRNA trafficking and mRNA splicing may explain the selective vulnerability of spinal cord motor neurons to decreased SMN protein; although not the only ones, these neurons have long axons and many targets, particularly in large muscles, and thus may be very dependent on axonal

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mRNA transport. Further, they may be extremely vulnerable to the mRNA splicing defect. Nevertheless, it continues to be unclear whether a splicing defect caused by SMN protein deficiency, disruption of an additional axonal SMN function, perturbation of an unknown function, or a combination of the above is responsible for the pathogenesis of SMA. The complete absence of the SMN protein in cells is embryonic lethal in mice and other organisms. The reason why motor neurons are specifically vulnerable to partial SMN deficiency is unclear. Patients with SMA also appear to have structural and physiologic abnormalities of the neuromuscular junction. Kong et al. showed that in severely affected SMA mice, before anterior horn cell death and/or axonal degeneration there is synaptic dysfunction at the neuromuscular junction in the form of decreased synaptic vesicle density at motor terminals, reduced quantal content, and slowed maturation of the acetylcholine receptor with prolonged retention of fetal characteristics. Kariya et al. also demonstrated structural and functional abnormalities at the level of the neuromuscular junction that precede overt symptoms in mice, as well as structural abnormalities in the neuromuscular junctions of humans with SMA, and hence proposed that SMA may be a “synaptopathy” (Kariya et al., 2008). Based on this concept and the electrophysiologic data suggesting dysfunction of the neuromuscular junction in patients with SMA types II and III, treatment approaches directed toward enhancing neuromuscular transmission may also be beneficial to patients with SMA.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of 5q SMA is listed in Box 139-1. This box also lists the non-5q SMAs, which are discussed in further detail in Chapter 140.

THE PATHOLOGY OF SMA SMA is characterized by spinal motor neuron loss and skeletal muscle atrophy. However, a precise understanding of how the cellular pathology of the disease evolves over its course continues to be handicapped by a paucity of suitable patient material. Our current appreciation of SMA pathophysiology stems largely from analyses of autopsy material, reflecting pathology at the end of the disease. Analyses of early disease pathology have relied mostly on murine models. Still, from the current studies, certain key findings emerge. These, almost invariably, include a profound loss of the large anterior horn cells of the spinal cord. More infrequently, motor neurons are found mispositioned. Anterior horn motor neurons that remain often appear swollen or chromatolytic, containing phosphorylated neurofilaments, ribosomes, and vesicles. Considering the degeneration of the spinal motor neurons, an expected pathologic characteristic is neurogenic atrophy of the skeletal muscles. Muscle from severely (type I) affected patients typically consists of a sea of small, rounded, atrophic fibers within which are sometimes seen islands of one or more large hypertrophic cells. In some instances, the atrophic fibers also appear immature with centrally rather than peripherally located nuclei, giving the appearance of a myopathic condition. Even though SMA has historically been described as a disease characterized by motor neuron cell body loss, more recent data suggest that the earliest pathologic effects of reduced SMN are observed distally, at the neuromuscular junctions (Kariya et al., 2008). This early pathology that affects the pre- and postsynapse was first observed in mouse models of the disease and has now been confirmed in human samples as well (Kariya et al., 2008).

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BOX 139-1  Differential Diagnosis of 5q Spinal Muscular Atrophy SPINAL CORD DISORDERS Neoplasms (SMA types I, II, III) Other myelopathies (SMA types I, II, III) OTHER MOTOR NEURON DISORDERS SMARD1 (SMA type I) Juvenile muscular atrophy of distal upper extremity (Hirayama disease) Fazio-Londe disease, Brown-Vialetto-van Laere syndrome Other non-5q SMAs (SMA types I, II, III) Juvenile ALS (SMA types I, II, III) NEUROPATHIES Congenital hypomyelinating or axonal neuropathies (SMA types I, II) Hereditary motor and sensory neuropathies (SMA types I, II, III) CIDP (SMA types II, III) NEUROMUSCULAR JUNCTION DISORDERS Botulism (SMA type I) Congenital myasthenic syndromes (SMA types I, II, III) Lambert-Eaton myasthenic syndrome (SMA type III) Autoimmune myasthenia gravis (SMA types II, III) MYOPATHIES Congenital myopathies (SMA types I, II, III) Congenital myotonic dystrophy (SMA type I) Congenital muscular dystrophies (SMA types I, II) Muscular dystrophies (DMD/BMD, LGMD) (SMA type III) Mitochondrial myopathies (SMA types I, II, III) Acid maltase/Pompe disease (SMA types I, II, III) Other metabolic myopathies (SMA types I, II, III) Inflammatory myopathies (SMA type III) Channelopathies (SMA type III) OTHER DISORDERS Chromosomal abnormalities (SMA types I, II, III) Prader-Willi syndrome (SMA type III) Central nervous system abnormalities (SMA types I, II, III) Hexosaminidase A deficiency (SMA types III, IV) ALS, amyotrophic lateral sclerosis; BMD, Becker muscular dystrophy; CIDP, chronic inflammatory polyneuropathy; DMD, Duchenne muscular dystrophy; LGMD, limb-girdle muscular dystrophy; SMARD1, spinal muscular atrophy with respiratory distress 1. (Modified with permission of Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol 2012;46:1–12.)

TREATMENT Currently, there is no cure for SMA. However, despite the presence of homozygous deletions of SMN1 in the majority of patients with SMA, the unique structure of the 5q11.1-13.3 inverted duplication provides potential therapeutic targets. There has been great interest in identifying agents that can increase the amount of the full-length SMN protein by upregulating expression of the SMN2 gene or promoting inclusion of exon 7. Researchers are also actively exploring several other approaches to treatment.

Clinical Trials in SMA: Therapeutics SMA is a unique “translational” disease because of the presence of the SMN2 gene, which is a well-validated target for therapeutic interventions. The status of therapeutics development is shown in Table 139-4. The effort on therapeutics is

TABLE 139-4  Status of Therapeutics Development in Spinal Muscular Atrophy Therapeutic Targets Increase SMN transcript

SMN2 exon 7 inclusion

Approaches

Clinical Trials

• Histone deacetylase inhibitors • Nonhistone deacetylase inhibitors • Quinazoline • Prolactin

• Valproic acid, sodium 4-phenylbutyrate • Hydroxyurea

• Antisense oligonucleotides • Small molecules

• Nusinersen

• Repligen RG3039

• Roche RG7916 • Novartis LMI070

Stabilization of the SMN protein

• Aminoglycoside • Proteasome inhibitors • Indoprofen

Neuroprotection

• Neurotrophic factors

Cell therapy

• Stem cells

Replacement of SMN1

• Gene therapy

• AveXis scAAV9. CB.SMN

Muscle sarcomere

Troponin activator

Cytokinetics (CK-2127107)

• Riluzole • Gabapentin • Olesoxime (TRO19622)

(With permission of Lippincott Williams and Wilkins/Wolters Kluwer Health: Singh P, Liew WK, Darras BT. Current advances in drug development in spinal muscular atrophy. Curr Opin Pediatr 2013;25:682–688.)

directed toward finding pharmaceutical compounds that can upregulate SMN2 expression or affect other modifying genes to produce more functional SMN protein.

Agents That Upregulate SMN2 Gene Expression and Promote Exon 7 Inclusion Small Molecules A class of drugs known as histone deacetylase inhibitors (HDACIs) has been investigated extensively as potential therapeutic agents in SMA (Singh et al., 2013; Darras et al., 2015). Histones, which are core proteins in chromatin, play a role in epigenetic regulation of gene expression via their acetylation status. Several compounds that are HDACIs have been shown to increase full-length SMN2 transcript levels in cell lines from patients, usually by activating the human SMN2 promoter, enhancing transcription, and correcting the splicing pattern. Clinical trials of HDACIs, phenylbutyrate, and valproic acid have shown no difference in motor function scores compared with the placebo group in a nonambulatory cohort of type II SMA. A proprietary small molecule developed by PTC Therapeutics, Inc., extends the life expectancy of the SMNΔ7 severe mouse model from 14 days to more than 6 months. Along with the quinazoline derivatives, this compound is further developed for clinical trials in humans. The distinct advantage of these small molecules is that they can cross the blood-brain barrier (BBB). The FDA-approved drug hydroxyurea, a non-HDACI, was identified in the course of drug screens using cell lines from SMA patients to increase the amount of full-length SMN



Genetic Disorders Affecting the Motor Neuron: Spinal Muscular Atrophy

transcript and protein in vitro. However, a small pilot study of hydroxyurea at 3 different doses for 8 weeks in 33 type II and III patients showed no statistically significant benefit. A randomized, double-blind, placebo-controlled trial failed to show any improvement over an 18-month period. Albuterol, a beta-adrenergic agonist, was evaluated in a pilot study of 13 SMA type II and III patients because of its reported positive effect on muscle strength in healthy individuals. At 6 months a significant improvement was noted in myometry, FVC, and DEXA scores, but there was no significant change in Medical Research Council strength score. Another pilot study of 23 SMA type II patients treated with salbutamol (a form of albuterol) for 12 months showed improved functional scores on the HFMS after 6 and 12 months, but this was not a placebo-controlled study and must be interpreted with caution (Pane et al., 2008). On an in vitro level, salbutamol has been shown to increase full-length SMN mRNA, SMN protein, and gem numbers by promoting inclusion of exon 7. The response was directly proportional to SMN2 gene copy number. This finding prompts further interest in exploring the effects of beta agonists on SMA with randomized controlled trials.

Neuroprotective, SMN Protein Stabilization Agents Other Small Molecules Riluzole and gabapentin, “the neuroprotective agents,” were studied to assess the effect on motor performance in SMA. Unfortunately, the results were not found encouraging or the studies were not adequate to show efficacy. Olesoxime (TRO19622), a novel neuroprotective compound, has been tested in a randomized, multicenter, parallelgroup, double-blind, placebo-controlled trial conducted in Europe. Preliminary results seem encouraging. CK-2127107, a selective skeletal fast troponin activator slows down the rate of calcium release from troponin C and thus increases fast skeletal muscle contractility; a phase 2/3 study (CY 5021) in Type II and III SMA patients is currently in progress.

Other Approaches SMN2 Splicing Modifiers Drugs have been developed to modify splicing of the SMN2 gene to include exon 7 and increase the amount of full-length transcript and, consequently, the amount of normal SMN protein. Antisense Oligonucleotides.  Antisense oligonucleotides (ASOs) have been developed that block an intronic splicing suppressor element, which in turn prevents skipping of exon 7 (Burghes and McGovern, 2010). Hua et al. in their work on transgenic mice found these intronic splicing suppressors to be located in intron 7 as tandem motifs, namely, hnRNP A1/A2. Blocking of these motifs by ASOs enhanced exon 7 inclusion in the SMA mouse model. Similar work by Singh et al. demonstrated enhanced production of full-length SMN mRNA in fibroblasts from patients treated by ASOs. Periodic intracerebroventricular deliveries of ASOs in SMA mice models have been found to improve the motor phenotype. Phase I/II clinical trials and two randomized, double-blind, sham procedure controlled phase III trials demonstrated the safety, tolerability and clinical efficacy of multiple doses of ASO (nusinersen), which is delivered intrathecally into the subarachnoid space of SMA type I and type II patients. Spinraza (nusinersen) was approved by the US FDA in December, 2016, for treatment of all types of SMA and all ages. It is the first approved drug treatment for SMA.

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Small Molecule Drugs.  Orally delivered small molecule drugs that modulate splicing and promote inclusion of exon 7 are in early phase of clinical development: LMI070 and RG7916. These are listed in Table 139-4.

Stem Cells Interest in the use of stem cells also continues, both as potential treatment for SMA and for use in constructing model systems for therapeutics development. During the last few years, pluripotent stem cells with the capacity to differentiate into motor neurons that lacked SMN1 expression were induced from a type 1 SMA patient and his mother; this could serve as an important model system for testing of new compounds and eventually for stem cell approaches to the treatment of SMA.

Gene Therapy Among other therapeutic targets, gene therapy has shown potential in animal models. Foust et al. demonstrated that self-complementary adeno-associated virus 9 (scAAV9) could cross the BBB and infect approximately 60% of motor neurons when injected intravenously into neonatal mice. When injected systemically with scAAV9 engineered to carry the wildtype SMN gene expressed high levels of protein in multiple tissues, these mice derived remarkable therapeutic benefit, surviving in some instances to 12 months or more with no evidence of muscle weakness. Considering proof-of-concept studies demonstrating the ability of scAAV9 to penetrate the mature BBB and infect adult motor neurons, an SMN replacement clinical trial to treat SMA type I is currently underway at Nationwide Children’s Hospital and The Ohio State University, United States.

CARE OF THE PATIENT WITH SMA Patients with SMA and their families benefit greatly from a multidisciplinary approach to care. This approach involves members from neurology/neuromuscular medicine, orthopedics, physical and occupational therapy, pulmonology, nutrition, and gastroenterology. For severely affected patients with type I SMA, early involvement of the pediatric advanced care or palliative care team can provide parents with support and assistance in making decisions that are consonant with their values and help to maximize their child’s quality of life. In 2007 a Consensus Statement for Standard of Care in Spinal Muscular Atrophy was released by a multidisciplinary team regarding the current best recommendations for management of patients with SMA (Wang et al., 2007).

Pulmonary Respiratory failure is the major cause of mortality in patients at the more severe end of the disease spectrum, namely types I and II SMA. Infants with type I SMA have weak intercostal muscles with relatively preserved diaphragm strength, resulting in a bell-shaped chest, pectus excavatum, and in some cases underdevelopment of the lungs. Patients with type II SMA have weak intercostal muscles with scoliosis contributing to progressive restrictive lung disease. The restrictive lung disease results in insidious onset of sleep hypoventilation. Proper use of BiPAP, with correct pressure adjustments and mask placement, has no significant side effects on patient hemodynamics. There should also be a low threshold for the use of antibiotics during acute illnesses in these patients, because of the risk of pneumonia (Wang et al., 2007). Patients should be followed regularly by a pulmonologist experienced in caring for patients with neuromuscular diseases, with home visits by a home ventilation team if available.

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Gastrointestinal Patients with type I SMA are extremely weak and hence tire during feedings, which can lead to failure to thrive and aspiration with recurrent respiratory infections. In a small retrospective study, Durkin et al. found that early laparoscopic Nissen fundoplication and gastrostomy in patients with type I SMA was associated with improved nutritional status in these patients, and also perhaps with a trend toward fewer long-term aspiration events. Lastly, patients with SMA are at risk of constipation, which can, if severe (especially in young type I patients), worsen reflux or even respiratory symptoms.

Nutrition Failure to thrive or growth failure is common in infants with type I SMA and in some severely affected type II patients. However, though many type II patients plot as having a “normal” body mass index (often as low as third percentile for a healthy child of their age), they may actually have excessive fat mass relative to their muscle mass. Clinically high functioning nonambulatory SMA patients (Hammersmith score ≥12) are at risk of becoming overweight. Hence close attention must be paid to nutritional status in patients with all types of SMA, and consultation with a dietician who is aware of these special concerns is vital.

Orthopedic Patients with SMA at the severe end of the disease spectrum require close orthopedic follow-up for the development of scoliosis and contractures. Surgical intervention for scoliosis is often required, and careful coordination of perioperative respiratory and nutritional support can help to minimize complications (Wang et al., 2007). With the advent of improved surgical techniques such as growing rods, the interventions are currently considered earlier in life. Fractures and hip subluxation are commonly seen in milder type II and type III SMA patients. Distal femur is the commonest fracture site followed by lower leg, ankle, and upper arm. Most of the fractures can be treated conservatively.

Fatigue Physiologic fatigue is a common complaint in milder SMA patients and can be measured by the decrement in distance walked from the first to sixth minute of the six-minute walk test (Montes et al., 2010). The mechanism(s) underlying fatigue in SMA remains to be elucidated, but it may be related at least in part to the neuromuscular junction defects described earlier. Anecdotal evidence suggests that albuterol PO in usual pediatric doses is an effective agent in the treatment of fatigue in SMA patients and thus it is frequently used; however, fatigue has not been studied directly in the conducted albuterol pilot studies that showed improvement in motor function (Pane et al., 2008).

CONCLUSIONS SMA is a chronic, inherited motor neuron disease for which there is no established treatment. Yet there is cause for optimism, as it is an area of active research, and knowledge about the molecular genetics and pathogenesis of SMA is ever increasing. Several groups are actively exploring pharmacologic treatments, whether through the use of approved drugs, identification of new agents via high-throughput screens, or development of novel pharmaceutical compounds. Standards of care have also been developed to optimize the long-term multidisciplinary management of patients with SMA. Although

it may seem at times that a treatment for SMA is far in the future, the advances made since the gene was identified in 1995 permit a modicum of hope to patients, their families, and those with the privilege to care for SMA patients. Acknowledgments This chapter was funded in part by NINDS R01 NS057482 and by the SMA Foundation (New York, NY).

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Burghes, A.H., McGovern, V.L., 2010. Antisense oligonucleotides and spinal muscular atrophy: skipping along. Genes Dev. 24, 1574–1579. Darras, B.T., Markowitz, J.A., Monani, U.R., et al., 2015. Spinal muscular atrophies. In: Darras, B.T., Jones, H.R., Jr., Ryan, M.M., et al. (Eds.), Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach, second ed. Academic Press, San Diego, pp. 117–145. Finkel, R.S., McDermott, M.P., Kaufmann, P., et al., 2014. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 83, 810–817. Kariya, S., Park, G.H., Maeno-Hikichi, Y., et al., 2008. Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum. Mol. Genet. 17, 2552–2569. Monani, U.R., Lorson, C.L., Parsons, D.W., et al., 1999. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet. 8, 1177–1183. Montes, J., McDermott, M.P., Martens, W.B., et al., 2010. Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology 74, 833–838. Pane, M., Staccioli, S., Messina, S., et al., 2008. Daily salbutamol in young patients with SMA type II. Neuromuscul. Disord. 18, 536–540. Prior, T.W., Russman, B.S., 1993. Spinal muscular atrophy. In: Pagon, R.A., Bird, T.C., Dolan, C.R., et al. (Eds.), GeneReviews [Internet]. University of Washington, Seattle, WA; 1993–2000 Feb 24 [updated 2013 Nov 14]. Singh, P., Liew, W.K., Darras, B.T., 2013. Current advances in drug development in spinal muscular atrophy. Curr. Opin. Pediatr. 25, 682–688. Wang, C.H., Finkel, R.S., Bertini, E.S., et al., 2007. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22, 1027–1049.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 139-3. PCR diagnosis of SMN1 deletion. Fig. 139-4. SMA carrier testing. Fig. 139-5. The neuromuscular junction defects in SMA. Fig. 139-6. The pathology of SMA. Fig. 139-7. A model depicting the postnatal requirements for the SMN protein in mice. Fig. 139-8. Mechanism of action for SMN antisense oligonucleotide. Table 139-2. Genetic diagnostic testing in spinal muscular atrophy Table 139-3. Outcome measures used in spinal muscular atrophy clinical trials

140  Other Motor Neuron Diseases of Childhood Michele L. Yang and Anne M. Connolly

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

ANATOMY: THE ANTERIOR HORN CELLS OF THE SPINAL CORD

HEREDITARY DISEASES AFFECTING SPINAL MOTOR NEURONS

Anterior horn cells (α-motor neurons), located in the anterior gray matter of the spinal cord, are found at every segment and are concentrated in the cervical and lumbosacral enlargements. Morphologic differentiation of the anterior horn cells is most evident from 12 to 14 weeks’ gestation. There is a period of normal differentiation, followed by programmed cell death. Anterior horn cells are clustered into medial and lateral cell divisions (Figure 140-1). The medial group is subdivided into ventromedial and dorsomedial components. The ventromedial component innervates the superficial larger muscles, and the dorsomedial component innervates the small, deep muscles adjacent to the spine. The lateral cell mass is also subdivided into groups. The ventrolateral group innervates extensor muscles, and the centrodorsal group innervates flexor muscles. These groups of neurons are located in a relatively small region; therefore deleterious influences harm cells from more than one group and weakness may be widespread. Motor neurons in the nuclei of brainstem cranial nerves are homologous to spinal cord anterior horn cells. Therefore pathologic mechanisms that compromise the cranial motor neurons may initiate symptoms and signs that mimic anterior horn cell dysfunction in the spinal cord. Muscular atrophy, severe weakness, and fasciculations without sensory deficit are signs of anterior horn cell disease. When sensory function is impaired in conjunction with anterior horn cell disease, dysfunction of adjacent tracts of the spinal cord or the peripheral nerves may be present.

Inherited motor neuron disease in childhood is most commonly caused by mutations of the SMN1 gene on chromosome 5q13 (see Chapter 139). However, a small proportion (4%) of patients do not have a mutation or deletion of SMN1. The clinical and genetic heterogeneity of this group of disorders can be overwhelming, particularly as the number of new genes identified increases yearly (Table 140-1) (Pestronk, 2003; Peeters et al., 2014). Classifying them by distribution of weakness (proximal, distal, bulbar), inheritance pattern (autosomal dominant, autosomal recessive, or X-linked), and other associated manifestations can guide the diagnostic workup. A simplified algorithm to the approach to the diagnosis of motor neuron disease is presented in Figure 140-2 by distribution of weakness, that is, proximal (Figure 140-2A) or distal (Figure 140-2B) (Finsterer and Burgunder, 2014).

DIAGNOSTIC WORKUP Disorders of the motor neuron typically result in flaccid weakness, hypotonia, and decreased reflexes, with varying degrees of atrophy depending on the chronicity of the disorder. Fasciculations may be present as well. Dysfunction of the motor neurons can result from acquired or hereditary etiologies. Therefore in any patient in whom this is a consideration, a thorough medical and family history, and detailed neurologic examination are crucial. If the child’s history and physical suggest a motor neuron disorder, multiple tests can be performed for confirmation, including serum creatine kinase (CK) and electrophysiologic testing (electromyography and nerve conduction study [EMG/NCS]). The serum CK can be normal or mildly elevated, usually not more than three times the upper limit of normal, about 600 mg/dl. Electrodiagnostic studies show normal or near-normal sensory responses and normal motor conduction velocities, often with reduction in amplitudes of compound motor action potentials. Chronic and/or acute denervation may be recognized by electromyography. Motor unit number estimate is a more of a research tool that is reduced in disorders of affecting the motor neuron.

SMA-like Motor Neuron Disorders Children with SMA-like motor neuron disorders present with symmetric proximal muscle weakness, affecting legs more than arms. This pattern of weakness is similar to those with 5q-associated SMA. Weakness typically is rapidly progressive, with respiratory insufficiency usually resulting in the need for mechanical ventilation, followed by death. Respiratory insufficiency may be the first clinical feature in patients with spinal muscular atrophy with respiratory distress (SMARD). In SMARD1, patients may have diaphragmatic paralysis with eventration of the diaphragm; the intercostal muscles are spared. Weakness and contractures occur first in the distal extremities. SMARD1 is caused by mutations of IGHMBP2. A new phenotype of SMARD2 with a similar clinical presentation has been associated with mutations of LAS1L. As in 5q-associated SMA, the main features of early onset scapuloperoneal SMA include progressive weakness of the extremities beginning at birth or early childhood. A characteristic feature of this subtype of SMA is vocal cord weakness with hoarseness and respiratory stridor. If this feature is present, mutations of TRPV4 should be considered. Arthrogryposis is an early feature in boys with X-linked SMA and arthrogryposis (XL-SMA, UBA1 gene) but otherwise the presentation is similar to that of 5q-associated SMA. Contractures typically occur in the proximal joints and fingers. Respiratory insufficiency also occurs early and is progressive, with death occurring in most patients before the age of 2 years because of respiratory failure.

Motor Neuron Disease With Central Nervous System Manifestations The presence of predominant central nervous system (CNS) findings such as spasticity, movement disorders, and intellectual disability is unusual in 5q-associated SMA. Cerebellar findings such as ataxia, nystagmus, or oculomotor apraxia in infants with motor neuron disease should prompt an

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TABLE 140-1  Motor Neuron Disease Plus Syndromes Clinical Patterns

Disease

Symptoms

Genes

Inheritance

Diagnostic Testing

SMA-like With proximal muscle weakness

DSMA1 Distal infantile SMA with diaphragm paralysis (DSMA1 or SMARD1)

Onset birth to 2 months Diaphragmatic paralysis with sparing of intercostal muscles Death or respiratory failure less than 3 months Severe distal weakness Distal SMA weakness at age 1 year with progression but variable onset of respiratory failure Occasional mild contractures of the knee and ankle Single patient Distal weakness at birth Early respiratory failure Fasciculations of tongue Mild contractures of fingers and toes Onset: congenital childhood Legs only Proximal and distal contractures Nonprogressive Vocal cord paralysis in some Onset at birth or infancy Pattern of weakness similar to classic SMA Proximal and finger contractures Myopathic facies Respiratory insufficiency Dysmorphic features Death less than 2 years of age

Immunoglobulin µ-binding protein 2 (IGHMBP2); 11q13.3

AR

Normal CK Eventration of diaphragm on chest x-ray Sural nerve: myelinated axon loss

LAS1L; Xq12

X-linked recessive

EMG localized to motor neuron

TRPV4; 12q24.11

AD

Mildly elevated CK EMG/NC: normal CMAP and SNAPs; giant motor units on EMG

UBE1; Xp11.3

X-linked recessive

Onset birth to 6 months Hypotonia, weakness, distal symmetric polyneuropathy Ataxia, nystagmus Mild to severe contractures Microcephaly Onset birth Progressive microcephaly Distal contractures Oculomotor apraxia

VRK1; 14q32

AR

EXOSC3; 9p13.2

AR

PCH1C

Onset 2–4 months Severe weakness Spasticity Vision and hearing impairment Stepwise decline with illnesses

EXOSC8; 13q13.3

AR

Leukoencephalopathy with dystonia and motor neuropathy

Onset: childhood to teens Dystonia Hypergonadotropic hypogonadism Azoospermia Saccadic eye movements Brisk reflexes in arms, diminished in legs Intention tremor, ataxia Hyposmia Onset: late teens to early adulthood Muscle atrophy, muscle cramping, fasciculations, proximal great than distal weakness Ataxia, dystonia, dysarthria

SCP2; 1p32.3

AR

MRI brain: hyperintensities in thalamus, “butterfly-like” lesions in pons, lesions in occipital regions

HEXA; 15q23

AR

MRI brain: cerebellar atrophy EMG/NCS: axonal sensorimotor polyneuropathy, CRDs

SMA with respiratory failure 2 (SMARD2)

SMA: scapuloperoneal

X-linked SMA with arthrogryposis (XL-SMA, SMAX2)

With CNS manifestations Cerebellar hypoplasia

Pontocerebellar hypoplasia (PCH) type 1A

PCH2

Movement disorders Dystonia

Hexosaminidase A deficiency (TaySachs disease), juvenile form

Normal CK MRI brain: cerebellar hypoplasia or absence EMG/NCS: axonal sensorimotor polyneuropathy MRI brain: cerebellar atrophy, small brainstem and cortex EMG/NCS: axonal sensorimotor polyneuropathy MRI brain: cerebellar hypoplasia Hypomyelination of lateral descending tracts



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TABLE 140-1  Motor Neuron Disease Plus Syndromes (Continued) Clinical Patterns

Disease

Symptoms

Genes

Inheritance

Diagnostic Testing

Mitochondrial membrane protein associated neurodegeneration (MPAN; NBIA4)

Onset: 3–39 years Dysarthria Spasticity Dystonia, parkinsonism Progressive distal great than proximal weakness Optic atrophy, slow saccades Cognitive decline Psychiatric manifestations

C19orf12; 19q12

AR

EMG/NCS: motor neuropathy Serum CK: high MRI: hypointensity of globus pallidus and substantia nigra; cerebellar atrophy

Spasticity

Achalasia-addisonismalacrima (AAA) syndrome (Allgrove syndrome)

Onset: childhood GI: achalasia, feeding difficulties, xerostomia, fissured tongue Endocrine: adrenal insufficiency Skin: hyperpigmentation, excessive creases on palms and soles, hyperkeratosis Long thin face, long philtrum Eyes: alacrimia, optic atrophy, pupillary abnormalities Intellectual disability Autonomic dysfunction Spasticity

AAAS; 12q13.13

AR

EMG/NCS: predominantly axonal motor neuropathy

Seizures

SMA with myoclonic epilepsy

Onset 3–5 years SMA-like with proximal weakness first in legs and then in arms Respiratory failure occurs later in course

ASAH1; 8q22

AR

Normal CK EEG: subcortical myoclonic epileptiform activity, sensitive to hyperventilation EMG: chronic denervation

Bulbar involvement

Brown-Vialetto-Van Laere (BVVL)

Onset 8–20 years Pontobulbar palsy Sensorineural hearing loss Ataxia caused by sensory neuropathy

SLC52A2 and SLC52A3

AR, rarely AD

Fazio-Londe disease (FL)

Onset in childhood, usually less than 12 years Respiratory insufficiency Pontobulbar palsy Ataxia caused by sensory neuropathy No hearing loss

SLC52A2 and SLC52A3

AR or AD

Nathalie syndrome

Onset 4–5 years Hearing loss Spinal muscular atrophy Cataract Dilated cardiomyopathy Delayed growth and sexual development Juvenile onset bulbar weakness Vocal cord paralysis ± sensorineural hearing loss Exercise-induced muscle cramping Tremors Gynecomastia Facial fasciculations

Unknown

AR

EMG/NCS: motor neuropathy with upper limbs more affected than lower Brain MRI: normal Sural nerve biopsy: severe chronic axonal neuropathy affecting large fibers predominantly, no regeneration seen EMG/NCS: motor neuropathy with upper limbs more affected than lower Brain MRI: normal Sural nerve biopsy: severe chronic axonal neuropathy affecting large fibers predominantly, no regeneration seen ECHO: dilated cardiomyopathy Autopsy: loss of cochlear neurons, atrophy of organ of Corti, atrophy of atria vascularis

UBQLN1

AR

hAR; X

Dominant X-linked

BVVL-like

Spinal and bulbar muscular atrophy (Kennedy’s disease)

Mildly elevated CK EMG/NCS shows motor neuronopathy

Continued on following page

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TABLE 140-1  Motor Neuron Disease Plus Syndromes (Continued) Clinical Patterns

Disease

Symptoms

Genes

Inheritance

Arthrogryposis

LCCS1

Onset: in utero Hydrops fetalis, arthrogryposis multiplex congenita Pulmonary hypoplasia Fractures Chest wall deformities Onset: birth Multiple joint contractures Markedly distended bladder Single family of Israeli-Bedouin origin Onset: birth Contractures Onset at birth or infancy Pattern of weakness similar to classic SMA Proximal and finger contractures Myopathic facies Respiratory insufficiency Dysmorphic features Death less than 2 years of age

GLE1; 9q34

AR

ERBB3;12q13

AR

DYNC1H1; 14q32.31 UBE1; Xp11.3

AD

LCCS2

SMA-LED X-linked SMA with arthrogryposis (XL-SMA, SMAX2)

Diagnostic Testing

Anterior horn cell atrophy on autopsy

X-linked recessive

AD, autosomal-dominant; AR, autosomal-recessive; CK, creatine kinase; CMAP, compound muscle action potential; CRDs, complex repetitive discharges on EMG; EMG/NCS, electromyography and nerve conduction study; LCCS, lethal congenital contracture syndrome; SMA, spinal muscular atrophy; SMARD, spinal muscular atrophy with respiratory distress; SNAP, sensory nerve action potential.

evaluation for pontocerebellar hypoplasia (PCH). Three types of PCH have been associated with an SMA-like phenotype: PCH1A (VRK1), PCH1B (EXOSC3), and PCH1C (EXOSC8). Children generally present at birth or in infancy with variable contractures and cerebellar hypoplasia. An MRI of the brain will identify cerebellar abnormalities. Electrophysiologic testing can demonstrate the presence of an axonal sensorimotor polyneuropathy. A few of the genetic motor neuron disorders can have associated movement disorders. Patients with leukoencephalopathy with dystonia and motor neuropathy can present in childhood with progressive distal weakness as well as cerebellar and extrapyramidal symptoms. Whereas the infantile form of hexosaminidase A deficiency is primarily characterized by CNS manifestations, the juvenile onset form may have an associated progressive motor neuropathy characterized by muscle atrophy with fasciculations, muscle cramping, and proximal greater than distal weakness in addition to a movement disorder with ataxia, dysarthria, and dystonia. Patients with achalasia-addisonism-alacrima syndrome (triple A syndrome) may present in childhood with intellectual disability, developmental delay, spasticity, and a progressive axonal motor neuropathy. The associated gastrointestinal, endocrine, skin, and autonomic dysfunction makes identification relatively straightforward. There are few genetic motor neuron disorders associated with seizures. When myoclonic seizures are present in a patient with suspected motor neuron disease, mutations of ASAH1 should be sought. Symptoms typically are seen between 3 and 5 years of age with progressive weakness of the legs, arms, and then respiratory muscles.

Motor Neuron Diseases With Predominant Bulbar Weakness Bulbar symptoms are often part of the presentation of many neurodegenerative disorders. However, when dysphagia, dysphonia, and dysarthria are the dominant presenting features, childhood progressive bulbar syndromes should be considered. Brown-Vialetto-Van Laere (BVVL) disease and Fazio-Londe (FL) disease are two distinct clinical entities

recognized to be allelic conditions and present along a phenotypic spectrum. The major features of BVVL disease are pontobulbar palsy, neuronopathy, respiratory insufficiency, and sensorineural hearing loss, presenting in the first or second decade of life. The course is generally progressive, but may appear episodic with worsening with illness. In contrast, FL disease is not associated with hearing loss, and onset is in the first to third decades of life. Patients may present initially with repeated respiratory infections and stridor, with progression to weakness, wasting, hypotonia, and decreased reflexes. In both BVVL and FL, patients often die of respiratory failure. The identification of biochemical abnormalities suggested a multiple acyl-CoA dehydrogenase deficiency (MADD)–like disorder and the finding of decreased plasma flavin levels in these patients indicated that riboflavin transporters could play a role. Subsequently, two genes were identified in patients with BVVL and FL. Solute carrier family 52, riboflavin transporter, member 3 (SLC52A3, previously known as C20orf52) encodes intestinal human riboflavin transporter 3, which is necessary for riboflavin absorption, and SLC52A2 (previously G proteincoupled receptor 172A) encodes human riboflavin transporter 2 (RFVT2, previously human riboflavin transporter 3 [hRFT3]). Although with both mutations a MADD-like biochemical profile is seen, plasma flavin levels are normal in patients with SLC52A2 mutations, likely because the encoded transporter is responsible for transport of riboflavin from blood into target cells. Because the SLC52A3-encoded transporter is responsible for uptake of riboflavin from food, flavin levels are low. Therefore acylcarnitine levels taken at birth should be interpreted with these differences in mind if BVVL or FL is suspected. Recognition that riboflavin transport is affected in these patients is an important advance in the management of these children. Treatment with high-dose riboflavin (10 mg/kg per day) appears to result in significant and sustained clinical and biochemical improvements. The recommendation is for treatment early in the disease course in suspected cases to maximize response. Spinal and bulbar muscular atrophy (SBMA, or Kennedy’s disease) is an X-linked motor neuron disease typically presenting in adult men in the 3rd to 5th decades. The classic presentation is of slow progression of proximal weakness, bulbar



weakness including asymmetric or symmetric facial weakness, and gynecomastia. However, some patients may complain of exercise-induced muscle cramps and hand tremors several years before weakness develops, as early as the second decade of life. Weakness and atrophy of the bulbar musculature is striking and may include an atrophied, furrowed tongue and atrophy of the face and jaw. Facial fasciculations around the mouth and chin are striking clinical features best elicited by having the patient whistle or blow out the cheeks. There are no signs of spinal cortical tract dysfunction, and deep tendon reflexes are diminished or normal. EMG/NCS findings and an unusually elevated CK are supportive findings, and should prompt testing for expanded CAG trinucleotide repeats in the androgen receptor gene (hAR).

Motor Neuron Disease With Arthrogryposis Arthrogryposis at birth can occur because of many causes, but in the context of motor neuron disease, this finding indicates severe and early motor neuron dysfunction. Lethal arthrogryposis with anterior horn cell disease (LAAHD) and X-linked spinal muscular atrophy (SMAX2) are the most severe forms of motor neuron disease. The clinical phenotype includes severely decreased fetal movements, severe multiple contractures at birth, hypotonia, chest wall deformities, pulmonary hypoplasia, and bony fractures. In both LAAHD and SMAX2, patients have severe respiratory insufficiency and die by age 2 years. LCCS2 is a rare disorder described in one family, presenting with multiple contractures at birth and markedly distended bladders. Spinal muscular atrophy with lower extremity predominance (SMA-LED) associated with DYNC1H1 mutations typically presents in early childhood, but has been associated with contractures at birth, from mild talipes to severe generalized arthrogryposis.

Motor Neuron Disease With Distal Weakness The diagnosis of a distal motor neuropathy or neuronopathy can be difficult, particularly if the presentation occurs later in adulthood (Drew et al., 2011). The phenotypic spectrum is wide and varies from a CMT-like presentation to juvenile amyotrophic lateral sclerosis (ALS) and hereditary spastic paraparesis with associated mild sensory abnormalities and upper motor neuron signs, respectively (Table 140-2). Electrophysiologic studies are one of the most helpful means of distinguishing between these diagnostic possibilities. This section will focus on those disorders presenting with lower motor neuron disease in childhood. They are characterized by a slowly progressive length-dependent weakness, starting in the first 2 decades of life, with distal weakness and atrophy, absent reflexes, and electrophysiologic findings of chronic distal denervation. Bulbar involvement, with the exception of vocal cord weakness, is unusual. The phenotypic variability of these disorders can complicate diagnostic workup of these disorders. The simplest method to approach the diagnosis is by organization by inheritance pattern and by the dominant weakness (Figure 140-2B). However, even with this approach, the diagnostic yield is low, with genotypic characterization in 20% of patients. Of these disorders, SMA with lower extremity predominance (SMALED) type 1 caused by DYNC1H1 mutations can be easily recognized by the unusual waddling gait and disproportionate weakness of the legs compared with the arms. Patients may present at birth with multiple contractures, but many of the patients present with delayed walking in childhood and a slowly progressive weakness and gait abnormality. Intellectual disability and migrational abnormalities have been noted in some patients as well. Interestingly, mutations of BICD2, which functions as an adaptor of the dynein molecular motor,

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result in SMA-LED2 with similar weakness and gait abnormalities as SMA-LED1. In both, obtaining a complete family history is important in identifying other affected family members and the autosomal-dominant inheritance pattern. Although mutations of TRPV4 can present with legpredominant weakness, a distinguishing feature that can identify the presence of this gene mutation is a hoarse voice resulting from vocal cord paralysis. Mutations of DCNT1 can also cause vocal cord paralysis, but the clinical picture is more variable. The lower motor neuron phenotype is more suggestive of ALS or SMA than a length-dependent neuropathy. Symptoms typically begin in adulthood with face-arm weakness first, with leg weakness presenting later. Some patients can present with pyramidal signs, as can patients with mutations of BSCL2 and HSPB1.

Amyotrophic Lateral Sclerosis With Onset in the First Two Decades of Life ALS represents a spectrum of motor system degeneration involving the corticospinal and corticobulbar pathways and motor neurons associated with the cranial nerves and anterior horn cells of the spinal cord. Onset may be as early as early childhood, although the majority present after the fourth decade of life. Dysfunction of upper and lower motor neurons produces clinical manifestations of both spasticity and muscular atrophy. To date, more than 25 genes have been associated with ALS or ALS associated with frontotemporal dementia (http:// neuromuscular.wustl.edu/synmot.html#Hereditaryals). The first causative gene described for ALS in adults (ALS1 is SOD, a gene that encodes a cytosolic Cu/Zn-binding superoxide dismutase, is causative in ALS1. There are six recognized ALS syndromes with onset in the first two decades of life (Table 140-3). First, ALS 2 is an autosomal-recessive disease caused by mutations in the Alsin gene. Alsin is a member of the guanine nucleotide exchange factors for the small guanosine triphosphatase, RAB5, and plays a role in endosomal trafficking. Children present in the first decade of life with spasticity involving face and limbs, and may develop pseudobulbar affects. Symptoms are very slowly progressive, with difficulty walking after age 40. Two allelic conditions, infantile-onset ascending paralysis and primary juvenile lateral sclerosis (OMIM 606353) are well recognized. More recently, another allelic variant with ALS and generalized dystonia was described. Alsin-deficient mice experience progressive axonal degeneration in the lateral spinal cord but lower motor neurons were preserved. The second juvenile-onset form of ALS is ALS 4, an autosomal-dominantly inherited distal motor neuronopathy with pyramidal symptoms. ALS 4 is allelic to recessively inherited oculomotor apraxia type 2 (AOA2). Symptoms of ALS 4 begin in the second decade of life with difficulty walking, and examination indicates both upper and lower motor neuron involvement. Bulbar symptoms are infrequent. Electrophysiology confirms localization to the anterior horn cell. The clinical course is slowly progressive, with use of wheelchair by fifth or sixth decade and a normal life span. The senataxin protein plays an essential role with DNA damage response. The third form of ALS with childhood onset is ALS 5. ALS 5 is recessively inherited and is caused by mutations in the SPG11 gene, which encodes spatacsin and is allelic with SPG11. The age of onset is 7 to 23 years, with a mean age of 16 years. Spasticity of limbs, face, and bulbar is present with amyotrophy and weakness. The course is slowly progressive with survival duration of 27 to 40 years. To date, three other genetic forms of juvenile ALS have been determined by small, informative families. They include ALS6 secondary to FUS, ALS 16 secondary to sigma-1 receptor, and

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TABLE 140-2  Distal Forms of SMA Disease

Symptoms

Genes

Inheritance

Diagnostic Testing

Distal SMA, X-linked 3 (SMAX3)

Onset: 1–61 years Early weakness of legs with slow progression; remain ambulatory Pes cavus Temperature sensitivity with worsening in cold Variable reflexes

ATP7A; Xp21.1

X-linked recessive

CK normal EMG/NCS: reduced or absent CMAP, normal SNAPs; widespread denervation on EMG

DSMA1 Distal infantile SMA with diaphragm paralysis SMARD1 (HMN6)

Distal SMA weakness at age 1 year with progression but variable onset of respiratory failure

IGHMBP2; 11Q13.3

AR

DSMA 2 Jerash type

Onset 6–10 years Distal weakness in legs and then arms within 2 years Atrophy of hands and feet Brisk reflexes at knees, absent at ankles

9p21.1-p12

AR

EMG/NCS: small CMAPs, normal SNAPs Normal CK

DSMA 3

Onset age 9 months to early adulthood Weakness of feet great than hands Diaphragmatic weakness with childhood onset

11q13.3

AR

EMG/NCS: normal nerve conduction studies; denervation on EMG

DSMA 4

Onset 2–11 years Proximal = distal weakness Scapular winging Progressive respiratory failure Contractures of the hips, elbows, hands Hyperlordosis Allelic with CMTR1C

PLEKHG5; 1p36.31

AR

EMG/NCS normal nerve conduction studies; denervation on EMG

DSMA 5 (distal motor neuropathy with young adult onset)

Onset age 16–23 years Foot drop Legs great than hands Absent reflexes Edema in legs Progressive to wheelchair Allelic with CMT 2T

DNAJB2; 2q35

AR

EMG/NCS: small CMAP, especially in legs, normal SNAPs

SMA, lower extremity predominant 1 (SMA-LED)

Onset: birth to early childhood Late walking Slowly progressive Weakness legs great than arms, quadriceps, psoas, and hip abductors typically weak out of proportion to rest of muscles Waddling gait

DYNC1H1; 14q32.31

AD

MRI legs: early involvement of the vastus lateralis and sartorius MRI brain: occasionally see polymicrogyria, cobblestoning

SMA, lower extremity predominant 2

Onset: in utero, infancy, young adulthood Delayed walking Weakness of legs great than arms, like in SMA-LED1 Contractures of ankles, knees Sleep disordered breathing Slow progression Normal sensation, bulbar function, and cognition

BICD2; 9q22.31

AD

MRI legs: early involvement of vastus lateralis and intermedius, rectus femoris; spares semitendinosus, medial adductors EMG/NCS: chronic denervation on EMG

DSMA-calf predominant (HMN2D)

Onset 13–48 years Presentation with difficulty standing or walking Weak calves Triceps also weak Fasciculations present

FBXO38; 5p31.1

AD

EMG/NCS: reduced amplitudes of CMAPs, normal SNAPs, fibrillation potentials

SMA, congenital nonprogressive of the lower limbs

Onset: congenital Weakness of legs only, proximal and distal Nonprogressive Some with vocal cord paralysis Contractures of knees and ankles

TRPV4; 12q24.11

AD

Mildly elevated CK EMG/NCS: giant motor units; normal motor and sensory NCSs

DSMA: upper extremity predominance (HMN5C)

Onset: 15 years (2–40 years) Weak hands (thenar great than first dorsal interosseous) Foot deformities Peroneal weakness Brisk DTRs Decrease vibration in legs

BSCL2; 11q12.3

AD

EMG/NCS: small CMAPs, normal or mildly decreased motor NCVs; large MUPs on EMG

DSMA: upper extremity predominance (HMN5A, SMAD1)

Onset: second decade Weakness of thumb and first dorsal interosseous Lower extremity involvement in 50% in 2 years Slow progression Rare pyramidal involvement

GARS; 7p14.3

AD



Other Motor Neuron Diseases of Childhood

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TABLE 140-3  Genetic Forms of ALS Associated With Presentation in Childhood Name

Inheritance Gene; Loci

Protein

140 Onset (Years)

Inheritance

OMIM

ALS 2

AR ALS2; 2q33

Alsin

1–3

AR

#20511

ALS 4

AD SETX; 9q34

Senataxin

6–21

AD

#602433

ALS 5

AR ALS5; 15q21

Spatacsin

5–23

AR

#610844

ALS 6 variant

Sporadic FUS; 16p11

Fusion

Sporadic

#608030

ALS 6–21

AR 6p 25; 21q22

Unknown

4–10

AR

ALS 16

AR SIGMAR1; 9p13

Sigma-1 receptor

1–2

AR

17–22

#614373

AD, autosomal-dominant; ALS, amyotrophic lateral sclerosis; AR, autosomal-recessive; #, OMIM gene identified.

a third form currently linked to 6p25 and 32q22. ALS6 is autosomal recessive, is caused by heterozygous mutations in the FUS gene, and can present with or without frontotemporal dementia. Although most present in the third and fourth decade, a juvenile form has been reported with onset between age 17 and 22 and may have rapid progression. It is allelic with familial essential tremor-4 caused by heterozygous mutations (ETM4). A single family has been found to have autosomal-recessive childhood ALS (ALS16) with onset at age 1 to 2 years because of sigma-1 receptor mutations (SIGMAR1). Progression in 2 of the 6 children led to wheelchair use by age 20 but no respiratory or bulbar weakness. Finally, another single family with four affected children has been shown to have autosomal-recessive ALS linked to 6p25 and 21q22.

OTHER ATYPICAL AND ACQUIRED MOTOR NEURON DISORDERS If weakness occurs acutely, acquired causes of motor neuron disease should be diagnostic considerations. Infectious, parainfectious, autoimmune, vascular, and traumatic etiologies can result in acute muscle weakness without sensory changes.

INFECTIONS With the introduction of the polio vaccine, poliovirus as an infectious cause of acute flaccid weakness has virtually been eradicated. However, recent resurgences of children with flaccid weakness remind us that viruses remain an important etiology to consider when suspecting an acquired cause of motor neuron disease. Poliovirus was one of the most common causes of acquired motor neuron disease. Typically acquired via the fecal-oral route, the virus is stable in the gastrointestinal tract, and can be detected in the throat and stool before the onset of illness. Less than 1% of all polio infections result in flaccid paralysis. Onset is usually indicated by upper respiratory tract symptoms with accompanying malaise, muscle pain, and stiffness. The patient may experience some degree of nuchal rigidity and a low-grade fever as the disease progresses. Paralytic symptoms generally begin 1 to 10 days after prodromal symptoms and progress for 2 to 3 days. Poliomyelitis is characterized by a triad of fever, nuchal rigidity, and spasm of the back, and may be mistaken for typical meningitis. Typically once the temperature normalizes, no further paralysis occurs. Patients with more rapid progression have more severe involvement, typically with respiratory and bulbar weakness. The weakness

is typically asymmetric, associated with decreased reflexes, and reaches a plateau without change for days to weeks. There is no accompanying sensory loss or changes in cognition. Although some persons with paralytic poliomyelitis recover completely, those with weakness present after 12 months will have permanent weakness. Cerebrospinal fluid (CSF) pleocytosis with mononuclear cells and a normal or slightly elevated protein concentration supports this diagnosis. Complete blood cell count show that polymorphonuclear cells may predominant early in the course. Poliovirus may be recovered from the stool or pharynx. Isolation of the virus from the CSF is diagnostic, but it is rarely found. Treatment is supportive, and typically requires prolonged rehabilitation as some degree of motor deficits persists after the acute infection. Postpolio syndrome may begin two or more decades after the illness, with progressive loss of strength and atrophy of an already affected limb. Through widespread use of the polio vaccine, the incidence had been drastically reduced in most parts of the world. Most sporadic cases of a polio-like syndrome are no longer associated with the poliovirus but are the results of other viral infections, including Epstein-Barr, enterovirus 71, enterovirus D68, echo 4 virus, and coxsackie virus (Solomon et al., 2014).

Vascular Etiologies The anterior spinal artery originates from where the vertebral arteries meet and traverses the anterior median sulcus over the entire course of the spinal cord. The radicular arteries are divided into anterior and posterior radicular arteries. Blood from the anterior radicular arteries that enter with the nerve roots between the third cervical and third lumbar segments flows into the anterior spinal artery (Figure 140-5). The anterior spinal artery is then separated further into several sulcal branches that pierce the central gray matter, perfuse the anterior horn cells, and form numerous small penetrating vessels that supply the white matter of the anterior and lateral columns. The anterior spinal artery is vulnerable between the T4 and T8 regions because the radicular artery that supplies it (artery of Adamkiewcz) has poor anastomoses and is effectively an end artery. The anatomic relationship between the two posterior spinal arteries provides a very different vascular pattern for the posterior cord compared with the anterior spinal arteries do for the anterior cord. The posterior circulation enjoys a more extensive collateral system. Therefore occlusion of the posterior spinal arteries usually does not cause severe clinical dysfunction.

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Occlusion or hypoperfusion of the anterior spinal artery results in weakness below the level of occlusion, loss of pain, and temperature at or below the level because of involvement of the lateral spinothalamic tracts, and autonomic dysfunction such as loss of bowel and bladder function. The posterior columns mediating proprioception and vibratory sense remain intact. Patients often complain of a diffuse, radicular, or girdlelike pain. Occasionally a partial syndrome is seen in which the gray matter of the spinal cord is preferentially affected, with preserved sensation and bowel and bladder control. In children, the most common etiology is iatrogenic, caused by aortic surgery such as during repair of a coarctation of the aorta. Other causes can include anemia, polycythemia, sickle cell disease, paradoxical embolism from a patent foramen ovale, atlantooccipital dislocation, cervical spondylosis, cervical spinal trauma or sprain, cocaine use, or infections such as tuberculosis. Although arteriovenous malformations of the spinal cord are rare, they should be considered in a child with acute, subacute, or chronic symptoms of back or radicular pain, sensorimotor changes, or bowel or bladder dysfunction. The most common presentation of a vascular malformation in the spinal cord in children is with weakness. Sudden focal pain may occur with an acute hemorrhage, whereas subacute symptoms that worsen and then improve with gradual deterioration over time may indicate alterations in blood flow because of venous hypertension or repeated hemorrhages. Typically, however, sensory changes are also present, as are changes in bowel and bladder function, suggesting a diagnosis other than primary motor neuron dysfunction. Over time, the acute flaccid paralysis evolves into spasticity. Imaging is key to the diagnosis, and conventional angiography may be required to adequately visualize the malformation to develop a surgical plan. Surgical options include microsurgical exclusion and/or endovascular embolization, but the neurologist should be aware that transient neurologic deficits can occur postoperatively.

Trauma There are rare case reports of adults and children who develop a delayed upper and lower motor neuron syndrome after exposure to an electrical injury or lightning. In children, electrical injuries typically occur in the household from putting electrical cords in the mouth or from wall outlets. Transient neurologic deficits immediately after an electrical shock are well described and usually recover after hours to several days. A persistent and progressive motor neuron syndrome has been described, developing at variable time intervals after the initial injury, but the relationship between electrical injury and a motor neuron syndrome is controversial. Trauma to the spinal cord may follow birth trauma, falls, motor vehicle accidents, or blows to the spinal column, resulting in incomplete or total transection of the spinal cord. However, impairment localized only to the anterior horn cells is unlikely unless the anterior spinal arteries are primarily affected.

Unknown Etiologies Monomelic amyotrophy is a rare form of motor neuron disease with clinical deficits limited to a restricted number of myotomes. Most cases are sporadic though a familial form has been reported and susceptibility genes have been identified. Many names have been used for this disorder, including juvenile muscular atrophy of a unilateral upper extremity, benign focal amyotrophy, juvenile segmental muscular atrophy, and Hirayama’s disease. Symptoms typically present in the second or third decade of life, with a male

preponderance of 5:1 to 10:1, male-to-female ratio. Most cases are limited to the arm, with insidious, painless weakness and atrophy of the hand muscles that progresses to the forearm. Of note, the brachioradialis and extensor carpi radialis are usually spared. No preceding injury or infection is typically identified. Progression is typically slow, over 1 to 3 years, and there may be atrophy of the other arm, though it is typically less marked and more confined to isolated muscles. The etiology of the disorder is unknown.

TREATMENT Other than the potentially riboflavin-responsive BVVL and FL, there are no specific treatments for either the inherited or the acquired motor neuron disorders. The mainstays of treatment remain physical therapy, orthotic support, and orthopedic procedures to protect joints and maximize mobility. Orthopedic procedures performed on patients with arthrogryposis often provided sufficient alignment and stability of the legs to allow independent ambulation. Talectomy before walking ability is acquired may prove beneficial. Scoliosis may be a prominent problem and may require surgical correction. Some improvement in arm and hand function is usually possible with physical therapy and exercise. Anesthesia for these patients requires special consideration. Otolaryngologic management may be necessary for poor suck reflex, omega-shaped epiglottis, airway compromise, achalasia, and micrognathia. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Drew, A.P., Blair, I.P., Nicholson, G.A., 2011. Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies. Curr. Mol. Med. 11, 650–665. Finsterer, J., Burgunder, J.M., 2014. Recent progress in the genetics of motor neuron disease. Eur. J. Med. Genet. 57, 103–112. Peeters, K., Chamova, T., Jordanova, A., 2014. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain 137, 2879–2896. Pestronk, A., 2003. Neuromuscular Disease Center. . Solomon, B.D., Baker, L.A., Bear, K.A., et al., 2014. An approach to the identification of anomalies and etiologies in neonates with identified or suspected VACTERL (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, cardiac anomalies, renal anomalies, and limb anomalies) association. J. Pediatr. 164, 451– 457, e451.

E-BOOK FIGURES AND TABLE The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 140-1. Alpha-motor neurons located in the anterior horn of the spinal cord (anterior horn cells) are clustered in a specific pattern. Fig. 140-2. A simplified algorithm for diagnosis of distal and proximal predominant motor neuron disease. Fig. 140-3. This 6-month-old boy has the neurogenic form of arthrogryposis. Fig. 140-4. A patient with Möbius’s syndrome who has bilateral weakness of cranial nerves VI and VII. Fig. 140-5. Arterial blood supply to the spinal cord. Fig. 140-6. Deformity of the cervical cord during flexion of the neck in patients with Hirayama’s disease. Table 140-4. Genetic forms of Möbius’s syndrome

141  Genetic Peripheral Neuropathies Kathryn M. Brennan and Michael E. Shy

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

DEFINITION This chapter focuses on those hereditary neuropathies present in the pediatric population. Inherited neuropathies are often referred to collectively as Charcot-Marie-Tooth (CMT) disease, an eponym used in recognition of the three men who initially described the disorder. CMT is, however, an umbrella term that encompasses a wide variety of inherited sensory and/or motor neuropathies. These inherited neuropathies also include other closely related neuropathies such as hereditary neuropathy with liability to pressure palsy (HNPP); distal hereditary motor neuropathy (dHMN), also known as distal spinal muscular atrophy (dSMA); and hereditary sensory neuropathy (HSN). HSN is sometimes referred to as hereditary sensory and autonomic neuropathy (HSAN). Collectively, CMT represents the commonest group of inherited neuropathies observed in the pediatric population and therefore is the main focus of this chapter.

PREVALENCE AND CLASSIFICATION CMT is the most common inherited neurologic condition, with a prevalence of around 1 : 2500. It is divided into subtypes based on the pattern of inheritance and by neurophysiological studies. Subtypes include AD demyelinating (CMT 1), AD axonal (CMT 2), AR (CMT 4) and X-linked (CMTX) (Harding, 1980a). CMT 1 typically has slow nerve conduction velocities (less than 38m/s in the upper extremities) and pathologic evidence of a hypertrophic demyelinating neuropathy whereas CMT 2 has relatively normal nerve conduction velocities with evidence of axonal degeneration (Harding and Thomas, 1980b). Because most forms of CMT have both motor and sensory involvement, CMT 1 and 2 are often known as hereditary motor and sensory neuropathy (HMSN) type I or II. Another subtype has emerged, known as CMT Intermediate, with nerve conduction demonstrating intermediate velocities (less than and greater than 38 m/s). Each type of CMT is now subdivided according to the specific genetic cause of the neuropathy (see Table 141-2). For example, the most common form of CMT1, termed CMT1A, is caused by a duplication of a fragment of chromosome 17 containing the peripheral myelin protein 22-kD (PMP22) gene, whereas CMT1B is caused by mutations in the myelin protein zero (MPZ) gene. Currently, mutations in more than 80 genes have been identified as causes of CMT neuropathies.

CLINICAL SEQUELAE OF INHERITED NEUROPATHY Symptoms of inherited peripheral neuropathy include weakness, sensory loss, abnormal balance, and autonomic dysfunction. Weakness is often said to be “length dependent” (i.e., distal and more severe in the legs than the arms). Deep and superficial muscles that are innervated by the peroneal nerve often cause more symptoms than muscles innervated by the

tibial nerve, such as the gastrocnemius. As a result, tripping on a carpet or curb and ankle sprains are frequent symptoms. Foot drop can ensue over time. In the hands, symptoms typically involve fine movements, such as using buttons or zippers and inserting and turning keys in locks. Cramping, the painful knotting of a muscle, frequently occurs with motor or sensorimotor neuropathies. The sensory symptoms of neuropathy reflect disease of small, thinly myelinated or nonmyelinated fibers serving in pain and temperature sensation and large myelinated fibers serving in position sense. Common symptoms of small-fiber sensory neuropathy include feeling as though the feet are “walking on pebbles” or “ice cold” and difficulty determining whether bath water is hot or cold with the foot. Painful dysesthesias are also associated with small-fiber abnormalities. Large-fiber sensory loss usually impairs balance, which may be worse at night when vision cannot overcome the loss of proprioception. Loss of proprioception is also frequently length dependent, so a patient may improve balance by lightly touching a wall with the hand to improve proprioceptive input to the brain. Autonomic symptoms may occur in the HSN group and various metabolic neuropathies. Symptoms include postural hypotension, cardiovascular incompetence, impaired sweating, urinary retention or incontinence, impotence, and constipation alternating with diarrhea. Often patients will not volunteer autonomic symptoms because they are not aware these symptoms could originate from a neuropathy, and so these particular symptoms need to be specifically addressed when assessing patients. Despite phenotypic variability, the typical clinical course of CMT1 and CMT2 patients includes normal development before weakness and sensory loss appear gradually within the first 2 decades of life. This is often referred to as the classical phenotype. This term is based on the original description by Harding and Thomas. Affected children are often slow runners and have difficulty with activities that require balance (e.g., skating, walking along a log across a stream) but have usually walked on time (i.e., before 15 months). Ankle-foot orthotics (AFOs) are frequently required by the third decade. Generally, hands are rarely as affected as the feet. Most patients remain ambulatory throughout life and have a normal lifespan. Patients with distal hereditary motor neuropathies (dHMNs) sometimes have mild sensory abnormalities, and patients with hereditary sensory neuropathies (HSNs) usually have some weakness. Indeed, the same mutation in the same gene can cause both CMT and dHMN within the same family (e.g., glycyl-tRNA synthetase or GARS mutations can cause both CMT2D and hereditary motor neuropathy type V).

PATHOPHYSIOLOGY Most of the genes mutated in CMT are involved in maintaining the structure or function of the peripheral nervous system. The first genes identified to cause CMT express proteins that are essential for compact (peripheral myelin protein 22

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[PMP22] and myelin protein zero [MPZ]) and noncompact (gap junction protein beta 1 [GJβ1]) myelin, and their altered expressions cause demyelination or dysmyelination. Geneprotein dosage has been shown to be important in some forms of CMT; too much PMP22 (i.e., with a duplication) causes CMT1A; too little (as seen with a deletion) causes HNPP. Abnormal expression of MPZ also causes demyelination, although in this case it is usually a result of point mutations in the MPZ gene. At a pathologic level, dysmyelination, demyelination, remyelination, and axonal loss are characteristic features of the various demyelinating forms of CMT1. In Dejerine-Sottas neuropathy, myelin may never have formed normally, which is referred to as dysmyelination. In CMT1, onion bulbs of concentric Schwann cell lamellae are usually present on nerve biopsies, with loss of both small- and large-diameter myelinated fibers and sometimes axons. Focal, sausage-like thickenings of the myelin sheath (tomaculae) are characteristic of hereditary neuropathy with liability to pressure palsies (HNPP) but may also be found in other forms of CMT1, particularly CMT1B.

NEUROPHYSIOLOGY Nerve conduction velocity (NCV) testing will differentiate between demyelinating and axonal neuropathies. In clinical practice, approximately 60% of CMT patients have CMT1, and approximately 20% have CMT2 (Saporta et al., 2011). Neurophysiology is also useful to detect sensory involvement that often is unreported by patients. It can also aid in the classification of axonal inherited neuropathies further into mixed motor and sensory axonal neuropathy (CMT2), pure motor axonal neuropathy (dHMN), and pure sensory axonal neuropathy (HSN/HSAN). Most CMT1 patients, particularly those with CMT1A, have a uniformly slow nerve conduction velocity of about 20 m/ sec. However, asymmetric slowing, which is characteristic of hereditary neuropathy with liability to pressure palsies, may be found in patients with missense mutations in PMP22, MPZ, EGR2, and, particularly in females, GJβ1. CMT1X, caused by mutations in GJβ1, comprises about 15% of all CMT patients. Males with CMT1X usually have NCVs in the “intermediate” range of 30 to 45 m/s. NCVs in women with CMT1X are often normal. Virtually all forms of CMT1 have axonal loss and demyelination. In cases where the motor and sensory responses are absent, it is worthwhile looking at proximal nerve conduction (e.g., axillary nerve latency) to fully investigate the possibility of a severe demyelinating rather than an axonal pathology.

GENETIC TESTING AND DIAGNOSTIC STRATEGIES Molecular testing—performed after the family history, neurologic examination, and neurophysiologic testing have suggested the probable candidate genes—is the “gold standard” for the diagnosis of inherited neuropathies. Strategies for focused genetic testing based on inheritance and clinical phenotype are in common use, with the choice of genes tested reflecting the specific population tested. For example, in Northern European and Northern American populations, most patients have dominant inheritance even if the cases are sporadic. Autosomal-recessive (AR) CMT is observed in less than 10% of these cases. However, in populations with high rates of consanguinity AR-CMT is likely to be much more common, even reaching levels of 40%.

An algorithm based on the North American population utilizes neurophysiological data, clinical information, and inheritance patterns to guide testing. Flow charts incorporating the clinical phenotype and electrophysiology findings, illustrated in Figures 141-2 and 141-3, guide the clinician on selection of appropriate testing strategies. With the use of such tools, most CMT clinics will reach a genetic diagnosis in approximately two-thirds of their total CMT population (Murphy et al., 2011). Approximately 90% of patients found to have a genetic diagnosis will have mutations in one of only four genes: PMP22, GJβ1, MPZ, and MFN2. Therefore, the flow charts emphasize the need for considering these particular genes first. Mutations that alter the amino acid sequence of PMP22, GJβ1, and MPZ almost always cause clinical neuropathy, whereas MFN2 and most other CMT genes can also have benign mutations in which the coding sequences are altered without causing disability. This is important to consider when interpreting genetic testing results. Once genetic testing has been done in a proband, other family members do not usually merit genetic testing and instead are identified by clinical evaluation and neurophysiology. The landscape of genetic testing is rapidly changing with the introduction of next-generation sequencing (NGS) into clinical practice in some areas, which enables sequencing of either the entire genome or exome (only the protein coding sequences) in days. However advanced genetic interrogation will require careful interpretation. Many genes, such as periaxin and MFN2, have a high number of polymorphisms that are not pathogenic. Currently, genetic testing is in a transition phase with both traditional Sanger sequencing and NGS (whole-genome sequencing/whole-exome sequencing [WGS/ WES]) technology being used by most dedicated CMT clinics.

SPECIFIC FORMS OF CMT CMT1: Autosomal-Dominant   Demyelinating Neuropathies CMT1 is the most common subtype of CMT and is caused primarily by mutations in four genes: PMP22, MPZ, LITAF, and EGR2. These genes are essential to formation of the myelin sheath and also Schwann cell function.

CMT1A CMT1A is the most common form of CMT in most populations, affecting 55% of genetically determined CMT and 36% of all CMT. It accounts for 80% to 90% of CMT1 cases. Patients usually present with the “classical CMT phenotype.” Patients usually will walk on time. Lifespan is not affected. Although patients frequently require ankle-foot orthotics, they rarely require wheelchairs for ambulation. Conduction velocities from the median and ulnar nerves are below 38 m/s and are typically in the 20s. The sensory action potentials are either reduced or absent. Nerve biopsy is not required but if performed reveals demyelination and onion bulb formation. Because there is a de novo mutation rate of 10%, children and adolescents without a family history with ulnar motor nerve conduction velocities (MNCVs) less than 35 m/s should first be screened for CMT1A before proceeding with other genetic testing. CMT1A is caused by a 1.4-Mb duplication on chromosome 17p11.2 in the region that carries the PMP22 gene.

CMT1B CMT1B is the fourth most common type of CMT and clinically is associated with three distinct phenotypes: (1) an earlyinfantile-onset severe phenotype with delayed walking and NCV less than 10 m/s, often referred to as Dejerine-Sottas



Genetic Peripheral Neuropathies Very slow MNCV (£15 m/s) Walked at ≥15 months of age

Slow MNCV (>15 and £35 m/s)

Test for MPZ CMT1B

141

Test for PMP22 dup CMT1A

Walked at 35 and £45 m/s)

Axonal CMT (MNCV >45 m/s or Unobtainable CMAP)

Symptom onset: classic

Symptom onset: adult

Is there male to male transmission?

Test for MPZ CMT1B

no yes

Symptom onset: Infancy or Severe in Childhood

Symptom onset: Classic or Adult Is there male to male transmission?

Test for GJB1 (Cx32) CMT1X

yes

negative

Test for GJB1 (Cx32) CMT1X

Test for MFN2 CMT2A

Is there male to male transmission? no

negative

Test for MPZ CMT1B

Test for GJB1 (Cx32) CMT1X

Does the patient have pure motor upper > lower limb onset?

negative

negative

yes

negative

yes

Is there an affected parent/child? no

Test for recessive forms

negative

no

Test for NFEL (rare) CMT2E

Test for GDAP1 (rare) CMT2K

negative

yes

negative

Test for MPZ CMT1B

negative

no

Test for GARS CMT2D

Research Testing (Including dominant intermediate forms)

negative Is there an affected parent/child? no Test for recessive forms

A

yes

negative

Research testing

B

Figure 141-3.  Algorithm for the genetic diagnosis of patients with Charcot-Marie-Tooth disease and intermediate (A) or normal (B) upper extremity motor nerve conduction velocities. (With permission from Saporta AS et al. Ann Neurol 2011; 69[1]): 22-33.)

through adulthood. Motor NCVs can be normal but are usually slowed around sites of entrapment such as the fibular head, carpal tunnel, and medial epicondyle. Usually, there is a history of recurrent focal mononeuropathies that are transient, lasting from hours to days or weeks and occasionally longer. HNPP is usually caused by a deletion of PMP22 or, less commonly, by point mutations in the PMP22 gene.

CMTX: X-Linked CMT CMT1X is the main X-linked form of CMT and is caused by mutations in GJβ1 gene, which encodes the protein connexin32 (Cx32) (Ouvrier, Geevasingha, and Ryan, 2007). This is the second most common form of CMT accounting, for approximately 10% to 15% of CMT. Despite the fact that there are a huge number of mutations described in GJβ1, the phenotype in males is virtually the same in all affected males, including those with entire gene deletions, suggesting that mutations lead to a loss of function of the protein. The majority of males will start to have symptoms in childhood, but approximately 20% will have a later onset. Males are typically more severely affected and tend to have marked atrophy of the intrinsic hand muscles and all compartments of the calf muscles. Males with CMT1X often display a “split hand syndrome,” with the abductor pollicis brevis being weaker and more wasted than the first dorsal interosseus. Females with GJβ1 will usually have abnormalities on neuro-

logic examination or nerve conduction testing. Typically, males with CMTX have MNCVs between 25 and 45 m/s, whereas women have MNCVs in the normal or nearly normal range. Therefore, the presence of nearly normal to intermediate MNCVs in females and slow to intermediate MNCVs in males in families with an absence of male-to-male transmission should prompt the clinician to consider CMT1X.

CMT2: Autosomal-Dominant   Axonal Neuropathies CMT2 is suggested by neurophysiology demonstrating NCVs of greater than 38 m/s in the context of small motor and/or sensory amplitudes. Clinical and electrophysiological data should enable axonal neuropathies to be classified further into pure or predominant sensory form (HSN/HSAN), the mixed motor and sensory form (CMT2), or the pure motor form (dHMN). It is more challenging to obtain a genetic diagnosis in CMT2 because there are many genes known to cause axonal CMT (see http://www.molgen.ua.ac/cmtmutations/), with each gene accountable for only a very small proportion of cases, with the notable exception of MFN2. Because diseasecausing CMT genes account for the minority of CMT2 patients (around 35%), most CMT2 patients still await an exact genetic diagnosis. Because the number of patients with CMT2 with a genetic diagnosis is, as yet, small, it is difficult to be accurate



about exact genotype–phenotype correlations, in particular with regard to age of onset. However, with the advent of improved molecular techniques, it is likely that the number of genetic causes of CMT2 will significantly increase over the next few years. We will discuss only CMT2A, the most common subtype seen. For descriptions of other subtypes, the reader is referred to the online version of this chapter.

CMT2A CMT2A is the most common type of CMT2, accounting for approximately 20% to 25% of patients with CMT2. This is mostly severe, with onset in infancy or early childhood and with many patients requiring a wheelchair to ambulate by the age of 20. CMT2A is caused by mutations in the nuclearencoded MFN2 gene. Often these patients have unrecordable CMAP amplitudes and nerve conduction studies (NCSs) even in the upper extremities, leading to the suggestion to test for MFN2 mutations as the initial genetic test in such patients. There are a high number of polymorphisms encountered in MFN2 genetic testing, so care must be taken when ascertaining whether the patient has disease-causing mutations. Most disease-causing mutations are in the GTP-ase domain, coiledcoil domains, or in other evolutionarily conserved regions of the protein. Rarely, some patients present later in life (during childhood, adolescence, or even adulthood) with a milder phenotype.

CMT4: Autosomal-Recessive Neuropathies CMT4 includes all forms of autosomal-recessive CMT. Typically, demyelinating conduction velocities are seen, although axonal forms of CMT4 exist. CMT4 mostly presents in infancy and should be considered when multiple family members in one generation are affected or if there is a history of consanguinity. We discuss the demyelinating forms first.

CMT4A CMT4A is caused by mutations in the GDAP1 gene. This is a severe early-childhood-onset neuropathy with weakness starting in the distal lower extremities and affecting the distal upper extremities within the first decade of life. Progression to wheelchair use is not uncommon, and there may be additional clinical features, such as vocal cord paralysis or hoarseness.

CMT4B1/B2/B3 CMT4B1 neuropathy is characterized by an onset in early childhood with symmetric weakness in all four limbs, with patients typically becoming wheelchair dependent by adulthood (Parman et al., 2004). Additional clinical features of scoliosis and diaphragmatic and facial weakness may be present. CMT4B2 is a similar form with a slightly later age of onset, but symptoms typically begin by age 5 with NCVs around or below 20 m/s. CMT4B1 and CMT4B2 are caused by mutations in myotubularin-related proteins 2 (MTMR2) and 13 (MTMR13), respectively. MTMR13 is also called set-binding factor (SBF-2). CMT4B3 is caused by AR mutations in SBF1 and also has a similar phenotype, including focally misfolded myelin, a pathologic feature of all the CMT4Bs.

CMT4C CMT4C is a recessive neuropathy of slightly later onset, with childhood-adolescent onsets reported. Scoliosis is a particularly common feature and may precede other findings. Occasional additional clinical findings include movement disorders (ataxia and tremors), facial and bulbar weakness, sensorineural deafness, and respiratory insufficiency. Caused by mutations

Genetic Peripheral Neuropathies

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in the SH3 domain and tetratricopeptide repeat domain 2 (SH3TC2) gene, it is the most common of the AR-CMTs in North American and Northern European populations.

CMT4F CMT4F is caused by mutations in the periaxin gene. Characteristically, patients have demyelinating conductions with a severe early onset neuropathy. Often patients have predominant sensory findings on examination, including sensory ataxia. As with MFN, there are a large number of polymorphisms in periaxin, and care should be taken to ensure that mutations segregate with the neuropathy in a family and that the phenotype is appropriate before concluding that mutations are disease causing. CMT4: Autosomal-Recessive Axonal Neuropathies (Also Known as AR-CMT2).  A small number of genes have been found to cause axonal forms of CMT4, also known as AR-CMT2. Distal Hereditary Motor Neuropathies.  The dHMNs are very similar to CMT in that they are inherited length-dependent and slowly progressive neuropathies with onset usually starting in the first 2 decades (Rossor, Kalmar, Greensmith, and Reilly, 2012). They are defined by being exclusively motor in nature. However, many forms have minor sensory abnormalities, and there is a degree of overlap between CMT2 and dHMN in that the same mutation in the same gene can cause both phenotypes within a family, which can be defined as being either CMT or dHMN. Bulbar involvement in dHMN apart from the recurrent laryngeal nerve is rare. Clinical examination confirms distal weakness and wasting with reduced or absent reflexes. Neurophysiology testing reveals reduced motor amplitude potentials with no sensory abnormalities, and electromyography (EMG) testing may reveal a predominantly distal pattern of denervation. Table 141-3 outlines this group of disorders. For many of the dHMNs, the exact genetic mutation remains to be elucidated. The reader is referred to the online version of the chapter for further details of this group of neuropathies. Hereditary Sensory Neuropathies.  The hereditary sensory neuropathies (HSNs) group includes hereditary neuropathies primarily affecting sensory neurons and includes the subtypes of hereditary sensory and motor neuropathies and hereditary sensory and autonomic neuropathies. With HSN, the sensory loss can range from distal numbness with or without loss of proprioception to a complete inability to experience pain and subsequent risk of painless injuries and foot ulcerations. The more severe sensory neuropathies associated with loss of pain can lead to an abnormal mechanical loading in the distal weight-bearing joints; consequent to that, there is significant risk of neuropathic arthropathy and spontaneous fractures. Despite the name of this subtype of neuropathy, motor involvement is commonly observed in patients. The hereditary sensory neuropathies are classified according to their genetic cause and clinical phenotype; however, the majority of these remain genetically unresolved. Table 141-4 summarizes this group of neuropathies. The reader is referred to the online version of the chapter for further details of this group of neuropathies. It is noteworthy that because some of these subtypes (e.g., HSN IV-VII) are both newly described and rare, the range of clinical phenotypes observed in some particular subtypes is unknown (Auer-Grumbach, 2008). Neuropathies Associated With Inherited Metabolic Disease.  It is important to be aware that neuropathies can present as part of a more complex disorder as a result of an inherited metabolic deficit. These conditions are generally

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TABLE 141-3  Classification of the Distal Hereditary Motor Neuropathies (HMNs) Type

Inheritance

Gene/Locus

Specific Phenotype

HMN I

AD

HSPB1/HSPB8/GARS/DYNCIH1

Juvenile-onset (2-20 years) dHMN

HMN II

AD

HSPB1/HSPB8

Adult-onset typical dHMN/CMT2F or dHMN/CMT2L

HMN III

AR

11q13

Early onset (2-10 years), slowly progressive

HMN IV

AR

11q13

Juvenile onset (months to 20 years), diaphragmatic involvement

HMN V

AD

GARS

Juvenile onset (5-20 years), upper limb onset, slowly progressive/CMT2D

HMN V

AD

BSCL2

Upper limb onset, +/2 spasticity lower limbs/Silver syndrome

HMN VI

AR

IGHMBP2

Spinal muscle atrophy with respiratory distress (SMARD1), infantile-onset respiratory distress

HMN VIIA

AD

2q14

Adult onset, vocal cord paralysis

HMN VIIB

AD

DCTN1/TRPV4

Adult onset, vocal cord paralysis, facial weakness

HMN/ALS4

AD

SETX

Early onset, pyramidal signs

HMN-J

AR

9p21.1-p12

Juvenile onset, pyramidal features, Jerash origin

Congenital distal SMA

AD

TRPV4

Antenatal onset, arthrogryposis

AD, autosomal dominant; AR, autosomal recessive; HSPB1, heat-shock protein B1; HSPB8, heat-shock protein B8; GARS, glycyl-tRNA synthetase; BSCL2, Berardinelli-Seip congenital lipodystrophy 2 (Seipin); DYNC1H1, cytoplasmic dynein heavy-chain 1; IGHMBP2, immunoglobulin mu binding protein 2; DCTN1, dynactin1; TRPV4, transient receptor vallanoid 4; SETX, sentaxin; SMA, spinal muscular atrophy. (Adapted from Reilly MM, Shy ME. J Neurol Neurosurg Psychiatry 2009 80 (12) 1304-14. Copyright 2009. From BMJ Publishing Group Ltd)

much rarer than the more common “umbrella” group of CMT. The neurologic examination needs to be extensive, and the clinician must search extensively for additional neurologic signs, such as ataxia and pyramidal and extrapyramidal deficits. Ophthalmologic involvement and deafness should be specifically investigated. In addition, a good systemic general examination should be performed to look for cutaneous involvement and organomegaly. If a metabolic disorder is suspected, then brain magnetic resonance imaging (MRI) should be done to ascertain if there is brain involvement. The history is also important. If there are recurrent episodes of neurologic deficit, then specific diagnoses can be considered (e.g., recurrent ataxia with axonal neuropathy in pyruvate dehydrogenase deficiency and acute axonal neuropathy or pure motor neuropathy in porphyria). The main metabolic neuropathies associated with neuropathy are outlined in Table 141-5. These metabolic disorders are discussed more extensively in Chapters 41 through 43. Other genetic neuropathies, such as giant axonal neuropathy and neuroaxonal dystrophy, are discussed in the online version of this chapter. Differential Diagnosis.  Inherited neuropathies must be distinguished from acquired neuropathies (see Chapter 142). Additionally, genetic disorders of the central nervous system (CNS), such as hereditary spastic paraplegia, may mimic inherited neuropathies by causing length-dependent weakness, sensory loss, and foot deformities such as pes cavus; these patients will frequently have upper motor neuron signs, such as increased reflexes or Babinski’s signs and do not have neurophysiologic evidence of neuropathy. Neuropathies may present as part of a more multisystem metabolic disorder, such as the leukoencephalopathies, or as part of a more widespread neurologic disorder, such as Friedrich’s ataxia or the spinocerebellar ataxias. Hence, the importance of accuracy in clinical phenotyping is paramount. Treatment Strategies.  Despite the great improvement in our biologic understanding of inherited neuropathies, there is still no treatment available for any type of CMT. Physical therapy, occupational therapy, and a few orthopedic

procedures are still the cornerstone of all inherited neuropathy treatment. A detailed family history and often examination of family members will be required for prognosis and genetic counseling. A dedicated multidisciplinary rehabilitation team can significantly contribute to the management of patients with inherited neuropathy and improve functionality and quality of life. Physical therapy strategies to maintain muscle strength and tone, prevent muscle contractures, and improve balance are a common need for most patients. Orthotic aids are an important component of treating these patients, providing support and improving balance for ambulation. Occupational therapy focused on developing tools and strategies to help patients with activities of daily living will benefit patients with inherited neuropathy, especially those with hand weakness. Tendon lengthening and tendon transfers can benefit a subset of patients with muscle contractures and tendon shortening and patients with significant weakness in functionally relevant muscles, respectively; however, the optimal timing of such procedures is still controversial. Foot surgery is sometimes offered to correct inverted feet, pes cavus, and hammertoes. This surgical intervention may improve walking, alleviate pain over pressure points, and prevent plantar ulcers. However, foot surgery is generally unnecessary and does not improve weakness and sensory loss. Two new technologies recently developed hold huge potential in the search for compounds to treat inherited neuropathy: cellular reprogramming and high-throughput drug screening. Cellular reprogramming is a technique that allows the generation of specific cell types (including stem cell–like cells, neurons, and glia) by genetically modifying readily available somatic cells such as fibroblasts or lymphocytes to generate patient-specific cell lines. These patientspecific cells lines will be particularly useful when combined with high-throughput screening of drug libraries containing thousands of compounds. In these highly automated platforms, the process of identifying compounds capable of correcting certain disease-related cell phenotypes is streamlined, allowing for a faster target selection of compounds to be tested in phase I animal studies.

Cerebrotendinous xanthomatosis Tangier disease Abetalipoproteinemia LCHAD Leigh NARP Acute intermittent porphyria

3. Lipid disorders

4. Mitochondrial

5. Other

Early infancy Early infancy/childhood Usually adolescence Usually after puberty

δ = aminolevulinic acid

Late childhood/adolescence Childhood/adolescence Birth but neuropathy develops in childhood

Variable: childhood-adult Childhood/adolescence adolescence

Infantile Infantile Infantile

Age of Onset

3-Hydroxy dicarboxylic aciduria Lactate/pyruvate Lactate/pyruvate

Cholestanol Cholesterol esters

VLCFA Phytanic acid Calcium oxalate

Oligosaccharides Oligosaccharides Oligosaccharides Oligosaccharides

Dermatan/heparan sulfate Dermatan/heparan sulfate Heparan sulfate Galactosylceramide Trihexosylceramide Sulfatide

Stored Material

Can be a pure motor axonal picture

Axonal or demyelinating Slow NCVs Sensory demyelinating neuropathy

Clinical symptoms mild; slow NCVs Sensory neuropathy; slow NCVs Sensory neuropathy; sensory CVs prolonged

Axonal or demyelinating Slow NCVs Axonal or demyelinating

Axonal degeneration and segmental demyelination

Axonal loss and segmental demyelination Segmental demyelination Segmental demyelination

Axonal loss and Schwann cell vacuoles Axonal loss and Schwann cell vacuoles Axonal degeneration and segmental demyelination

Schwann cell inclusions and segmental demyelination Schwann cell inclusions, onion bulbs and segmental demyelination Axonal degeneration and segmental demyelination

Schwann cell inclusions and segmental demyelination Lamellar inclusions (perineural cells) and axonal loss Schwann cell ↑ sulfatide and segmental demyelination Entrapment neuropathy Axonal inclusion Schwann cell vacuoles and axonal inclusions Axonal spheroids

NCVs < 10 in young onset Small-fiber function abnormal NCVs < 10

Slowing at entrapment sites Slowing at entrapment sites II = Slowing at entrapment sites Marked axonopathy

Entrapment neuropathy Entrapment neuropathy Entrapment neuropathy

Neuropathic Features

Slowing at entrapment sites Slowing at entrapment sites Slowing at entrapment sites

Neurophysiology

LCHAD, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; NARP = neuropathy, ataxia and retinitis pigmentosa; NCVs = nerve conduction velocities; VLCFA = very-long-chain fatty acids.

Adrenomyeloneuropathy Refsum disease Hyperoxaluria

Fucosidosis α and β mannosidosis Sialidosis I and II Schindler disease

• Glycoproteinoses

2. Peroxisomal

Krabbe disease Fabry disease Metachromatic leukodystrophy

Hurler Hunter Sanfilippo A-D

1. Lysosomal • Mucopolysaccharidoses

• Sphingolipidoses

Disease

Category

TABLE 141-5  Inherited Metabolic Disorders Associated With Neuropathy

Genetic Peripheral Neuropathies

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Vital to clinical trials in inherited neuropathy is the establishment of solid outcome measures. This can be challenging with neuropathies that progress slowly over many years. To this end, a validated scoring system based on symptoms, signs, and neurophysiological data has been developed for adults that has excellent inter- and intraobserver correlations and can detect changes over 1 year. A more sensitive pediatric scoring system exists for those patients between the ages of 3 and 21, which takes into account growth-related changes and should prove useful in future clinical trials. Sequential yearly MRI of limb muscles looking at progressive replacement of muscle with fatty tissue may also prove to be a valuable outcome measurement and is currently under investigation in a cohort of CMT1A patients.

CONCLUSION We have entered an exciting period in the study of inherited neuropathy. Investigating CMT has led to the description of several key genes and proteins together with the functional relevance of many others, leading to a better understanding of normal peripheral nerve function and the development of treatment strategies in some of the more common demyelinating inherited neuropathies. Significant challenges remain to be overcome, however, to develop and test treatments to modify disease progression in this heterogenous group of genetic neuropathies. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Auer-Grumbach, M., 2008. Hereditary sensory neuropathy type I. Orphanet J. Rare Dis. 3 (1). Harding, A.E., Thomas, P.K., 1980a. Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J. Med. Genet. 17 (5), 329–336.

Harding, A.E., Thomas, P.K., 1980b. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103, 259. Murphy, S.M., Herrmann, D.N., McDermott, M.P., et al. 2011. Reliability of the CMT neuropathy score (second version) in CharcotMarie-Tooth disease. J. Peripher. Nerv. Syst. 16 (3), 191–198. Murphy, S.M., Laura, M., Fawcett, K., et al., 2012. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J. Neurol. Neurosurg. Psychiatry 83, 706. Ouvrier, R., Geevasingha, N., Ryan, M.M., 2007. Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood. Muscle Nerve 36 (2), 131–143. Parman, Y., Battaloglu, E., Baris, I., et al., 2004. Clinicopathological and genetic study of early-onset demyelinating neuropathy. Brain 127, 2540. Reilly, M.M., Shy, M.E., 2009. Diagnosis and new treatments in genetic neuropathies. J. Neurol. Neurosurg. Psychiatry 80 (12), 1304– 1314. Rossor, A.M., Kalmar, B., Greensmith, L., et al., 2012. The distal hereditary motor neuropathies. J. Neurol. Neurosurg. Psychiatry 83, 6. Saporta, A.S., Sottile, S.L., Miller, L.J., et al., 2011. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann. Neurol. 69, 22.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 141-1 The molecular processes and respective genes involved in CMT. Table 141-1 A basic classification of CMT and other inherited neuropathies Table 141-2 Classification of Charcot-Marie-Tooth Disease Subtypes Table 141-4 Classification of the Distal Hereditary Sensory Neuropathies (HSNs)

142  Acquired Peripheral Neuropathies Stephen A. Smith

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Acquired peripheral neuropathies are caused by a number of infectious, toxic, or metabolic conditions. They may be acute or chronic and classified by the type of peripheral nerve involved—primarily motor, sensory, or autonomic. Pathologically, neuropathies are demyelinating or axonal, depending on whether the main disruption involves the axon or the myelin sheath supported by the Schwann cell. This chapter discusses acquired toxic and metabolic neuropathies occurring in children.

ANATOMY The peripheral nervous system consists of cranial nerves III through XII, the spinal roots, the nerve plexuses, the peripheral nerves, and the autonomic ganglia. Neuronal cell bodies subserving the nerves in the peripheral nervous system reside in the brainstem; anterior horn cells of the spinal cord; intermediolateral cell column, where the autonomic system originates; and the dorsal root ganglia for afferent sensory function. Peripheral nerves innervate all skeletal muscles via large myelinated nerve fibers. Sensory input from skin, joints, and muscles is transmitted via a combination of unmyelinated and myelinated nerve fibers from the periphery to the central nervous system (CNS). Evaluation of peripheral nerve diseases includes obtaining a clear history of the distribution and rate of progression of the condition; conducting an appropriate examination; obtaining an electromyogram with nerve conduction velocities, amplitudes, and latencies plus indicated muscle needle electrode study; and, in some instances, performing a sural nerve biopsy. A search for toxins, such as heavy metals, or doing diagnostic tests for metabolic conditions may be indicated. Acquired peripheral neuropathies are not familial or inherited.

FACIAL NERVE PARALYSIS (BELL’S PALSY) Acute dysfunction of cranial nerve VII, caused by lesions of the facial nerve nucleus in the pons or axial or extraaxial facial nerve, is called Bell’s palsy. The result is partial or complete paralysis of the upper and lower facial muscles. Bell’s palsy most often results from edema and inflammation of the nerve as it traverses the facial canal within the temporal bone. Lesions involving the facial nerve nucleus or nerve distal to the nucleus result in paralysis of upper (forehead) and lower facial muscles.

Clinical Features The incidence of Bell’s palsy is 2.7 per 100,000 below the age of 10 years, and 10.1 per 100,000 during the second decade of life. Female and male incidence is equal. Ear pain near the mastoid process is the first manifestation of impending facial nerve involvement half of the time. Unilateral inability to close the eyelid and maintain normal facial movement is the initial indication of motor involvement. Facial weakness develops

rapidly over several hours to 3 days, resulting in paresis to complete paralysis. Bell’s palsy commonly follows an upper respiratory tract infection, indicating possible postinfectious demyelination. Drinking and eating are impaired because of the inability to close the mouth on the involved side. The differential diagnosis of facial paralysis includes infections, both acute and chronic infections of the inner ear (Özkale et al., 2015), herpes simplex infection, herpes zoster (Ramsay Hunt syndrome), Mycoplasma pneumoniae infection, Epstein-Barr virus infection, and Lyme disease (Borrelia spp. infection), tumor, acute myeloid leukemia, chemotherapy toxicity, trauma, hypertension, and hypertension secondary to Guillain-Barré syndrome. Bilateral, congenital facial paralysis, usually in conjunction with ophthalmoplegia involving cranial nerve VI, presents in the newborn as Möbius’s syndrome. The condition is the result of aplasia or hypoplasia of cranial nerves and nuclei VI and VII. Simple asymmetry of facial expression when infants and children are crying is common. The majority of children with asymmetric crying facies are normal.

Laboratory Findings Uncomplicated facial palsy that resolves relatively quickly does not need detailed evaluation. Palsy that persists or seems atypical requires study. Magnetic resonance imaging (MRI) often reveals gadolinium enhancement of the facial nerve in typical cases of Bell’s palsy. MRI can be used in children to find rare tumors invading or compressing the facial nerve.

Treatment and Prognosis The prognosis for recovery in children is good. Most children do not need drug therapy. A number of drugs have been used, particularly steroids of limited, if any, benefit. Surgical decompression has been recommended in some patients when progressive paralysis and nerve degeneration occur, but benefit is difficult to prove (Zandian et al., 2014). Prednisone is the most widely used drug; it is given in high dosage for 1 week, followed by slow withdrawal of the drug in the second week. The degree to which steroid therapy can alter the natural history of Bell’s palsy is unknown, although it appears to be more helpful in completely paralyzed than paretic individuals. Most children recover completely without treatment. Recovery usually begins within 2 to 4 weeks, reaching its maximum within 6 to 12 months and most within 3 months. In metaanalyses comparing steroids to antiviral treatment, usually acyclovir, there is no added advantage in adding antiviral treatment to steroid treatment.

BRACHIAL PLEXUS Nerve roots from the fifth cervical through the first thoracic nerves form the three primary trunks of the brachial plexus. Once formed, they divide promptly into anterior and posterior divisions. The posterior divisions join to form the posterior

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cord, which gives rise to the upper and lower subscapular, thoracodorsal, axillary, and radial nerves. The anterior divisions of the fifth, sixth, and seventh nerves form the lateral cord, and the anterior divisions of the eighth cervical and first thoracic nerves form the medial cord. The lateral cord subsequently gives rise to the musculocutaneous nerve and a branch to the coracobrachialis. The medial cord gives rise to the ulnar, medial antebrachial cutaneous, and medial brachial cutaneous nerves. Additional branches from the lateral and medial cords unite to form the median nerve.

sural nerve biopsy and autopsy evaluation, suggests that the neuropathy is primarily axonal. The neuropathy is predominantly motor, with associated abdominal pain, dysautonomia, and CNS involvement. It has been made worse with exposure to antiepilepsy medications, phenytoin and carbamazepine, but not clonazepam. Acute, severe, colicky abdominal pain is a typical manifestation of an acute episode, accompanied by CNS and peripheral nervous system impairment. Peripherally, motor weakness is most striking, but sensory impairment may also occur.

METABOLIC NEUROPATHIES Diabetes Mellitus

Vitamin Deficiency

It has been known for a long time that up to 10% of children with insulin-dependent diabetes mellitus have symptoms and signs caused by peripheral neuropathy associated with diabetes. These bilaterally symmetric changes, especially in the lower extremities, include mild distal weakness, loss of touch and pain sensation, and decreased ankle tendon reflexes. Despite good management of diabetes, impaired nerve function occurs. Subclinical diabetic neuropathy is now estimated to occur in half of all children with type 1 diabetes after 5 years of known disease. Reduced motor nerve excitability determined by compound muscle action potential (CMAP) measurements is reduced early in type 1 diabetes mellitus, probably before irreversible axonal damage occurs. It is clear that careful clinical and electrophysiologic follow-up is required to monitor altered peripheral and autonomic nerve function in childhood-onset diabetes mellitus (Höliner et al., 2013). Blood sugar control, as measured by hemoglobin A1c, and duration of diabetes are significant in the causation of diabetic peripheral neuropathy. The importance of strict metabolic control is helpful in slowing the development and progression of diabetic neuropathy. Peripheral neuropathy is common in young, insulin-dependent diabetics.

Uremic Neuropathy Uremic neuropathy is rarely diagnosed in children. When recognized, it is characterized by burning sensations in the feet and a symmetric motor sensory neuropathy with progressive muscle weakness. Motor nerve and sensory nerve conduction velocities are decreased early in the course of the disease, often before clinical symptoms appear. Electrophysiologic findings in an adolescent showed a primary axonal sensorimotor polyneuropathy. Sural nerve biopsy showed focal loss of myelinated axons along with axonal degeneration. The facial nerve is a sensitive indicator of uremic neuropathy.

Acute Intermittent Porphyria This rare inborn error of metabolism, inherited on an autosomal-dominant basis, is caused by mutations in the hydroxymethylbilane synthase (HMBS) gene on chromosome 11q23.3. Acute intermittent porphyria (AIP) is diagnosed on the basis of characteristic clinical symptoms, elevated levels of urinary porphyrin precursors aminolevulinic acid (ALA) and porphobilinogen (PBG), and a decreased erythrocytic HMBS activity, although an identifiable HMBS mutation provides the ultimate proof for AIP. Gene carriers are at risk of developing potentially fatal neurogenic attacks if exposed to precipitating factors, including certain medications like tricyclic antidepressants, barbiturates, halothane, valproic acid, sulfonamides, estrogens, and alcohol. Axonal damage, observed on both

Classic thiamine deficiency in children causes peripheral neuropathy, encephalopathy, and high-output cardiac failure. Infantile beriberi disease has been described in infants born to mothers with thiamine deficiency (Renthal et al., 2014). Thiamine deficiency can develop secondary to anorexia nervosa in adolescents producing a peripheral neuropathy and Wernicke encephalopathy. Vitamin E (alpha-tocopherol) deficiency may be associated with peripheral neuropathy and ataxia. It may also occur in children with cystic fibrosis, chronic cholestasis, abetalipoproteinemia, short bowel syndrome, and intestinal malabsorption states.

Congenital Pernicious Anemia Two forms of pernicious anemia in children are associated with peripheral neuropathy. One occurs as a congenital or early onset disease in children. Congenital pernicious anemia occurs before age 5 years as a result of a vitamin B12 deficiency caused by isolated absence of gastric intrinsic factor that may produce a severe and irreversible neuropathy (Dobrozsi et al., 2014). A later-onset form of pernicious anemia resembles that seen in adults. This is histamine-fast achlorhydria associated with gastric mucosal atrophy and the presence of antibodies to parietal cells and intrinsic factor in the serum. These children may experience a variety of endocrinologic disorders. Pathologic changes develop in spinal cord and, less commonly, in peripheral nerve and brain. Infants who are breastfed by strictly vegetarian mothers or who have undiagnosed pernicious anemia are at risk for developing a megaloblastic anemia because of a deficiency of vitamin B12.

Abetalipoproteinemia Abetalipoproteinemia, known as Bassen-Kornzweig syndrome, is a rare condition characterized by progressive ataxic neuropathy, retinitis pigmentosa, steatorrhea, hypolipidemia, deficiency of fat-soluble vitamins, failure to thrive, and acanthocytosis. The disease results from mutations in the gene encoding microsomal triglyceride transfer protein (MTTP) located on chromosome 4q24. Affected individuals are unable to make beta-lipoproteins to carry fats, cholesterol, and fatsoluble vitamins A, D, E, and K in the blood, and therefore fat absorption is impaired. Sufficient levels of fats, cholesterol, and vitamins are necessary for normal growth and development. Nerve cells and the retina are particularly vulnerable.

Pathology Degeneration of posterior columns, spinal cerebellar pathways, and cerebellum, caused by vitamin E deficiency, is the major pathologic change. Loss of anterior horn cells is found in the spinal cord. Posterior column degeneration leads to abnormal somatosensory-evoked potentials. Sural nerve



biopsy shows decreased numbers of large myelinated fibers and clusters of regenerating fibers. The posterior fundus of the eye shows a loss of photoreceptors, loss or attenuation of pigment epithelium, and preservation of submacular pigment epithelium, with an excessive accumulation of lipofuscin. Macrophage-like pigmented cells invade the retina.

Clinical Characteristics The most significant neurologic finding is a progressive ataxia that may be present as early as 2 years of age but certainly by age 6. Generalized weakness, ptosis, and extraocular muscle weakness develop. The lower cranial nerves may be involved, with facial and tongue weakness plus twitching movements. A progressive peripheral sensory neuropathy causing hypesthesia, hypalgesia, and proprioceptive loss is associated with absent tendon reflexes. Generalized muscle weakness and wasting may be severe. Intestinal malabsorption produces bulky, foul stools and leads to a delay in normal growth.

Alpha-Lipoprotein Deficiency (Tangier Disease) Tangier disease is an uncommon autosomal recessive disorder of lipoprotein metabolism, notable for the absence of normal high-density lipoprotein (HDL) from plasma and the accumulation of cholesterol esters in multiple organs. Extremely low plasma cholesterol levels are present. Physical examination shows patches of yellow-orange lymphoid tissue in the tonsils and pharynx, and hepatosplenomegaly. Yellow patches are present on the surface of the liver, and liver biopsy specimens contain cholesterol esters. Fiberscopic rectal examination shows orange-brown spots present throughout the rectum. Foam cells are present in lymphoid tissues. . Onset is between age 2 and 67 years. Sural nerve biopsy shows a reduction of smaller myelinated and unmyelinated fibers, and abnormalities in the paranodal regions. There is lipid deposition, redundant myelin foldings, myelin splitting and vesiculation, and small tomacula. Abnormal lipid storage is found in Schwann cells of unmyelinated fibers. Conduction block is present on electrophysiologic nerve study.

Clinical Characteristics Recurrent neuropathy occurs in children with fluctuating asymmetric sensory involvement, mostly in the lower extremities, sometimes accompanied by progressive development of weakness of both distal and proximal muscles. Complaints of numbness and tingling in the distal extremities are early symptoms, followed by signs of the neuropathy and weakness. A dissociated loss of pain and temperature sensation may occur.

Krabbe’s Disease (Globoid Cell Leukodystrophy) Galactosylceramide lipidosis, known as Krabbe’s disease or globoid cell leukodystrophy, is an autosomal-recessive neurodegenerative disorder that presents most often in infants of 3 to 5 months of age. The clinical profile is a highly irritable infant with spasticity, optic atrophy, intellectual delay, and polyneuropathy, which may be the initial presentation. Children have gross motor delay, absent tendon reflexes, elevated CSF protein levels, and delayed motor nerve conduction velocities before neurodegenerative disease is evident.

Metachromatic Leukodystrophy Metachromatic leukodystrophy is a recessively inherited disease affecting children and adults caused by mutations in

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the ARSA or PSAP genes resulting in a failure of the catabolism of sulfatide, the sulfate ester of galactose cerebroside. Infants may present with cranial neuropathy and multiple cranial nerve enhancement on MRI. Clinically, in the infantile form of metachromatic leukodystrophy, the infant acquires normal milestones until 1 to 2 years of age and then begins to show signs of the disease. An unsteady gait is an early sign, accompanied by loss of language, intellectual deterioration, and, later, spasticity. Spinal fluid protein is elevated, and nerve conduction velocities are slowed. The juvenile form of the disease occurs after several years of age, again with gait disturbance followed by intellectual deterioration.

Refsum’s Disease (Heredopathia Atactica Polyneuritiformis) and Peroxisome   Biogenesis Disorders Refsum’s disease is a recessively inherited condition caused by a deficiency of phytanoyl-coenzyme A hydroxylase allowing the accumulation of phytanic acid in body tissues. Retinitis pigmentosa and anosmia are early signs of the disease that is carried on chromosome 10 as a result of PHYH gene mutations. Refsum’s disease is one of the peroxisomal disorders, Zellweger’s syndrome and neonatal adrenoleukodystrophy being the other two. They are characterized by absence of catalase-positive peroxisomes and general impairment of peroxisomal functions. Presentations include anorexia, ataxia, ichthyosis, and sensorineural hearing loss with malabsorption and steatorrhea presenting early on. Clinical characteristics can be divided into three groups: congenital abnormalities, such as skeletal deformities; retinitis pigmentosa, which develops slowly; and lesions, including neuropathy, rash, and cardiac arrhythmias, which can deteriorate or improve according to plasma phytanic acid level. Phytanic acid, a branched chain fatty acid, is present in a wide range of foodstuffs, including dairy produce, meat, and fish. There is toxic accumulation of phytanic acid in blood, fat, and neurons. Normally, phytanic acid levels are virtually undetectable in plasma. However, patients with Refsum’s disease have extremely high levels with phytanic acid accounting for 5% to 30% of their total fatty acids.

TOXIC NEUROPATHIES Diphtheria Diphtheria is an uncommon disease in the Western Hemisphere because most individuals are immunized with diphtheria-pertussis-tetanus vaccine. The disease occurs in unimmunized children and in adults who have lost immunity. An exotoxin produced by Corynebacterium diphtheriae infection in the throat produces cardiomyopathy and neuropathy. A systemic radiculoneuropathy may develop, with onset 1 to 16 weeks after infection and marked by sensory loss.

Neuropathy of Serum Sickness Serum sickness is a systemic illness resulting from hypersensitivity to an injected foreign protein, such as tetanus or diphtheria antisera, producing encephalomyelitis, neuropathy, or brachial plexus neuropathies. Fever, joint swelling, abdominal pain, diarrhea, and cutaneous eruptions develop within days of receiving foreign protein. Deposition of antigen-antibody complexes is associated with disease.

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Antibiotic-Induced Neuropathy A number of antibiotic, antifungal, and antituberculous drugs have been known to cause peripheral neuropathy in a small percentage of cases. For example, chloramphenicol can cause mild, primarily sensory, peripheral neuropathy after long-term use at relatively high doses. Nitrofurantoin may produce a polyneuropathy of sudden onset on rare occasion. Isoniazid causes an axonal neuropathy responsive to pyridoxine therapy in 1% to 2% of patients. The primarily sensory neuropathy begins with paresthesias. There have been a number of reports of peripheral neuropathy, mainly in adults, associated with the use of fluoroquinolones, ciprofloxacin and levofloxacin , ofloxacin, lomefloxacin, and trovafloxacin.

Pyridoxine-Induced Polyneuropathy Pyridoxine is an essential cofactor in the metabolism of proteins, carbohydrates, fatty acids, and brain amines. Pyridoxine taken in large doses can cause a sensory neuropathy, with paresthesias, diffuse sensory loss, sensory ataxia, and autonomic dysfunction. Prescribing 50 mg/day or greater amounts for prolonged periods is discouraged. Pyridoxine deficiency causes a sensory neuropathy, unless severe when motor nerve fibers may also be involved along with CNS dysfunction. Treatment is straight forward with increased dietary pyridoxine intake from foods high in pyridoxine such as vegetables, potatoes, eggs, and dairy products.

Nitrous Oxide–Induced Polyneuropathy Severe myeloneuropathy and macrocytic anemia associated with a low vitamin B12 level are reported after prolonged exposure to nitrous oxide. B12 supplementation alone does not result in improvement, but the addition of methionine does arrest the progression of neuropathy. Chronic nitrous oxide exposure inhibits methionine synthetase activity, which remains suppressed after nitrous oxide exposure has ended, underscoring the need for treatment with methionine. Continuous exposure to nitrous oxide for longer than 3 hours causes neuropathy, especially in B12-deficient individuals (Richardson, 2010).

Chemotherapeutic Agent–Induced Neuropathy Peripheral neuropathy may develop after the use of chemotherapeutic agents to treat neoplasms. Painful sensorimotor peripheral neuropathy may develop after high-dose cytosine arabinoside therapy, and is manifested pathologically by axonal degeneration and scattered destruction of myelin sheaths. The neuropathy is marked by dysesthesias, muscle aching, and progressive weakness. Cytosine arabinoside neuropathic pain may respond to carbamazepine. Vincristine is often used in children to treat acute lymphoblastic leukemia and may cause acute axonal sensorimotor neuropathy. Less commonly, it may cause autonomic and cranial nerve neuropathy.

Vaccine-Induced Polyneuropathy The diphtheria-pertussis-tetanus vaccine may rarely produce segmental demyelination and axonal neuropathy from the tetanus toxoid component. Although very rare, demyelinating symmetric neuropathy, when it does occur, responds to immunomodulatory therapy. Rare transient postvaccination polyneuropathy has been reported with complete recovery. CDC

(http://www.cdc.gov/flu) recommendations for people who should receive influenza vaccinations are as follows: Children aged 6 months and older. Pregnant women People 50 years of age and older People of any age with certain chronic medical conditions such as chronic lung, heart, liver, or kidney diseases; blood disorders; and diabetes mellitus People who live in nursing homes and other long-term care facilities People who live with or care for those at high risk for complications from influenza Healthcare workers Household contacts of persons at high risk for complications from influenza Household contacts and out-of-home caregivers of children less than 6 months of age. Hepatitis B vaccination has been associated with neuropathy in case reports from adults. Acute sensory neuropathy has been reported in a 13-yearold after bacille Calmette-Guérin (BCG) vaccination.

Heavy Metal Neuropathy Excessive exposure to various forms of lead, both organic and inorganic, produces an axonal neuropathy. It is rare in children but presents typically with foot drop but also with weakness of wrist and finger extensors. Arsenic is a metalloid element, and high-dose exposure can cause severe systemic toxicity and death. The NALP2 polymorphism is associated with increased risk of tissue and chromosomal damage from arsenic exposure. Arsenic is an essential ultratrace element in animals. Rare instances of arsenic poisoning, often intentional, have been reported, producing an axonal, sensory-predominant neuropathy. One source of toxic methylmercury (MeHg) is from the consumption of marine fish and mammals. There is concern for potential neurodevelopmental effects from early life exposure to low levels of MeHg. Continuing exposure may include development of peripheral neuropathy. The European project DEMOCOPHES analyzed mercury (Hg) in hair in 1799 mother-child pairs from 17 European countries comparing results to marine fish and seafood consumption. Eating marine fish and seafood once per week had mercury levels well below health-based limit values established by USA-EPA and WHO. Concern is raised for higher exposures given the presence of mercury in the environment for many years to come and the bioaccumulation in aquatic food chains. The study recommends continuing monitoring of methylmercury exposure (Bora et al., 2014).

VASCULITIC NEUROPATHIES Cryoglobulinemia may present with a sensory neuropathy and painful dysesthesia because of small-fiber axonal involvement usually in adults, and often in the context of hepatitis C. Rare instances of cryoglobulinemia are reported in children. One child had lower-extremity and one-hand vasculitis, non– hepatitis C, M-spike disease with presumed nerve involvement responsive to steroids. Fever is more common in children with cryoglobulinemia than in adults. Demyelinating neuropathy after vaccination is a rare event with distally predominant sensory symptoms with no or mild distal weakness. Immunomodulatory therapy is effective for treatment. In a study in infants to investigate immune responses to influenza vaccine after two doses of trivalent inactivated influenza vaccine 4 weeks apart, no findings for neuropathy were reported (Hwang et al., 2014).



Organophosphorus pesticides are used as insecticides in agriculture and as eradication agents for termites around homes. Organophosphate intoxication causes cholinergic symptoms early and subsequently a neuropathy with axonal degeneration producing muscle cramping and calf pain along with tingling and burning sensations in the feet. Distal muscle weakness may develop. Neuropsychological assessment of healthy school-aged children exposed to organophosphate pesticides has demonstrated cognitive impairment. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bora, B., Pino, A., Alimonti, A., et al., 2014. Toxic metals contained in cosmetics: a status report. Regul. Toxicol. Pharmacol. 68, 447. Dobrozsi, S., Flood, V.H., Panepinto, J., et al., 2014. Vitamin B12 deficiency: the great masquerader. Pediatr. Blood Cancer 61, 753. Höliner, I., Haslinger, V., Lütschg, J., et al., 2013. Validity of the neurological examination in diagnosing diabetic peripheral neuropathy. Pediatr. Neurol. 49, 171. Hwang, K.P., Hsu, Y.L., Hsieh, T.H., et al., 2014. Immunogenicity and safety of a trivalent inactivated 2010–2011 influenza vaccine in Taiwan infants aged 6–12 months. Vaccine 32, 2469.

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Özkale, Y., Erol, I., Saygi, S., et al., 2015. Overview of pediatric peripheral facial nerve paralysis: analysis of 40 patients. J. Child Neurol. 30, 193. Renthal, W., Marin-Valencia, I., Evans, P.A., 2014. Thiamine deficiency secondary to anorexia nervosa: an uncommon cause of peripheral neuropathy and Wernicke encephalopathy in adolescence. Pediatr. Neurol. 51, 100. Richardson, P.G., 2010. Peripheral neuropathy following nitrous oxide abuse. Emerg. Med. Australas. 22, 88. Zandian, A., Osiro, S., Hudson, R., et al., 2014. The neurologist’s dilemma: a comprehensive clinical review of Bell’s palsy, with emphasis on current management trends. Med. Sci. Monit. 20, 83.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 142-1 Normal sural nerve in an infant. Fig. 142-2 Schematic pathway of the facial nerve (cranial nerve VII). Fig. 142-3 Relationship of the brachial plexus to peripheral nerves of the shoulder and arm. Box 142-1 Facial weakness in childhood Table 142-1 Clinical localization of facial nerve lesions

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143  Inflammatory Neuropathies

Malcolm Rabie, Stephen Ashwal, and Yoram Nevo

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Inflammatory neuropathies are important causes of peripheral nerve disease in childhood because of their relative frequency and response to treatment. Their main etiologies in childhood are acute and chronic immune-mediated polyradiculoneuropathies. Other etiologies such as collagen vascular diseases, rheumatoid arthritis, systemic lupus erythematosus, or mixed connective tissue disease are rare in children. Acute and chronic immune-mediated polyradiculoneuropathies are acquired autoimmune-mediated disorders in which peripheral nerves become inflamed leading to varying degrees of weakness. They are not exclusively demyelinating; axonal forms responding favorably to immunotherapy also occur. Current data suggest that loss of immunologic tolerance to myelin or axonal antigens trigger autoreactive T-cells and circulating autoantibodies (cellular and humoral factors) either independently or in concert with each other, which then play a fundamental role in the cause of these immunemediated neuropathies (Dalakas, 2015). Nodal, paranodal, and juxtaparanodal regions of the node of Ranvier may present antigenic targets in some of these disorders, causing nerve conduction failure and rapid recovery (Dalakas, 2015). Acute onset immune-mediated polyradiculoneuropathy or Guillain-Barré syndrome (GBS) is the most common acquired immune-mediated peripheral neuropathy, and the most frequent cause of acute flaccid paralysis worldwide, constituting one of the serious neurologic emergencies (Yuki and Hartung, 2012). However, GBS is an uncommon disorder and is less frequent among children than in adults. GBS typically has been linked to inflammatory destruction of myelin sheaths in peripheral nerves and roots, termed acute inflammatory demyelinating polyradiculoneuropathy (AIDP). The categorization of GBS has evolved. For many years GBS was considered synonymous with AIDP, the demyelinating form most commonly encountered in the Western world, until axonal forms were defined in 1986 and in the 1990s in East Asia (northern China and Japan). In 2001 this led to the division of GBS based on whether motor or sensory nerve fibers are involved and whether myelin sheaths or axons are predominantly affected. Four main subtypes are described: (1) acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (motor and sensory nerve fibers involved); (2) acute motor axonal neuropathy (AMAN); (3) acute motor and sensory axonal neuropathy (AMSAN); and (4) Miller Fisher syndrome (MFS/ FS). Additional GBS variants with atypical features are rare (Table 143-3) (Yuki and Hartung, 2012). Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), although rare in childhood, is the second most common cause of chronic sensorimotor peripheral neuropathy in children. This slow onset immune-mediated disorder presents with either a monophasic subacute course that later relapses, or a slowly progressive course. CIDP patients have proximal and distal symmetric weakness, paresthesias, and hyporeflexia or areflexia. In both GBS and CIDP, high CSF protein with a normal cell count is present. Evidence-based data regarding the efficacy of GBS and CIDP immunotherapy in children are lacking, relying on retrospective data, open-label studies on small numbers of

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children, and data derived primarily from adult trials. Immunotherapy (intravenous human immunoglobulin [IVIg] or plasma exchange [PE]) shorten GBS recovery time with most children recovering completely. Childhood CIDP usually responds to corticosteroids, IVIg, and PE. CIDP children who become resistant to corticosteroids or IVIg, or who become steroid dependent, present a therapeutic challenge. Childhood CIDP prognosis is mostly favorable.

GUILLAIN-BARRÉ SYNDROME GBS is a descriptive clinical entity, presenting as a monophasic, nonfebrile, postinfectious illness characterized by acute or subacute progression lasting up to 28 days, a variable plateau phase, and then recovery over weeks to months or in some cases over a more prolonged period. Weakness beginning distally in the legs; ascending rapidly, progressively, and symmetrically to the arms, face, and muscles of respiration, with or without sensory disturbances, hyporeflexia, or areflexia; and a high cerebrospinal fluid (CSF) protein with normal cell count (albuminocytologic dissociation) are the hallmarks for its diagnosis in children and adults. GBS usually remits spontaneously. The spectrum of GBS presents either typically (classic GBS) or atypically (Figure 143-1), with prominent differences in geographic distribution (Asbury, 2000).

Epidemiology GBS incidence worldwide is reported as 0.16 to 4/100,000/ year. A systematic literature review estimated overall GBS incidence in children aged 0 to 15 years as 0.34 to 1.34/100,000/ year from Latin America, Middle East, USA, Finland and Taiwan. It affects all ages, genders, and races, and is rare in children younger than age 2 years or in adults greater than age 80 years. Men are about 1.5 times more likely to be affected than woman (Hughes and Cornblath, 2005). AIDP is the most common GBS subtype in North America, Europe, and Australia affecting all ages (Asbury, 2000). In northern China, Japan, Asia, Latin America, and the developing world, axonal forms occur more frequently (Hughes and Cornblath, 2005; Yuki and Hartung, 2012). Atypical cases such as polyneuritis cranialis and MFS are much less common.

Antecedent Events Initial GBS symptoms usually present 1 to 6 weeks after antecedent respiratory or gastrointestinal infections, or vaccinations in about 26% to 85% of children and approximately 60% of adults, suggesting that a range of bacteria and viruses trigger the syndrome (Box 143-1) (Hughes and Cornblath, 2005; Korinthenberg, 2013). Campylobacter jejuni infection may be followed by any subtype of GBS but is more frequent with axonal forms (Hughes and Cornblath, 2005). GBS declined with USA influenza vaccination campaigns between 1990 and 2003; however, a very small increased risk of GBS (1 per million above background incidence) occurred with influenza vaccinations between 1992 and 1994. Rabies



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TABLE 143-3  Guillain-Barré Syndrome Subtypes and Rare Variants Described in Childhood Relative Frequency

Associated IgG-Antiganglioside Antibodies

SUBTYPES Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) Acute motor axonal neuropathy (AMAN) Acute motor and sensory axonal neuropathy (AMSAN) Miller Fisher syndrome (MFS/FS)

Common (more in Western world) Common (more in developing countries) Rare Uncommon

None/GM1 (~10%) GM1, GD1a GM1, GM1b, GD1a GQ1b, GT1a

VARIANTS Bickerstaff brainstem encephalitis (BBE) Polyneuritis cranialis (PC) Pharyngeal-cervical-brachial variant (PCB) Acute sensory neuropathy Acute pandysautonomia Acute opthalmoparesis Paraparesis

Rare Rare Rare Very rare Very rare Very rare Very rare

GQ1b, GT1a GQ1b, GT1a GT1a > GQ1b ≫ GD1a GQ1b, GT1a

vaccine has a GBS risk of about 1 in 1000 individuals. The risk of GBS or CIDP relapse after immunization is low. However, precaution is required when there is a history of GBS or CIDP, and specifically if they occurred within 6 weeks after a vaccination. For specific vaccination guidelines after immune-mediated neuropathies, the Red Book published by the American Academy of Pediatrics should be consulted. Rarely, GBS can be the presenting manifestation or develop during the course of lymphoma or systemic lupus erythematosus.

GQ1b, GT1a

BOX 143-2  Classic Guillain-Barré Syndrome Presentation in Children • Symmetric ascending paralysis • Diminished or absent reflexes • Often severe pain—may lead to a delay in diagnosis

Clinical Features of AIDP (GBS)

Acute Motor Axonal Neuropathy

AIDP appears similar in children and adults, except children recover faster with fewer residua. The main presenting feature is initial rapid bilateral relatively symmetric ascending weakness beginning in the legs and progressing to the arms, face, and respiratory muscles within ≤4 weeks before a plateau is reached. Eighty percent of children reach maximum severity with inability to walk unaided within 2 weeks after onset, and 90% to 98% of children and adults reach maximum severity by 4 weeks (Hughes and Cornblath, 2005). Early generalized hyporeflexia or areflexia is typical. Cranial nerve involvement occurs early in about 30% of children, and later on in nearly 50%. The facial nerve is the most common cranial nerve affected, often bilaterally. After 7 to 10 days about 60% of children and adults are unable to walk, and respiratory compromise occurs in about 17% to 30% of adults (Hughes and Cornblath, 2005) and about 15% (4.4% to 24%) of children. Respiratory insufficiency and need for artificial ventilation correlate with severe upper limb involvement, degree of disability at nadir (disease peak), and dysautonomias in childhood GBS (Korinthenberg, 2013). Pain is a very prominent early complaint in about 50% to 79% of children and adults at the peak of the disease, and precedes the weakness in some children. In preschool children, weakness and pain often present with gait disturbances or refusal to walk (Asbury, 2000). Transient dysautonomias, including arrhythmias and labile blood pressure, may be life-threatening and are reported in about 20% of adults and 3.7% to 77% of children with GBS. Transient bladder dysfunction occurs in 15% to 19.5% of childhood GBS. Children with a more severe acute phase may need catheterization and bladder decompression. Impaired swallowing, gastroesophageal dysmotility, pseudoobstruction, hypotension, urinary incontinence/retention, bowel incontinence/constipation, hyperhidrosis, and vasomotor instability may occur in GBS. Rarely cardiac arrest secondary to autonomic dysfunction is described in children. Box 143-2 outlines the classic GBS clinical presentation in children.

Initially AMAN described a summer epidemic of acute ascending paralysis in children in northern China, strongly associated with prior Campylobacter jejuni infections (Asbury, 2000). Compared with AIDP, AMAN patients less frequently have cranial nerve involvement and generally have pure motor neuropathy involving only motor axons with sparing of the sensory axons. Around 10% of patients with AMAN have normal or exaggerated tendon reflexes throughout the disease, which could cause a diagnostic delay (Yuki and Hartung, 2012). AMAN patients have little or no dysautonomias, more rapid progression, and an earlier disease peak than AIDP (Hughes and Cornblath, 2005; Yuki and Hartung, 2012). Differences between AIDP and AMAN in childhood are outlined in Table 143-4.

Other Subtypes and Variants of GBS Several clinical subtypes of GBS have been characterized and are discussed online (Table 143-3) (Yuki and Hartung, 2013).

Diagnostic Challenges of GBS in Childhood Pain and walking difficulties may cause misdiagnosis of this potentially life-threatening disease in children. Presentation early in life may be less classic, with acute severe hypotonia, and may raise concerns of an encephalopathic process with meningismus, vomiting, and headache. Back pain and Babinski sign in an uncooperative child early on in GBS make differentiation from a spinal cord process difficult. Less commonly, weakness starting proximally may be confused with muscle disease. Occasionally botulism with weakness in the face and arms may cause diagnostic confusion.

GBS Diagnostic Criteria GBS diagnostic criteria and exclusionary features (Asbury, 2000) are outlined in Box 143-3.

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PART XVII  Neuromuscular Disorders

BOX 143-3  Clinical and Laboratory Features in the Diagnosis of Guillain-Barré Syndrome

BOX 143-4  Differential Diagnosis of Guillain-Barré Syndrome

I.  REQUIRED FOR DIAGNOSIS • Progressive motor weakness of more than one limb • Areflexia—loss of ankle-jerk reflex and diminished knee and biceps reflexes suffice, if other features are consistent with the diagnosis

CEREBRAL • Bilateral strokes • Hysteria

II.  STRONGLY SUPPORTIVE OF THE DIAGNOSIS • Progression—weakness may develop rapidly but cease to progress after 4 weeks; roughly 50% will plateau within 2 weeks, 80% by 3 weeks, and 90% after 4 weeks • Relative symmetry • Mild sensory symptoms or signs • Cranial nerve involvement; facial weakness develops in about half of patients • Autonomic dysfunction • Absence of fever at the onset of neurologic symptoms • Recovery—usually recovery begins 2 to 4 weeks after progression ceases; it may be delayed for months • Variants • Fever at onset of symptoms • Severe sensory loss with pain • Progressive phase longer than 4 weeks • Lack of recovery or major permanent residual deficit • Sphincter dysfunction—sphincters are usually spared, although transient bladder paralysis may occur • CNS involvement III.  FEATURES CASTING DOUBT ON THE DIAGNOSIS • Marked persistent asymmetry in motor function • Persistent bowel or bladder dysfunction • Bowel or bladder dysfunction at onset of symptoms • Discrete sensory level IV.  FEATURES THAT EXCLUDE THE DIAGNOSIS • History of recent hexacarbon abuse • Evidence of porphyria • Recent diphtheria • Features consistent with lead neuropathy and evidence of lead intoxication • A pure sensory syndrome • Definite diagnosis of an alternate paralytic disorder (With permission of Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol 1990;27:S21.)

Differential Diagnosis A variety of other peripheral and occasional CNS disorders can be confused with GBS. These are outlined in Box 143-4 and the reader is referred to the specific chapters discussing these conditions.

Laboratory Findings Supportive of GBS Cerebrospinal Fluid Characteristically the CSF has albuminocytologic dissociation, with a raised protein and no significant evidence of inflammation (1 year (Nevo, 2002). In adults subacute inflammatory demyelinating polyneuropathy (SIDP) is intermediate between GBS and CIDP, reaching nadir between 4 and 8 weeks with no relapse. SIDP has more antecedent infections than CIDP, a high rate of full recovery (64% to 100%), and is set apart from GBS by steroid responsiveness. SIDP cases have been described in children. However, because childhood CIDP is defined as starting from >4 weeks, SIDP is therefore included in CIDP in childhood.

CIDP Laboratory Evaluation Cerebrospinal Fluid and Electrodiagnosis Most children and adults with CIDP have an elevated CSF protein with 3 months) had mild residua in 78%, and severe residua in 22%. Hattori et al. (1998) showed the above short- and long-progression groups. Ryan et al. (2000) identified two populations with very good long-term outcome in general, and mild persistent deficit in cases with progressive deterioration.

OTHER CAUSES OF IMMUNE-MEDIATED NEUROPATHIES IN CHILDREN These rare causes of inflammatory neuropathy in childhood are discussed online. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Asbury, A.K., 2000. New concepts of Guillain-Barré syndrome. J. Child Neurol. 15, 183–191.

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Connolly, A.M., 2001. Chronic inflammatory demyelinating polyneuropathy in childhood. Pediatr. Neurol. 24, 177–182. Dalakas, M.C., 2015. Pathogenesis of immune-mediated neuropathies. Biochim. Biophys. Acta 1852, 658–666. Hattori, N., Ichimura, M., Aoki, S., et al., 1998. Clinicopathological features of chronic inflammatory demyelinating polyradiculoneuropathy in childhood. J Neurol Sci 154, 66–71. Hughes, R.A., Cornblath, D.R., 2005. Guillain-Barré syndrome. Lancet 366, 1653–1666. Korinthenberg, R., 1999. Chronic inflammatory demyelinating polyradiculoneuropathy in children and their response to treatment. Neuropediatrics 30, 190–6. Korinthenberg, R., 2013. Acute polyradiculoneuritis: Guillain-Barré syndrome. Handb. Clin. Neurol. 112, 1157–1162. McMillan, H.J., Kang, P.B., Jones, H.R., et al., 2013. Childhood chronic inflammatory demyelinating polyradiculoneuropathy: combined analysis of a large cohort and eleven published series. Neuromuscul. Disord. 23, 103–111. Nevo, Y., Pestronk, A., Kornberg, A.J., et al., 1996. Childhood chronic inflammatory demyelinating neuropathies: clinical course and long-term follow-up. Neurology 47, 98–102. Nevo, Y., 1998. Childhood chronic inflammatory demyelinating polyneuropathy. Eur. J. Paediatr. Neurol. 2, 169–177. Nevo, Y., Topaloglu, H., 2002. 88th ENMC international workshop: childhood chronic inflammatory demyelinating polyneuropathy (including revised diagnostic criteria), Naarden, The Netherlands, December 8–10, 2000. Neuromuscul. Disord. 12, 195–200. Rossignol, E., D’Anjou, G., Lapointe, N., et al., 2007. Evolution and treatment of childhood chronic inflammatory polyneuropathy. Pediatr Neurol 36, 88–94. Ryan, M.M., Grattan-Smith, P.J., Procopis, P.G., et al., 2000. Childhood chronic inflammatory demyelinating polyneuropathy: clinical course long-term outcome. Neuromuscul Disord 10, 398–406. Simmons, Z., Wald, J.J., Albers, J.W., 1997. Chronic inflammatory demyelinating polyradiculoneuropathy in children: I. Presentation, electrodiagnostic studies, and initial clinical course, with comparison to adults. Muscle Nerve 20, 1008–1015. Ware, T.L., Kornberg, A.J., Rodriguez-Casero, M.V., et al., 2014. Childhood chronic inflammatory demyelinating polyneuropathy: an overview of 10 cases in the modern era. J. Child Neurol. 29, 43–48. Yuki, N., Hartung, H.P., 2012. Guillain-Barré syndrome. N. Engl. J. Med. 366, 2294–2304.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 143-1 Presentations of Guillain-Barré syndrome subtypes and variants. Fig. 143-2 Nerve conduction studies in Guillain-Barré syndrome. Fig. 143-3 Cross section through a sciatic nerve from a Lewis rat during the acute phase of experimental allergic neuritis. Fig. 143-4 Teased fiber preparation of osmicated axons. Table 143-1 Etiologies of neuropathy in 249 Children (1980 to 1992) Table 143-2 Causes of inflammatory and immune neuropathy in 112 children Table 143-4 Distinguishing AIDP and AMAN in Children Box 143-1 Infectious agents associated with Guillain-Barré syndrome Box 143-5 Revised diagnostic criteria for childhood CIDP Box 143-6 Clinical pointers in chronic demyelinating neuropathies

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144  Congenital Myasthenic Syndromes Duygu Selcen and Andrew G. Engel

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Congenital myasthenic syndromes (CMS) are inherited disorders of neuromuscular transmission associated with abnormal weakness and fatigability on exertion. CMS were described as early as 1937 but received little attention until the autoimmune origin of acquired myasthenia gravis in the late 1970s and of the Lambert-Eaton syndrome in the 1980s were described. Then it became apparent that myasthenic disorders occurring in a familial or congenital setting must have a different etiology. By the first decade of this century, clinical, ultrastructural, in vitro microelectrode, and molecular genetic studies of CMS patients revealed a phenotypically and genetically heterogeneous group of disorders.

CLINICAL MANIFESTATIONS Some patients with CMS can present as early as in fetal life by decreased motility. Patients harboring mutations in rapsyn (Ohno et al., 2002), in the AChR delta subunit, in the fetal AChR gamma subunit (Hoffmann et al., 2006), in ChAT, or in SNAP25B (Shen et al., 2014) can have multiple joint contractures at birth. In the neonatal period, most patients are hypotonic with a weak cry, poor suck, and symmetric eyelid ptosis; they may also have stridor, choking spells, respiratory insufficiency, or apneic episodes. The symptoms are worsened by crying or activity and increase by the end of the day. Motor milestones are delayed, and most patients never learn to run or climb stairs well. They fatigue abnormally on exertion and cannot keep up with their peers in sports. Many have impaired eye movements. Small muscle bulk and spinal deformities can become apparent in later life but in some patients, severe scoliosis is present in infancy. The slow-channel CMS and the CMS caused by mutations in DOK7, GFPT1, and DPAGT1 are slowly progressive and can lead to severe disability in later life. Low-expressor mutations in nonepsilon AChR subunits are associated with a severe clinical phenotype; by contrast, most low-expressor mutations in the AChR epsilon subunit have a mild and static course because expression of the fetal gamma subunit can partially substitute for the defect in the epsilon subunit. The mildest forms of CMS present with fatigable oculobulbar or limb muscle weakness later in life. The edrophonium or neostigmine test can be positive in some but not in all CMS such as in endplate acetylcholinesterase deficiency, in some cases of the slow-channel syndrome, or in Dok-7 myasthenia. Box 144-1 lists generic and specific clinical features of the various CMS.

DIAGNOSIS A generic diagnosis of CMS can be made on the basis of classical clinical manifestations, a positive family history, and a decremental electromyographic response. The differential diagnosis of CMS is broad and includes various neuromuscular conditions. The physical examination should include detailed manual muscle testing as well as tests for fatigable weakness such as measuring the arm and leg elevation time, the number of

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times a patient can rise from squatting or from a low stool, whether eyelid ptosis increases with sustained upward gaze, and the number of steps the patient can climb or the distance the patient can walk before having to rest. Respiratory muscle strength can be evaluated by measuring the maximal inspiratory and expiratory pressures and the vital capacity. The EMG examination should include repetitive stimulation of nerves at 2 to 3 Hz in search of a decrease of the amplitude or area of the fourth, compared with the first, evoked compound motor action potential in multiple muscles, and especially in muscles that are significantly weak. The repetitive compound muscle action potential (CMAP) typical in the slow-channel syndrome and endplate acetylcholinesterase deficiency is detected by a repetitive CMAP elicited by a single nerve stimulus. A decremental EMG response is frequently present in facial and trapezius muscles when it cannot be detected in other muscles. If repetitive nerve stimulation studies fail to show a decremental response, then single fiber EMG (SFEMG) is needed to exclude a defect of neuromuscular transmission. However, the SFEMG can also be abnormal in patients with myopathies. Antiacetylcholine receptor, antimuscle specific tyrosine kinase (MuSK), and antivoltage-gated P/Q type calcium channel antibodies should be searched in sporadic patients whose symptoms present after the age of 1 year, and antiAChR antibodies should be searched both in mother and the infant with arthrogryposis and weakness to exclude autoimmune myasthenia. Infantile botulism may need to be excluded if the clinical features suggest acute- or subacuteonset fatigable weakness, ptosis, dry mouth, dilated pupils, and loss of light reflex and accommodation. The genetic diagnosis of a specific CMS is important as it guides the therapy. Identification of the culprit gene is greatly facilitated when clinical and EMG studies point to a candidate gene (Box 144-3). Testing for CMS mutations in previously identified CMS genes is now commercially available and offered as a panel of tests. In recent years, whole exome sequencing has also been used to identify CMS mutations. If a novel CMS disease gene is discovered, then expression studies with the genetically engineered mutant protein should be used to confirm its pathogenicity. Deeper insights into disease mechanisms and clues to etiology can be obtained by in vitro analysis of neuromuscular transmission and structural studies of the neuromuscular junction. They are important for identifying direct effects of the mutations on neuromuscular transmission, characterizing novel CMS, and providing clues for therapy.

PRESYNAPTIC CONGENITAL MYASTHENIC SYNDROMES 1.  Endplate Choline Acetyltransferase (ChAT) Deficiency ChAT catalyzes the resynthesis of ACh by transfer of an acetyl group from acetyl-CoA to choline in cholinergic neurons.



Congenital Myasthenic Syndromes

BOX 144-1  Generic Clinical Features of the Congenital Myasthenic Syndromes GENERIC FEATURES • Fatigable weakness involving ocular, bulbar, and limb muscles since infancy or early childhood • Similarly affected relative • Decremental EMG response at 2–3 Hz stimulation • Negative tests for anti-AChR antibodies, MuSK, and P/Q type calcium channels EXCEPTIONS AND CAVEATS • In some congenital myasthenic syndromes, the onset is delayed • There may be no similarly affected relatives • The symptoms can be episodic • EMG abnormalities may not be present in all muscles, or are present only intermittently • Weakness may not involve cranial muscles

BOX 144-3  Clinical Clues Pointing to a Specific Congenital Myasthenic Syndrome or Disease Protein • Dominant inheritance: slow-channel CMS, SNAP25 and synaptotagmin • Refractory or worsened by AChE inhibitors: ColQ, Dok-7, MuSK, Agrin, LRP4, plectin, and laminin-β2 • Repetitive compound muscle action potential (CMAP) evoked by single nerve stimuli: slow-channel CMS and ColQ deficiency • Delayed pupillary light response: some patients with ColQ deficiency • Congenital contractures: rapsyn, AChR δ or γ subunit, ChAT, SNAP 25 • Greater than 50% decrease of CMAP amplitude after subtetanic stimulation at 10 Hz for 5 min followed by slow recovery over 5–10 minutes: ChAT deficiency • Sudden apneic episodes provoked by fever or stress: ChAT, rapsyn, sodium channel myasthenia • Limb-girdle and axial distribution of weakness: Dok7, GFPT1, DPAGT1, ALG2, ALG14, LRP4, and occasionally rapsyn and ColQ • Selectively severe weakness and atrophy of distal limb muscle: slow-channel syndrome and in some patients with agrin deficiency • Tubular aggregates of the sarcoplasmic reticulum in muscle fibers: GFPT1, DPAGT1, ALG2 • Autophagic myopathy: GFPT1 and DPAGT1 • Stridor and vocal cord paralysis in neonates or infants: Dok-7 • Nephrotic syndrome and ocular malformations (Pierson syndrome): laminin-β2 • Association with seizures or intellectual disability: DPAGT1 • Intellectual disability and cerebellar ataxia: SNAP25 • Developmental anomalies of eye, brain, and heart: mitochondrial citrate carrier deficiency • Association with epidermolysis bullosa simplex: plectin deficiency

Pathogenic mutations, alone or in combination, alter the expression, catalytic efficiency, or structural stability of the enzyme (Ohno et al., 2001). When neuronal impulse flow is increased as during exercise, the decreased rate of ACh resynthesis progressively depletes the ACh content of the synaptic

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vesicles, which decreases the amplitude of the EPP and of the CMAP. Some patients present with hypotonia, bulbar paralysis, and apnea at birth. Others are normal at birth and develop apneic attacks during infancy or childhood precipitated by infection, excitement, or no apparent cause. In some children an acute attack is followed by respiratory insufficiency that lasts for weeks. Few patients are apneic, ventilator dependent, and paralyzed since birth, and some develop cerebral atrophy after episodes of hypoxemia. Others improve with age but still have variable ptosis, ophthalmoparesis, fatigable weakness, and recurrent cyanotic episodes; some complain only of mild to moderately severe fatigable weakness. The symptoms are worsened by exposure to cold because this further reduces the catalytic efficiency of the mutant enzyme. A useful clinical test is to monitor the EMG decrement and the CMAP amplitude during 10 Hz stimulation over 5 minutes and for 10 to 15 minutes after stimulation. A decrease lower than 50% of the potential from the baseline followed by return to the baseline in 2 to 3 minutes is a nonspecific finding that occurs in different CMS. In contrast, in patients with ChAT deficiency the recovery occurs slowly over 5 to 15 minutes. Treatment consists of prophylactic therapy with pyridostigmine, which increases the number of AChRs activated by each quantum. The parents should be provided with an inflatable rescue bag and a fitted mask, should be instructed in the intramuscular injection of neostigmine methylsulfate, and are advised to have an apnea monitor.

2.  SNAP25B Myasthenia SNAP25B is one of the three essential SNARE proteins required for synaptic vesicle exocytosis. A patient with severe CMS associated with cortical hyperexcitability, ataxia, multiple joint contractures at birth, and intellectual disability harbored a dominant negative mutation in SNAP25B. Treatment with 3,4-diaminopyridine (3,4-DAP), which increases the number of ACh quanta released by nerve impulse, improved the patient’s weakness but not her ataxia or intellectual disability.

3.  Synaptotagmin-2 Myasthenia Synaptotagmin 2 is a synaptic vesicle-associated calcium sensor. In two kinships, dominant mutations in this gene caused a Lambert-Eaton syndrome-like disorder with lower limb predominant weakness, areflexia, and a motor neuronopathy. They had low amplitude CMAP that were greatly facilitated by exercise (Herrmann et al., 2014).

SYNAPTIC BASAL LAMINA ASSOCIATED CONGENITAL MYASTHENIC SYNDROMES 1.  Endplate Acetylcholinesterase Deficiency The EP species of acetylcholinesterase (AChE) is an asymmetric enzyme composed of catalytic subunits encoded by ACHET and a collagenic structural subunit encoded by COLQ that anchors the enzyme in the synaptic basal lamina. The clinical course of patients with EP AChE deficiency is variable. Patients typically present in the neonatal period or infancy with apnea and generalized weakness that persist through life. In some patients, the ocular ductions are spared and in some the pupillary light reflex is delayed. Milder cases may present later in childhood with limb-girdle weakness. Absence of AChE from the EP prolongs the lifetime of ACh in the synaptic cleft because each ACh binds multiple AChRs

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before leaving the synaptic space by diffusion. This prolongs the duration of the MEPP and EPP, and when the EPP outlasts the absolute refractory period of the muscle fiber, it generates a second (or repetitive) muscle fiber action potential, reflected by a repetitive CMAP that is unaffected by edrophonium (Ohno et al., 1998). Therapy is still unsatisfactory, but ephedrine and albuterol (Liewluck et al., 2011) were noted to have a gradually developing beneficial effect.

2.  Congenital Myasthenic Syndrome Associated With β2-Laminin Deficiency β2-Laminin, encoded by LAMB2, is a component of the basal lamina of different tissues and is highly expressed in kidney, eye, and the neuromuscular junction. Synaptic β2-laminin governs the appropriate alignment of the axon terminal with the postsynaptic region and, hence presynaptic and postsynaptic trophic interactions. Defects in β2-laminin result in Pierson syndrome with renal and ocular malformations. In a single report, a patient carrying two heteroallelic frameshift mutations in LAMB2 had Pierson syndrome associated with ocular, respiratory, and proximal limb muscle weakness. The renal defect was corrected by renal transplant at age 15 months. A trial with a cholinesterase inhibitor resulted in profound weakness requiring hospitalization and ventilatory support. The patient responded to treatment with ephedrine but still had significant weakness.

POSTSYNAPTIC CONGENITAL   MYASTHENIC SYNDROMES Most postsynaptic CMS stem from molecular defects in the muscle form of the nicotinic AChR. The muscle form of nicotinic AChR is a pentameric transmembrane macromolecule with a subunit composition of α2βδε at adult EPs, and α2βδγ at fetal EPs and extrajunctional sites. The genes encoding the α (CHNRA1), δ (CHRND), and γ (CHRNG) subunits are located in chromosome 2q, and those encoding the β (CHRNB) and ε (CHRNE) subunits are on chromosome 17p. At the human EP, AChR is concentrated on the crests of the junctional folds.

1.  Primary Acetylcholine Receptor Deficiency The clinical phenotypes vary from mild to severe. Patients with recessive mutations in the ε subunit are generally less affected than those with mutations in other subunits because compensatory expression of the fetal γ subunit can partially substitute for the defective ε subunit. The sickest patients have severe ocular, bulbar, and respiratory muscle weakness from birth and survive only with respiratory support and tube feeding. They may be weaned from a ventilator and begin to tolerate oral feedings during the first year of life but have bouts of aspiration pneumonia; they may need intermittent respiratory support during childhood and adult life. Motor milestones are severely delayed; they seldom learn to negotiate steps and can walk for only a short distance. Older patients close their mouth by supporting the jaw with the hand and elevate their eyelids with their fingers. Facial deformities, prognathism, malocclusion, and scoliosis or kyphoscoliosis become noticeable during the second decade. Muscle bulk is reduced. The tendon reflexes are normal or hypoactive. The least affected patients pass their motor milestones with slight or no delay and show only mild ptosis and limited ocular ductions. They are often clumsy in sports, and fatigue easily. In some instances, a myasthenic disorder is suspected

only when the patient develops prolonged respiratory arrest on exposure to a curariform drug during a surgical procedure. Patients with intermediate clinical phenotypes experience moderate physical handicaps from early childhood. Ocular palsies and eyelid ptosis become apparent during infancy. They fatigue easily, walk and negotiate stairs with difficulty, cannot keep up with their peers in sports, but can perform most activities of daily living. Most patients respond favorably but incompletely to AChE inhibitors. The additional use of 3,4-DAP results in further improvement but the limited ocular ductions, pronounced in most patients with AChR deficiency, are typically refractory to therapy. Recently, albuterol was found to benefit patients responding poorly to pyridostigmine and 3,4-DAP.

2.  Kinetic Defects in Acetylcholine Receptor 2.1  Slow-channel Myasthenia The slow channel myasthenia is caused by dominant gain of function mutations that either enhances the affinity or the gating efficiency of AChR (Engel et al., 2003). Either mechanism prolongs the duration of the EP potentials and currents. As in EP AChE deficiency, when the length of the EPP exceeds the absolute refractory period of the muscle fiber, it triggers a repetitive CMAP; however, unlike in AChE deficiency, the repetitive response is enhanced by edrophonium. The onset of symptoms ranges from infancy to early adult life. There is severe selective involvement of the cervical, scapular, and the wrist and finger extensor muscles. The slow-channel syndromes are refractory to, or are worsened by, cholinergic agonists but are improved by long-lived open-channel blockers of the AChR, such as quinine or quinidine, or by fluoxetine (Harper et al., 2003).

2.2  Fast-channel Myasthenia They are recessively inherited disorders caused by either decreased affinity for ACh or reduced gating efficiency, or by destabilization of the channel kinetics, or by a combination of these mechanisms; they leave no anatomic foot prints. Each of these derangements results in abnormally brief channel openings reflected by an abnormally fast decay of the EP potentials and currents. They are thus physiologic and structural opposites of the slow-channel syndromes. A fast-channel mutation dominates the clinical phenotype when the second allele harbors a null mutation or if it occurs at homozygosity. The clinical consequences vary from mild to severe; no clinical clues point to the diagnosis of fast-channel myasthenia. Most patients respond to a combination of 3,4-DAP and pyridostigmine, but some are refractory to therapy.

3.  Prenatal Congenital Myasthenic Syndrome Caused by Mutations in Acetylcholine Receptor Subunits and Other Endplate Specific Proteins The first identified prenatal myasthenic syndrome was traced to mutations in the fetal AChR γ subunit. In humans, AChR harboring the fetal γ subunit appears on myotubes around the ninth developmental week and becomes concentrated at nascent nerve-muscle junctions around the sixteenth developmental week. Subsequently, the γ subunit is replaced by the adult ε subunit and is no longer present at fetal EPs after the thirty-first developmental week. Thus pathogenic mutations of the γ-subunit result in hypomotility in utero during the 16th and 31st developmental week. The clinical consequences at



birth are multiple joint contractures, small muscle bulk, multiple pterygia (webbing of the neck, axilla, elbows, fingers, or popliteal fossa), fixed flexion contractures of the fingers (camptodactyly), rocker-bottom feet with prominent heels, and characteristic facies with mild ptosis and a small mouth with downturned corners. Myasthenic symptoms are absent after birth because by then the normal adult ε subunit is expressed at the EPs. A lethal fetal akinesia syndrome is caused by biallelic null mutations in the AChR α, β, and δ subunits as well as in rapsyn, Dok-7, and MuSK.

4.  Sodium-channel Myasthenia Thus far, only one patient with this syndrome has been identified. The patient had abrupt attacks of respiratory and bulbar paralysis since birth, lasting from 3 to 30 minutes, and was normokalemic. Intracellular microelectrode studies of neuromuscular transmission revealed that suprathreshold EPPs failed to generate muscle action potentials pointing to Nav1.4, encoded by SCN4A, as the culprit. After the defect in Nav1.4 was established, the patient was treated with pyridostigmine, which improved her endurance, and with acetazolamide, which prevented further attacks of respiratory and bulbar weakness.

5.  Congenital Myasthenic Syndrome Caused by Plectin Deficiency Plectin, encoded by PLEC, is a highly conserved and ubiquitously expressed intermediate filament-linking protein. By virtue of its tissue and organelle-specific isoforms, it links cytoskeletal filaments to target organelles in different tissues. Mutations in plectin result in epidermolysis bullosa simplex (EBS), a progressive muscular dystrophy in many patients and a myasthenic syndrome in some. In two patients investigated by the authors, microelectrode studies of intercostal muscle EPs showed low-amplitude MEPPs. Morphologic studies revealed clustering of nuclei, endomysial fibrosis, and focal calcium accumulation in some fibers, as in Duchenne dystrophy. Electron microscopy studies showed degeneration and disarray of muscle fiber organelles, plasma membrane defects accounting for calcium accumulation in the muscle fibers, and extensive degeneration of the junctional folds all attributable to lack of cytoskeletal support. Both patients were refractory to pyridostigmine.

CONGENITAL MYASTHENIC SYNDROMES CAUSED BY DEFECTS IN ENDPLATE DEVELOPMENT OR MAINTENANCE To date, mutations in proteins essential for EP development and maintenance have been detected in MuSK, neural agrin, LRP4, Dok-7. Agrin, secreted into the synaptic space by the nerve terminal, binds to the lipoprotein-related protein LRP4 in the postsynaptic membrane. The Agrin-LRP4 complex binds to and activates MuSK. This enhances MuSK phosphorylation and leads to clustering of LRP4 and MuSK. Activated MuSK in concert with postsynaptic Dok-7 and other postsynaptic proteins acts on rapsyn to concentrate AChR in the postsynaptic membrane, enhances synapse specific gene expression by postsynaptic nuclei, and promotes postsynaptic differentiation. Clustered LRP4, in turn, promotes differentiation of motor axons. The agrin-LRP4-MuSK-Dok-7 signaling system is also essential for maintaining the structure of the adult neuromuscular junction.

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1.  Agrin Myasthenia Patients with mutations in agrin can present with mild to severe muscle weakness with eyelid ptosis and facial weakness. One patient responded partially to pyridostigmine, but the other two patients did not respond to pyridostigmine or 3,4-DAP. In one report five patients in three kinships had a distinct phenotype associated with wasting that first affected the lower and later the upper distal limbs, sparing of the axial and cranial muscles, and slowly progressive weakness. The patients responded to albuterol or ephedrine but not to pyridostigmine.

2.  LRP4 Myasthenia The first reported patient was 17-year-old girl with moderately severe fatigable limb-girdle weakness, dysplastic synaptic contacts, and borderline EP AChR deficiency. The patient has two heterozygous missense mutations in the third β-propeller domain of LRP4. Subsequently, two sisters with moderately severe LRP4 myasthenia and a homozygous mutation in LRP4 were found to have structurally and functionally abnormal EPs and EP AChR deficiency. Expression studies revealed that the mutation hinders LRP4 from binding to, activating, and phosphorylating MuSK. Both patients respond partially to albuterol.

3.  MuSK Myasthenia The patients with mutations in MuSK present at birth or early life with eyelid ptosis or respiratory distress. Subsequently, the ocular, facial and proximal limb muscles, and sometimes the bulbar muscles are affected. Pyridostigmine therapy is ineffective or worsens the disease (personal observation). A program of 3,4-DAP therapy improved symptoms in one patient. Importantly, a recent report indicates that therapy with albuterol has been highly effective in two brothers. No clear genotype-phenotype correlations have emerged.

4.  Dok-7 Myasthenia Patients with mutations in DOK7 have limb-girdle weakness with lesser facial and cervical muscle involvement, but a few have severe bulbar weakness and significant oculoparesis (Beeson et al., 2006). Some are initially misdiagnosed as having limb-girdle muscular dystrophy. The clinical course is mild to severe. Type 1 fiber preponderance, type 2 fiber atrophy, mild myopathic changes, and target formations are associated features. Importantly, this CMS is rapidly worsened by pyridostigmine but responds well over a period of time to ephedrine or albuterol.

5.  Rapsyn Myasthenia Most patients with mutations in RAPSN present in the first year and a few later in life. Arthrogryposis at birth and other congenital malformations occur in close to one third of patients. Intercurrent infections or fever can trigger respiratory crises and can cause anoxic encephalopathy. The ocular ductions are intact in most patients. Most patients respond well to pyridostigmine; some derive additional benefit from 3,4DAP, and some benefit from the added use of ephedrine or albuterol. There are no genotype-phenotype correlations except that near-Eastern Jewish patients with a homozygous E-box mutation (c.-38A>G) have a mild phenotype with ptosis,

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prognathism, severe masticatory and facial muscle weakness, and hypernasal speech.

CONGENITAL MYASTHENIC SYNDROMES ASSOCIATED WITH CONGENITAL DEFECTS OF GLYCOSYLATION Glycosylation increases the solubility, folding, stability, assembly, and intracellular transport of nascent peptides. Oglycosylation occurs in the Golgi apparatus with addition of sugar residues to hydroxyl groups of serine and threonine; N-glycosylation occurs in the endoplasmic reticulum in sequential reactions that decorate the amino group of asparagine with a core glycan composed of 2 glucose, 9 mannose and 2 N-acetylglucosamine (GlcNAc). To date, defects in four enzymes subserving glycosylation have been found to cause CMS: GFPT1 (glutamine fructose-6-phosphate transaminase); DPAGT1 (dolichyl-phosphate [UDP-N-acetylglucosamine] N-acetylglucosaminephosphotransferase 1); ALG2 (alpha1,3/1,6-mannosyltransferase); and ALG14 (UDP-N-acetylglucosaminyltransferase subunit). Tubular aggregates of the sarcoplasmic reticulum (SR) in muscle fibers are a phenotypic clue to the diagnosis but are not present in all patients. Because glycosylated proteins are present at all EP sites, the safety margin of neuromuscular transmission is compromised by a combination of presynaptic and postsynaptic abnormalities.

1.  GFPT1 Myasthenia GFPT1 controls the flux of glucose into the hexosamine pathway, and, thus, the formation of hexosamine products and the availability of precursors for N- and O-linked glycosylation of proteins. A defect in GFPT1 predicts hypoglycosylation and, hence, defective function of several endplateassociated proteins. Most patients present in the first decade. As in Dok-7 myasthenia, the weakness affects mainly the limbgirdle muscles. Only a few patients have respiratory complications. The course is relatively benign in most, but one patient whose mutations abrogated expression of the muscle-specific exon of GFPT1 had severe facial, bulbar, and respiratory muscle weakness, and has been quadriplegic since birth. This patient has an autophagic vacuolar myopathy, reduced evoked quantal release, and low MEPP amplitude. Most patients respond to pyridostigmine. Some patients derive additional benefit from albuterol and 3,4-DAP.

2.  DPAGT1 Myasthenia DPAGT1 catalyzes the first committed step of N-linked protein glycosylation. DPAGT1 deficiency predicts impaired asparagine glycosylation of multiple proteins distributed throughout the organism, but in the first five patients harboring DPAGT1 mutations only neuromuscular transmission was adversely affected; this was attributed to reduced AChR expression at the EP, but the patient EPs were not examined. As in GFPT1 deficiency, muscle fibers harbor tubular aggregates, and the weakness tends to spare the craniobulbar muscles. A subsequent study of two siblings and of a third patient extended the phenotypic spectrum of the disease. These patients have moderately severe to severe weakness and are intellectually disabled. The siblings respond poorly to pyridostigmine and 3,4-DAP; the third patient responds partially to pyridostigmine and albuterol. Intercostal muscle studies showed fiber type disproportion, small tubular aggregates, and an autophagic vacuolar myopathy.

3.  ALG2 and ALG14 Myasthenia ALG2 catalyzes the second and third committed steps of N-glycosylation. ALG14 forms a multiglycosyltransferase complex with ALG13 and DPAGT1 and catalyzes the first committed step of N-glycosylation. These defects are predicted to cause endplate AChR deficiency. Two siblings with mutations in ALG14 have fatigable limb-girdle muscle weakness with sparing of ocular muscles. Both patients benefit from pyridostigmine. Four siblings with mutations in ALG2 presented in infancy or less than age 2 years with hypotonia and delayed motor milestones and never achieved ambulation, one other patient presented at age 4 years with limb-girdle weakness, and responded to pyridostigmine.

OTHER MYASTHENIC SYNDROMES 1.  PREPL Deletion Syndrome The hypotonia-cystinuria syndrome is caused by recessive deletions involving the contiguous genes SLC3A1 and PREPL at chromosome 2p21. The major clinical features are type A cystinuria, growth hormone deficiency, muscle weakness, ptosis, and feeding problems. A patient with isolated PREPL deficiency had myasthenic symptoms since birth, including marked hypotonia, ptosis and facial and bulbar muscle weakness. She had growth hormone deficiency but no cystinuria and responded transiently to pyridostigmine during infancy. She harbors a paternally inherited nonsense mutation in PREPL and a maternally inherited deletion involving both PREPL and SLC3A1; therefore the PREPL deficiency determines the phenotype. PREPL expression was absent from the patient’s muscle and EPs.

2.  Myasthenic Syndrome Associated With Defects in the Mitochondrial Citrate   Carrier SLC25A1 The mitochondrial SLC25A1 mediates the exchange of mitochondrial citrate/isocitrate with cytosolic maleate that is cleaved into acetyl-CoA and oxaloacetate by ATP-citrate lyase. Mutations of SLC25A1 were shown to interfere with brain, eye, and psychomotor development. Exome sequencing of two siblings born to consanguineous parents with CMS and intellectual disability revealed homozygous missense mutation in SLC25A1. Another patient harboring two missense mutations in SLC25A1 had hypotonia, severe intellectual disability, epilepsy, postnatal microcephaly, as well hypoplastic optical nerves, agenesis of the corpus callosum, sensorineural deafness and 2-hydroxyglutaric aciduria. At 18 months of age the patient had no spontaneous voluntary movements and was shown to have neuromuscular transmission defect.

3.  Myasthenic Syndromes Associated With Congenital Myopathies Eyelid ptosis, ophthalmoparesis, weakness of facial muscles, exercise intolerance, a decremental EMG, and response to pyridostigmine have been documented in patients with centronuclear myopathies caused by mutations in amphiphysin, myotubularin, and dynamin 2, as well as in patients with no identified mutations. Two patients with congenital fiber type disproportion caused by mutation in tropomyosin 3 had mild abnormalities in single fiber EMG, suggesting CMS. Finally, two siblings harboring mutations in ryanodine receptor 1 had fatigable ptosis and facial and generalized weakness, and responded partially to pyridostigmine.



Congenital Myasthenic Syndromes TABLE 144-2  Treatment of Congenital Myasthenic Syndromes Type of Congenital Myasthenia

Therapy Options

Choline acetyltransferase deficiency

Pyridostigmine; parental neostigmine sulfate for apneic episodes

SNAP25B-myasthenia

3,4-DAP*

Acetylcholine esterase deficiency

Albuterol or ephedrine

Laminin β2 deficiency

Partial response to ephedrine

Primary AChR deficiency

Pyridostigmine, 3,4-DAP, albuterol can have additional benefit in severe cases

Slow-channel syndrome

Quinine, quinidine, or fluoxetine

Fast-channel syndrome

Pyridostigmine and 3,4-DAP

Agrin-myasthenia

Partial response to ephedrine or albuterol; one patient with partial response to pyridostigmine

LRP4-myasthenia

Partial response to albuterol in two patients

MuSK-myasthenia

Variable response to 3,4-DAP, good response to albuterol in one patient

Dok-7 myasthenia

Albuterol or ephedrine

Rapsyn myasthenia

Pyridostigmine, 3,4-DAP, albuterol

GFPT1, DPAGT1, ALG2, and ALG4 associated myasthenia

Pyridostigmine, 3,4-DAP additional benefit, albuterol in one patient

PREPL deletion syndrome

Pyridostigmine beneficial in infancy

Plectin deficiency

Refractory to pyridostigmine and 3,4-DAP

Na-channel myasthenia

Pyridostigmine and acetazolamide

CMS associated with congenital myopathies

Pyridostigmine with some response

*3,4-DAP = 3,4-diaminopyridine

TREATMENT Current therapies for CMS include cholinergic agonists, namely pyridostigmine and 3,4-DAP, long-lived open-channel blockers of the acetylcholine receptor ion channel such as fluoxetine and quinidine, and adrenergic agonists such as salbutamol and ephedrine. Some agents that can be beneficial in one type of CMS can be harmful in another type. Hence a specific diagnosis is essential for the treatment of these patients. Table 144-2 summarizes the pharmacotherapy of the recognized CMS.

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REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Beeson, D., Higuchi, O., Palace, J., et al., 2006. Dok-7 mutations underlie a neuromuscular junction synaptopathy. Science 313, 1975–1978. Engel, A.G., Ohno, K., Sine, S.M., 2003. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat. Rev. Neurosci. 4, 339–352. Harper, C.M., Fukodome, T., Engel, A.G., 2003. Treatment of slowchannel congenital myasthenic syndrome with fluoxetine. Neurology 60, 1710–1713. Herrmann, D.N., Horvath, R., Sowden, J.E., et al., 2014. Synaptotagmin 2 mutations cause an autosomal-dominant form of LambertEaton myasthenic syndrome and nonprogressive motor neuropathy. Am. J. Hum. Genet. 95, 332–339. Hoffmann, K., Muller, J.S., Stricker, S., et al., 2006. Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am. J. Hum. Genet. 79, 303–312. Liewluck, T., Selcen, D., Engel, A.G., 2011. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Muscle Nerve 44, 789–794. Ohno, K., Brengman, J., Tsujino, A., et al., 1998. Human endplate acetylcholinesterase deficiency caused by mutations in the collagenlike tail subunit (ColQ) of the asymmetric enzyme. Proc. Natl. Acad. Sci. U.S.A. 95, 9654–9659. Ohno, K., Engel, A.G., Shen, X.M., et al., 2002. Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. Am. J. Hum. Genet. 70 (4), 875–885. Ohno, K., Tsujino, A., Brengman, J.M., et al., 2001. Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans. Proc. Natl. Acad. Sci. U.S.A. 98, 2017–2022. Shen, X.M., Selcen, D., Brengman, J., et al., 2014. Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability. Neurology 83, 2247–2255.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Box 144-2 Differential Diagnosis of Congenital Myasthenic Syndromes Box 144-4 Detailed Investigation of Congenital Myasthenic Syndromes Table 144-1 Classification of the CMSa Table 144-3 Medications Commonly Used in Congenital Myasthenic Syndromes*

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145  Acquired Disorders of the Neuromuscular Junction Nicholas J. Silvestri, Richard J. Barohn, and Gil I. Wolfe

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

ACQUIRED DISEASES OF THE NEUROMUSCULAR JUNCTION Both acquired and inherited disorders of the neuromuscular junction (NMJ) are seen in childhood. As with adults, the most common NMJ disorders are autoimmune and respond to immunosuppressive therapy. These include myasthenia gravis (MG) and, rarely, Lambert–Eaton myasthenic syndrome (LEMS). Botulism, a toxin-mediated disorder of the NMJ, most commonly occurs in infancy. All NMJ disorders have the ability to produce generalized weakness and fatigability, with a propensity for oculobulbar involvement. Electrophysiological studies will detect an impairment of neuromuscular transmission in most of these disorders. Fortunately, most of these disorders are treatable.

AUTOIMMUNE MYASTHENIA GRAVIS MG, the best understood autoimmune disease of the nervous system, is most commonly caused by antibodies to acetylcholine receptor (AChRs). Circulating IgG antibodies directed against AChRs bind to the postsynaptic membrane and activate the terminal complement sequence (C5b-9), resulting in lysis of the AChR with complement-mediated muscle endplate degeneration. AChR-antibody formation has also been shown to block neuromuscular transmission and accelerate turnover of AChR cross-linked by IgG. As a result of these processes, the postsynaptic membrane becomes simplified, with decreased junctional folds. The process that initiates the immune-mediated NMJ dysfunction is still unknown. The thymus gland may play a role; 75% of MG patients who undergo thymectomy have thymic pathologic findings, with 15% being tumors of the thymus, and the remainder consisting of lymphoid hyperplasia. There may be a hereditary predisposition to develop MG because there is an increased incidence of certain HLA antigens in various MG populations (Meriggioli and Sanders, 2009).

CLINICAL FEATURES MG has a prevalence of approximately 125 cases per million population. Approximately 11% to 24% of all MG patients have disease onset in childhood or adolescence (Millichap and Dodge, 1960). Overall, there is a slight female predominance of 3 : 2, although males predominate in older age groups. The disease can arise at any age, but peaks are observed in the third and sixth decades (Grob et al., 2008). MG is characterized by weakness and fatigability of ocular, bulbar, and extremity striated muscles. The ocular manifestations are ptosis and diplopia, whereas the bulbar manifestations are dysarthria, dysphagia, dysphonia, and dyspnea. Masticatory weakness presents with jaw fatigue and jaw-closure weakness. Proximal limb and axial muscles tend to be weaker than distal extremity muscles. Symptoms of MG tend to worsen with stress, with illness, with exertion, and as the day

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progresses. These temporal symptoms, however, may be difficult to elicit in many patients. Myasthenic crisis, characterized by respiratory weakness and the inability to handle secretions or swallow, may punctuate a more stable clinical course in some children.

CATEGORIES OF MYASTHENIA GRAVIS   IN CHILDHOOD Autoimmune MG in children is most commonly divided into neonatal transient and juvenile types. Neonatal transient MG occurs in infants of myasthenic mothers. Placental transfer of AChR-antibody or immunocytes results in transient impairment of neuromuscular transmission in the neonate. Findings such as a weak suck or cry, ptosis, dysphagia, generalized weakness, decreased spontaneous movement, or respiratory distress are usually present in the first few hours of life but may not be evident until the third day (Millichap and Dodge, 1960). The majority of infants have hypotonia or transient weakness, and a very small proportion present with arthrogryposis multiplex congenita. The hypotonia and transient weakness usually resolve in the first 4 weeks but may persist for months and even lead to persistent facial and bulbar manifestations. The severity of the disorder in the infant does not correlate with the degree of maternal involvement, but there is evidence that a higher maternal antibody titer may predict severity. A prior history of neonatal MG in a sibling is the only predictive factor. Fortunately, only 10% to 15% of infants born to myasthenic mothers develop the disorder. Prior thymectomy or remission of disease in the mother does not prevent development of neonatal transient MG but has decreased its likelihood. In terms of treatment, if there is no significant respiratory or swallowing impairment, medications are not necessary. In more severe cases, oral pyridostigmine is given in syrup form (60 mg/5 ml) at an initial dose of 0.5 to 1 mg/kg every 4 to 6 hours. Treatment for 4 to 6 weeks is usually all that is required. Careful monitoring of pregnant women with MG is critical because there is a 40% chance of disease exacerbation during pregnancy and a 30% risk in the puerperium. Perinatal mortality is approximately 68 per 1000 births, 5 times the risk in uncomplicated pregnancies. Juvenile MG represents the childhood onset of autoimmune MG seen in adults, but there are differences in the presentation (Chiang, Darras, and Kang, 2009). Onset is usually after 10 years of age, and disease manifestations appear before puberty in half the cases. Onset before 1 year of age is exceptional. Pubertal status might affect the clinical presentation, with higher incidence of ocular MG in prepubertal patients and generalized MG in postpubertal patients. Female predominance was observed only after the age of 10 years. As with adults, ptosis is the most common clinical finding, frequently accompanied by ophthalmoparesis (Figure 145-2). Ptosis was unilateral at onset in one-third of juvenile MG patients but subsequently spread to the other eye in nearly



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and edrophonium dramatically improves the motility, the test is considered positive. However, subjective diplopia may not resolve unless edrophonium produces orthophoria in the eyes, which is rare. Significant improvement in dysarthria or in swallowing is another indication of a positive edrophonium test. A mild improvement in limb strength or subjective wellbeing is not sufficient to claim a positive test. In addition, a positive edrophonium test is not specific because transient subjective improvement is reported in other neurologic disorders, such as motor neuron disease and peripheral neuropathy. Details on how to perform this test are located in the online version of this chapter and elsewhere. Positive results on edrophonium testing are seen in up to 90% of juvenile MG cases (Afifi and Bell, 1993).

Electrophysiologic Testing Repetitive Nerve Stimulation Figure 145-2.  Ptosis of the right eyelid in a young woman with juvenile MG. Hypertropia of the left eye is also present.

90% of cases (Afifi and Bell, 1993). Evidence for ptosis and restriction of eye movement can often be found on careful examination. Facial and oropharyngeal weakness are other common findings, producing dysarthria, dysphagia, and difficulty chewing. Facial weakness without ocular involvement is an unusual but recognized presentation of juvenile MG. Extremity weakness can occur and is usually most prominent proximally. Bulbar weakness characterized by slow chewing, dysphagia, nasal dysarthria, and weak cough develops in up to 75% of patients (Rodriguez et al., 1983). Respiratory failure from either diaphragmatic or intercostal muscle weakness or airway compromise related to bulbar dysfunction produces myasthenic crisis, an exacerbation severe enough to endanger life. As in adults, the disease may be generalized at onset, but isolated ocular involvement is a more common presentation, followed by generalization at a later time. However, children with ocular MG appear more likely than adults to remain with purely ocular disease. As many as 85% of adults with ocular MG later go on to develop generalized disease. In children this percentage is closer to 50% to 75% (Afifi and Bell, 1993; Castro et al., 2013).

CLINICAL AND LABORATORY TESTS In most instances the clinician can be confident about the diagnosis of MG based on abnormalities brought out through the neurologic history and examination. However, one or more tests are usually performed to confirm the clinical diagnosis.

Edrophonium (Tensilon) Test The intravenous (IV) administration of up to 10 mg of edrophonium is often the first diagnostic test performed in the evaluation of a potential MG patient. However, the edrophonium test has a number of pitfalls. The most common mistake is that the physician performing the test does not have an objective parameter to measure before and after edrophonium administration. The most useful parameter is the degree of ptosis. The best indication of a positive test is a significant increase in the palpebral fissure aperture or the opening of a completely ptotic eye. If no ptosis is present, the edrophonium test may be difficult to interpret even in clear-cut cases of MG. If the patient has a severe restriction of extraocular movement

The classic electrophysiologic demonstration of an NMJ transmission defect is the documentation of a decremental response of the compound muscle action potential (CMAP) to repetitive nerve stimulation (RNS) of a motor nerve. Decrement is attributable to failure of some muscle fibers to reach threshold and contract when successive volleys of ACh vesicles are released at the NMJ. Failure to reach the threshold EPP to achieve muscle contraction is called blocking. The percentage of decrease in amplitude and area is calculated between the first CMAP produced by a train of stimuli and each successive one. In most laboratories, five or six responses are obtained at 2 or 3 Hz, and the maximal percentage of decrement can be measured at the fourth or fifth response. A decrement of greater than 10% is considered a positive RNS study. In some patients, a decremental response can be demonstrated at baseline; in others, it is only observed after a brief period of exercise and improves after rest (Figures 145-3 and 145-4). As with the edrophonium test, RNS does not have to be performed on every MG patient if the diagnosis is certain based on clinical findings and a positive AChR-antibody.

Single-Fiber Electromyography Single-fiber electromyography (EMG) is a more sensitive measure of neuromuscular transmission than RNS and can be considered in select children. In MG the time required for the EPP at the NMJ to reach threshold is extremely variable. The measurement of this variability in the EPP rise time is known as jitter. The jitter value, calculated in microseconds, is the most important piece of data obtained from single-fiber EMG. Everyone, including healthy individuals, has some degree of jitter. Myasthenic patients have increased jitter values. In addition, blocking occurs in myasthenics if a muscle fiber’s EPP never reaches threshold and depolarization does not occur. The frequency of blocking, expressed as a percentage, is also determined with single-fiber EMG. In healthy individuals the percentage of blocking is 0%. Single-fiber EMG is undoubtedly the most sensitive test for MG in adults. It is abnormal in 94% of generalized and 80% of ocular MG patients. However, single-fiber EMG has several disadvantages. It is a tedious and lengthy study that requires considerable patient cooperation and is poorly tolerated by many children. Stimulated single-fiber EMG can be performed under sedation, requires less patient cooperation, and may be preferred in children, although it is still a lengthy procedure. An abnormal single-fiber electromyographic study is not specific for MG because increased jitter commonly occurs as a result of other neuromuscular diseases, including motor neuron disease, peripheral neuropathy, and many myopathies. Fortunately, it is seldom necessary to perform single-fiber

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PART XVII  Neuromuscular Disorders Resp NPamp NParea (#) (%chg) (%chg) 1 0.0 0.0 2 –13.5 –20.2 3 –25.1 –32.9 4 –27.2 –36.7 5 –27.4 –36.7

5.0 mV

Baseline

A

2 ms Immediately post 10 sec exercise

Resp NPamp NParea (#) (%chg) (%chg) 1 0.0 0.0 2 –3.6 –6.1 3 –4.9 –7.3 4 –6.4 –7.2 5 –6.1 –8.1

B Figure 145-3.  Repetitive nerve stimulation (RNS) of the ulnar nerve at 3 Hz, recorded from the adductor digiti minimi. A, Baseline, abnormal amplitude decrement of 27%. B, Immediately after 10 seconds of exercise the decrement has resolved, demonstrating repair. NPamp, negative peak amplitude; NParea, negative peak area; Resp, response.

vated titers, but this is not an indication to continue immunosuppressive therapy.

Anti-MuSK Antibodies Since 2001, IgG from 40% to 70% of seronegative generalized patients has been found to bind to the extracellular domain of muscle-specific receptor tyrosine kinase (MuSK). Marked female predominance with mean age of onset in the fourth decade has been typical, although pediatric cases have been reported. Three main patterns of anti-MuSK MG have been observed; one of them is clinically indistinguishable from anti-AChR generalized MG. The other two patterns are severe oculobulbar weakness and prominent neck, shoulder and respiratory involvement largely sparing ocular musculature. In these two phenotypic variants limb strength is relatively intact. Anti-MuSK antibodies are rarely seen in pure ocular MG. We consider testing for anti-MuSK antibodies in all suspected MG patients who are AChR-antibody negative. Anti-MuSK MG is somewhat more refractory to conventional treatment compared with anti-AChR MG. Treatment.  Most patients with juvenile MG who require maintenance therapy are treated with anticholinesterase agents with or without a variety of immunosuppressive medications. Pyridostigmine is recommended as an initial intervention. As with the adult form of the disease, corticosteroids and other immunomodulatory treatments are used, although few randomized controlled clinical trials have been performed in the pediatric MG population. Thymectomy plays an important role in treating older children at most centers. Plasmapheresis and IV gamma globulin (IVIG) are generally reserved for more refractory patients or for those in myasthenic crisis. Plasmapheresis and IVIG are also used to maximize function before thymectomy. As mentioned previously, short-term supportive care and anticholinesterase agents are usually adequate for neonatal transient MG.

Acetylcholinesterase Inhibitors EMG to diagnose MG in children. It is probably most useful in children who present difficult diagnostic dilemmas and who otherwise have normal laboratory studies for MG.

Antibody Testing Anti-AChR Antibodies Finding elevated AChR-antibody levels in the serum of a suspected MG patient is the most specific and reassuring diagnostic test. When the AChR-antibody assay is positive, it can be argued that no other diagnostic studies for MG are needed. Thus the clinician who is initially making the diagnosis is often in the position of performing the edrophonium and electrophysiologic tests while awaiting the serologic results. AChR-antibody levels are not elevated in all MG patients. The assay is most helpful in adult generalized MG; it is positive in 85% of such patients. Ocular MG patients, however, have a measurable AChR-antibody in only 50% of cases. Children represent another group of MG patients who are often antibody negative. In one study, 50% of prepubertal children with autoimmune juvenile MG were seropositive. Seropositive rates of 68% and 91% were observed in peripubertal and postpubertal disease onset, respectively. Similarly, seropositivity was more common in girls with onset of juvenile MG after 11 years of age. Seronegativity was more common in pure ocular forms, mild disease, and remission (Afifi and Bell, 1993). AChR-antibody titers correlate poorly with MG severity. Indeed, MG patients in clinical remission may still have ele-

In juvenile MG the aggressiveness of management should be in accordance with disease severity. In general, management attempts should first focus on pyridostigmine. A total daily dose up to 7 mg/kg a day is delivered in 5 to 6 divided doses. Typical doses in older children and adults are 60 mg 3 to 5 times a day. If symptoms are poorly controlled on a pyridostigmine dose exceeding 300 mg/day, it is probably necessary to add immunomodulating therapy. Although weakness, a nicotinic receptor side effect, is relatively uncommon, muscarinic side effects occur frequently. The most common of these are gastrointestinal cramps and diarrhea. Oral hyoscyamine sulfate, glycopyrrolate, and over-the-counter loperamide can be prescribed on an as-needed basis or prophylactically with selected pyridostigmine doses to minimize these side effects.

Thymectomy When a child’s symptoms can no longer be controlled by anticholinesterase agents alone, a decision must be made regarding whether to pursue thymectomy or immunosuppressive therapy. There is a general consensus that generalized MG patients between puberty and 60 years of age benefit from thymectomy. However, randomized studies of thymectomy that control for medical therapy have never been performed. The use of thymectomy in very young children, in itself, is controversial because of concerns for a subsequent impairment in immune protection or an enhanced risk of cancer. A review of incidental thymectomy and thymectomy as treatment for MG in young children, however, did not find a



Acquired Disorders of the Neuromuscular Junction

Baseline

Immediately post-exercise

Resp NPamp (#) (%chg) 1 0.0 2 2.3 3 1.3 4 3.4 5 7.0

NParea (%chg) 0.0 0.3 0.2 –0.8 2.8

2 min post-exercise

Resp NPamp NParea (#) (%chg) (%chg) 1 0.0 0.0 2 –11.0 –12.6 3 –18.6 –18.7 4 –16.6 –16.9 5 –19.2 –19.2

Immediately post 10 sec exercise

Resp NPamp (#) (%chg) 1 0.0 2 –9.6 3 –13.1 4 –12.4 5 –12.2

B

5.0 mV

A

Resp NPamp NParea (#) (%chg) (%chg) 1 0.0 0.0 2 –7.1 –9.2 3 –8.5 –12.6 4 –10.1 –15.9 5 –6.0 –14.0

1101

2 ms 1 min post-exercise

Resp NPamp NParea (#) (%chg) (%chg) 1 0.0 0.0 2 –9.1 –10.5 3 –13.9 –17.6 4 –12.6 –19.4 5 –9.1 –15.8

C

D 4 min post-exercise

Resp NPamp NParea (#) (%chg) (%chg) 1 0.0 0.0 2 –15.1 –16.1 3 –23.0 –24.1 4 –23.0 –23.9 5 –24.7 –26.1

E

NParea (%chg) 0.0 –12.5 –16.8 –15.3 –15.0

F

Figure 145-4.  Repetitive nerve stimulation (RNS) of the ulnar nerve at 3 Hz, recorded from the adductor digiti minimi. At baseline (A) there is only a borderline decrement at response 4. After exercise, a 12% to 13% decrement develops immediately (B) at 1 minute (C) postexercise, and this worsens at 2 and 4 minutes (D and E), demonstrating postexercise exhaustion. After 10 seconds of brief exercise (F), the decrement improves. NPamp, negative peak amplitude; NParea, negative peak area; Resp, response.

consistent association between thymectomy and these proposed risks in children older than 1 year. Thymectomy has been widely used for the treatment of juvenile MG, showing a higher likelihood of remission when performed within 2 years of symptom onset compared with nonsurgical patients. Transsternal, transcervical, and thoracoscopic procedures are all performed and have all demonstrated benefit in clinical trials. Several studies have suggested benefit anywhere from 3 to 10 years after surgery. Favorable predictors for postoperative remission included surgery during the first year after disease onset, bulbar symptoms, onset of symptoms between ages 12 and 16 years, and the presence of other autoimmune disorders. The presence of a thymoma is, of course, the one absolute indication for thymectomy. All newly diagnosed MG patients must undergo computed tomography or magnetic resonance imaging of the chest to search for thymoma. Routine chest radiographs may not detect up to 25% of thymic tumors. Although there is a consensus among neurologists that thymectomy should be considered in all but the youngest children with generalized MG who are not controlled on anticholinesterase agents alone, there is less enthusiasm for the procedure in pure ocular MG.

Corticosteroids Prednisone continues to be used as an immunosuppressive agent of first choice in MG. Despite its many potential side

effects, prednisone is considered by many to be the most effective oral immunosuppressive agent for the treatment of MG. Although corticosteroids can potentially suppress the immune system in a variety of ways, the exact explanation for the beneficial response in MG is unknown. Typically, oral prednisone is initiated at 1 to 1.5 mg/kg daily. If clinical improvement occurs in the first 4 weeks, the patient can be immediately switched to an alternate-day dose of 1 to 1.5 mg/kg. Daily regimens extending beyond a month must be followed by a slower alternate-day taper. If corticosteroid therapy is initiated at moderate to high doses, an improvement is usually apparent in 2 to 3 weeks. The main concern when initiating prednisone therapy at these doses is the transient worsening that occurs in one-third to one-half of patients. The mechanism may involve a direct effect of corticosteroids to impair NMJ transmission. Thus an advised practice is to admit MG patients to the hospital for 5 to 7 days when initiating high-dose prednisone therapy. If the patient remains stable over this interval, the patient can be safely discharged on oral prednisone. After significant improvement is observed, there should not be a rush to taper off the prednisone. Most patients remain on alternate-day dose prednisone for at least 6 to 8 months. When beginning the taper, it is best to proceed slowly by reducing the dose no faster than 5 mg every 2 weeks. When the patient’s dose has been reduced to 20 mg every other day, tapering at an even slower rate is advisable. Although an attempt should be made to fully taper the patient off

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prednisone, it is not uncommon for patients to require lowdose therapy (5–10 mg every other day) for many years or indefinitely. The side effects of corticosteroids are well appreciated and significant (Andrews, 2004). Children should be closely monitored for cataracts, hypertension, diabetes mellitus, weight gain, growth retardation, and cognitive or affective disturbance. Adverse effects of corticosteroids on early stages of bone mineralization and development are also of concern, emphasizing the need for “steroid-sparing” strategies in children who are refractory to tapering.

Azathioprine Azathioprine (Imuran), an antimetabolite that blocks cell proliferation and inhibits T lymphocytes, has been used more frequently in recent years because of the side effects associated with corticosteroids. Most reports describe its use in adults. It is used most often in patients who have a relapse on prednisone or who have been on prednisone for lengthy periods in the hope that the steroid dose can be decreased or eliminated. Azathioprine is also used at times as a first-line immunosuppressive agent instead of prednisone. Retrospective studies of azathioprine therapy have demonstrated that 70% to 90% of MG patients improve regardless of whether or not it is used as a first- or second-line immunosuppressive drug. However, the clinical response is slow, not appearing for 12 months or more. Thus if a patient already on pyridostigmine is quite weak and a rapid response is required, azathioprine is not a practical choice. The initial dose of azathioprine in children should be no more than 25 to 50 mg daily for 1 week. If there are no side effects, the dose is increased to a target level of 2 to 3 mg/kg per day. Although azathioprine is generally well tolerated, there are three important and limiting side effects. Approximately 10% of patients have an idiosyncratic systemic reaction within the first several weeks of therapy that consists of fever, abdominal pain, nausea, vomiting, and anorexia. When the drug is stopped, the symptoms resolve quickly. If the patient is rechallenged, the symptoms invariably recur. In addition, patients can develop leukopenia and hepatotoxicity. Blood counts and hepatic enzymes need to be monitored monthly. If the white blood cell count falls below 4000 cells/mm3, it is advisable to decrease the dose. If it falls below 3000 cells/ mm3, medication should be temporarily withheld until the cell count normalizes. Similarly, medication should be temporarily withheld if there is evidence of hepatocellular dysfunction. Although the patient can be rechallenged after the laboratory values normalize, toxicity often recurs, requiring discontinuation of the drug. Patients should be evaluated for thiopurine methyltransferase (TPMT) deficiency because this may lead to severe myelosuppression. Azathioprine dosing needs to be adjusted in hepatic and renal impairment, and potential interactions with other medications should be considered on initiation. Late development of malignancy following chronic use of azathioprine is a concern (Andrews, 2004).

Cyclosporine Cyclosporine (Sandimmune, Neoral) is an accepted option for immunosuppressive therapy in adult MG. Data are not available on its use in juvenile MG, although it is frequently used in pediatric transplant patients. Cyclosporine inhibits helper T lymphocytes and allows the expression of suppressor T lymphocytes. It blocks the production and secretion of interleukin-2 by helper T cells. Cyclosporine has been subjected to randomized, double-blinded, placebo-controlled trials in MG. These studies demonstrated that cyclosporine was more effective than placebo in improving MG when a

quantitative MG scale was used as the primary efficacy measure. Corticosteroid doses could be reduced after cyclosporine was initiated. The onset of clinical benefit for cyclosporine is 1 to 2 months. This is somewhat faster than azathioprine and slower than prednisone. Doses for cyclosporine range between 4 and 6 mg/kg per day in two divided doses. Side effects include hirsutism, tremor, gum hyperplasia, paresthesias, and hepatotoxicity. Hypertension and nephrotoxicity are the main limitations to therapy. Over one-quarter of adult patients taking cyclosporine had serum creatinine levels increase between 30% to 70% above baseline levels, and 11% of them also developed skin cancers. Such high rates of neoplasia have not been reported in other studies. Blood pressure, renal function, and trough plasma cyclosporine levels are monitored monthly. A similar medication, tacrolimus, has also been widely used in adult patients with MG with success.

Mycophenolate Mofetil Mycophenolate mofetil (MM; CellCept) is another immunosuppressive agent commonly used in practice at MG centers, having shown initial promise in several uncontrolled, open series demonstrating favorable responses in two-thirds of adult patients. MM had a relatively rapid onset of action, with improvement observed at a mean of 9 to 11 weeks and maximal improvement by approximately 6 months. However, in some subjects the initial response was delayed up to 40 weeks. With its more rapid onset of action and favorable side-effects profile, MM began replacing azathioprine as the first-line “steroid sparer” in many MG centers. Unfortunately, two randomized controlled studies failed to demonstrate additional efficacy for MM when added to prednisone. Study design may have been at fault in these negative trials. MM blocks inosine monophosphate dehydrogenase, resulting in selective inhibition of B and T lymphocyte proliferation by blocking purine synthesis. It has been well tolerated in the MG population. The most common adult dosing regimen is 1 gm by mouth twice daily, although doses up to 3 gm a day have been used. It is used in the pediatric transplant population at doses of 600 mg/m2 twice daily. Children with body surface areas greater than 1.5 gm/m2 are dosed at 1 gm twice daily. Main side effects are diarrhea, vomiting, increased risk for infection, and leukopenia, which is relatively uncommon. Complete blood counts are checked weekly for the first month and then less frequently. Long-term safety for MM is still in question, but there have been rare reports of primary central nervous system (CNS) lymphoma with use of MM in MG.

Cyclophosphamide The use of cyclophosphamide (Cytoxan), a nitrogen mustard alkylating agent that blocks cell proliferation, is mainly reserved for refractory MG patients, but its reported use is limited. One study reported 42 adults who had been treated with cyclophosphamide; 23 were also on prednisone. At the time of the retrospective data analysis, 25 of the 42 patients became asymptomatic, and 12 were in complete remission off all medications. Eight of 10 children with juvenile MG improved when cyclophosphamide was added to regimens including azathioprine and corticosteroids. The high rate and severity of toxicity are the drawbacks for cyclophosphamide. In one study, alopecia occurred in 75%, leukopenia in 35%, and nausea and vomiting in 25%. The increased risk of bladder and lymphoreticular malignancy with prolonged administration of cyclophosphamide should be of particular concern. As a result, cyclophosphamide should be considered only in the most refractory cases of juvenile MG.



Plasmapheresis Plasma exchange is primarily employed in the short-term, acute management of severe disease, including crisis, and in readying weak patients for thymectomy. Plasmapheresis removes pathogenic antibodies from the circulation of MG patients, with improvement measured in several days rather than weeks for corticosteroids and months for immunosuppressive agents. Two other circumstances in which plasmapheresis is considered include the treatment of severely weak patients admitted for initiation of prednisone therapy and as a chronic intermittent therapy in patients with refractory disease. Plasmapheresis has been life-saving in some children. Generally a course of plasmapheresis consists of four to six exchanges in which approximately 50 ml/kg of plasma are removed at each treatment. Decisions regarding the number of exchanges and total amount removed are largely driven by the status of the patient, including clinical response and tolerability of the hemodynamic shifts from the procedure. Improvement is often seen within 48 hours after the first or second exchange. Treatments are usually administered every other day or on no more than 2 of 3 consecutive days so that a full course is completed in 7 to 10 days (Andrews, 2004). The main limitations of plasmapheresis are (1) IV access— a double-lumen catheter is required in younger children; (2) complications, including pneumothorax, hypotension, sepsis, and pulmonary embolism; (3) the expense of the procedure; and (4) the relatively brief clinical benefit, which persists for only a few weeks.

Intravenous Immunoglobulin Over the last two decades, IVIG has been used by neurologists for various immune-mediated neuromuscular diseases, including MG, in which response rates of approximately 75% were observed in early retrospective series. Although no studies have focused on the pediatric population, children and adolescents have responded favorably to IVIG (Andrews, 2004). The initial dose of IVIG is usually 2 g/kg. This can be given over 2 to 5 days. When given over the shorter interval, the infusion runs nearly continuously. A common practice is to then schedule two or three subsequent infusions of 0.4 to 1 g/ kg at 2- to 4-week intervals. Patients are then reevaluated to determine whether further treatments are needed. Advantages of IVIG over plasma exchange include relative ease of administration and favorable side-effects profile in both children and adults. Headache, transient flu-like symptoms, and hyperactivity are the adverse events most common to the pediatric population. Migraine patients are prone to develop a severe headache related to aseptic meningitis. Major complications are observed in up to 5% of adults, including cardiovascular, cerebrovascular, and deep venous thrombotic events; congestive heart failure; and acute nephrotoxicity.

Drugs to Avoid Children, like adults with MG, are sensitive to nondepolarizing neuromuscular blocking agents. Intermediate-acting nondepolarizing blockers such as atracurium and vecuronium should be used with care. It is advisable to administer small increments of these agents, using neuromuscular monitoring as a guide. Other commonly used drugs known to exacerbate MG or interfere with neuromuscular transmission are listed in Box 145-2.

Lambert–Eaton Myasthenic Syndrome Lambert–Eaton myasthenic syndrome (LEMS) is an acquired autoimmune disorder of neuromuscular transmission in

Acquired Disorders of the Neuromuscular Junction

1103

BOX 145-2  Drugs That May Worsen Myasthenia Gravis or Interfere With Neuromuscular Transmission ANTIBIOTIC AGENTS • Aminoglycosides • Erythromycin • Tetracycline • Penicillins • Sulfonamides • Fluoroquinolones • Clindamycin • Lincomycin • Telithromycin ANESTHETIC AGENTS • Neuromuscular blocking agents • Lidocaine • Procaine ANTICONVULSANT AGENTS • Phenytoin • Mephenytoin • Trimethadione CARDIOVASCULAR DRUGS • Beta blockers • Procainamide • Quinidine RHEUMATOLOGIC DRUGS • Chloroquine • D-Penicillamine MISCELLANEOUS • Iodinated contrast • Chlorpromazine • Corticosteroids • Lithium

which there is an autoimmune attack on voltage gated calcium channels (VGCC) on the presynaptic nerve terminal, ultimately resulting in a reduction in presynaptic release of ACh and defective neuromuscular transmission.

Clinical Features LEMS begins gradually and is characterized by fatigability and weakness in a limb-girdle distribution. Unlike MG, patients may note that the weakness is worse soon after awakening, and better later in the day. While exercise can transiently improve strength, persistent exertion causes fatigue. Cranial nerve and respiratory involvement is less common than in MG. Patients also have autonomic involvement including dry mouth and eyes, impotence, blurred vision, and orthostasis (Sanders, 2003). On examination, there is a limb-girdle pattern of weakness and reduced or absent deep tendon reflexes. In only about 50% of patients can one convincingly demonstrate improvement in strength or reflexes after brief exercise. A malignancy is present in approximately 50% of adult LEMS patients. The tumor is usually a small-cell carcinoma of the lung, but other malignancies such as renal cell carcinoma and hematologic tumors occur. Malignancy is more common in men than in women, and is more likely in the setting of chronic smoking or after age 50 years. LEMS can be the presenting manifestation of a small-cell carcinoma, and can precede the detection of the tumor by months. Patients with small-cell carcinoma tend to have a more rapidly

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progressive course than those without malignancy, with dysarthria, difficulty chewing, weakness, dry mouth, and impotence appearing earlier in the disease course. LEMS is only rarely described in children.

Diagnostic Tests A diagnosis of LEMS is often first suggested by findings on nerve conduction studies and repetitive nerve stimulation (RNS). The classic electrophysiologic triad of LEMS is as follows: (1) low-amplitude compound muscle action potentials (CMAPs) that increase dramatically after brief exercise, (2) decremental response at low rates of RNS (2–5 Hz), and (3) incremental response at high rates of RNS above 20 Hz. Diffusely reduced CMAPs on routine motor nerve conduction studies should raise suspicion of LEMS. Antibody testing in LEMS for antibodies to P/Q-type VGCC is readily available and is positive in a large majority of patients with this disorder.

Treatment As with MG, treatment of LEMS should be individualized, tailored according to clinical severity, underlying disease, and life expectancy. Upon confirmation of the diagnosis, an extensive search for an underlying malignancy is imperative. This should begin with radiologic studies and may require bronchoscopy. Initial treatment should be directed against the malignancy because this may improve neurologic manifestations. When no malignancy is found, repeat screening every 6 to 12 months is advised, especially in patients at greater risk. Aggressive immunotherapy is easier to justify in LEMS patients without cancer because there is concern that such agents may adversely affect management of malignant disease by interfering with normal immunosurveillance. In general, a trial of pyridostigmine is the first pharmacologic intervention, although it is often of limited benefit. Ideally, drugs that enhance the presynaptic release of ACh vesicles should be used (Sanders, 2003). 3, 4-diaminopyridine (3, 4-DAP) increases the duration of the presynaptic action potential by blocking outward potassium efflux. This indirectly prolongs the activation of VGCC and increases calcium entry in nerve terminals. Most patients tolerate the drug well, and side effects such as paresthesias tend to be minor. There is a risk of seizures when daily doses exceed 100 mg. Usually doses up to 20 mg three times a day are used. Expert recommendations for laboratory monitoring include liver function tests, complete blood count (CBC), blood urea nitrogen (BUN), and creatinine every 3 months for the first year and then less frequently. There are only a few clinical studies of immunosuppressive therapy in LEMS. Plasmapheresis, corticosteroids, and azathioprine can be effective in both neoplastic and nonneoplastic LEMS. IVIG has also been effective. In general, the regimens and doses for the immunotherapies outlined for MG can be applied to LEMS. Response to immunosuppression tends to be less dramatic for LEMS than for MG.

Botulism Botulism is caused by a toxin produced by Clostridium botulinum, a gram-positive anaerobic organism found commonly in soil and agricultural products. Eight immunologically distinct toxins have been identified, with most human cases caused by types A, B, or E (Cherington, 2004). Recovery time varies between toxin types; for instance, type A toxin produces more persistent paralysis than types B and E. After binding irreversibly to receptors on presynaptic nerve terminals, the toxin is translocated across the membrane and blocks the calciumdependent release of ACh. The action of the toxin appears

independent of calcium entry. The impaired release of ACh results in failed neuromuscular transmission. The damage to nerve terminals may be permanent, resulting in a prolonged clinical recovery believed to be dependent on the formation of new neuromuscular junctions. Infantile botulism, first described in 1976, is now the most common form of the disease, representing over 70% of approximately 110 annual cases in the United States.

Infantile Botulism Most reported cases of infantile botulism in the United States occur in California, Pennsylvania, and Utah, states with high counts of C. botulinum spores in the soil. After spores of C. botulinum are ingested, they germinate and propagate in the gastrointestinal tract, producing toxin in vivo. Consumption of honey and corn syrup has been associated with infantile botulism, but in most cases the source of infection is not evident. Infantile botulism typically presents between 6 weeks and 9 months of age, often heralded by the onset of severe constipation. A descending paralysis with cranial nerve palsy, poor suck, feeble cry, and reduced facial expressions ensues, followed by limb weakness. The child appears hypotonic, with ptosis, decreased extraocular motility, sluggish pupillary light responses, facial diplegia, weak suck, and a reduced gag response. Deep tendon reflexes and spontaneous bowel sounds are reduced. There is usually no associated fever. Both respiratory and autonomic compromise may occur. The diagnostic approach should consider other possible etiologies, including systemic infection, tick paralysis, organophosphate poisoning, Guillain-Barré syndrome, congenital myopathies, and autoimmune and congenital myasthenic conditions. Electrophysiologic studies support a presumptive diagnosis of botulism while waiting for the bacteriologic studies to return. Sensory nerve conduction studies are normal. Compound muscle action potential amplitudes are normal to reduced, with preserved motor conduction velocities. Repetitive stimulation will confirm a presynaptic defect in neuromuscular transmission. Decremental responses are variably seen on slow rates of repetitive nerve stimulation, but increments are present at rapid rates (20–50 Hz). Fibrillation potentials are seen on EMG in approximately 50% of infants, and shortduration, low-amplitude motor units in over 90%. Diagnosis is confirmed by isolation of the organism or toxin in stool samples. Toxin isolation is accomplished by the mouse neutralization test, usually performed at state health departments. Polymerase chain-reaction assays are increasingly available. In infantile botulism, the toxin is only rarely found in serum. Treatment of infantile botulism is generally supportive, with complete recovery requiring several weeks to months. Botulism immune globulin, approved by the U.S. Food and Drug Administration (FDA) in late 2003, reduced the hospital stays for both ventilated and nonventilated children. Overall, median hospital stays fell from 40 to 23 days. Case-fatality rates of hospitalized patients in the United States are below 5%. Nasogastric or parenteral nutrition is needed if the child is unable to drink or eat. Mechanical ventilation may also be required. Aminoglycosides and other agents that impair neuromuscular transmission should be used with extreme caution. The length of hospitalization averages 4 weeks, but some infants may require supportive care for as long as 5 months.

Foodborne Botulism The classic form of botulism almost always follows ingestion of food contaminated by preformed toxin. The classic presentation is the development of bulbar symptoms, including blurred vision, diplopia, ptosis, dysarthria, and dysphagia within 12 to 36 hours after ingestion of the contaminated



food. A descending pattern of weakness follows and, in some cases, respiratory paralysis. Supportive care measures have improved survival rates, and nearly full recovery is expected for surviving patients. Treatment with antitoxin mainly plays a role in this form of botulism, but it is not likely to be effective unless administered in the first 24 to 48 hours; the antitoxin does not reverse established paralysis. Beneficial effects are more likely with type E toxin (Cherington, 2004). Use of antitoxin remains controversial because of the lack of efficacy in some cases and the 20% risk of serious allergic side effects related to the equine source. The incidence of hypersensitivity increases further with polyvalent antitoxin. Antitoxin is obtained from the Centers for Disease Control and Prevention (CDC) in Atlanta.

Wound Botulism Wound botulism appears 4 to 14 days following infection with C. botulinum. Although considered rare, an increasing number of cases have been recognized in drug abusers. Wound botulism can be severe, with ventilatory support required in a majority of patients. The organism can be isolated directly when an obvious wound is present. Wound debridement, appropriate antibiotic therapy, and supportive care are the keys to management. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Afifi, A.K., Bell, W.E., 1993. Tests for juvenile myasthenia gravis: comparative diagnostic yield and prediction of outcome. J. Child Neurol. 8, 403–411. Andrews, P.I., 2004. Autoimmune myasthenia gravis in childhood. Semin. Neurol. 24, 101–110. Castro, D., Derisavifard, S., Anderson, M., et al., 2013. Juvenile myasthenia gravis: a twenty-year experience. J. Clin. Neuromuscul. Dis. 14, 95–102.

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Cherington, M., 2004. Botulism: update and review. Semin. Neurol. 24, 155–163. Chiang, L.M., Darras, B.T., Kang, P.B., 2009. Juvenile myasthenia gravis. Muscle Nerve 39, 423–431. Grob, D., Brunner, N., Namba, T., et al., 2008. Lifetime course of myasthenia gravis. Muscle Nerve 37, 141–149. Meriggioli, M.N., Sanders, D.B., 2009. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 8, 475–490. Millichap, J.G., Dodge, P.R., 1960. Diagnosis and treatment of myasthenia gravis in infancy, childhood, and adolescence: a study of 51 patients. Neurology 10, 1007–1014. Rodriguez, M., Gomez, M.R., Howard, F.M., Jr., et al., 1983. Myasthenia gravis in children: long-term follow-up. Ann. Neurol. 13, 504–510. Sanders, D.B., 2003. Lambert-Eaton myasthenic syndrome: diagnosis and treatment. Ann. N. Y. Acad. Sci. 998, 500–508.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 145-1 Diagram of the NMJ. Fig. 145-5 Recruited single-fiber EMG of the extensor digitorum communis muscle. Fig. 145-6 Recruited single-fiber EMG from the extensor digitorum communis in a patient with MG. Fig. 145-7 Treatment algorithm for MG. Fig. 145-8 RNS of the ulnar nerve, recorded from the abductor digiti minimi in a patient with LEMS. Table 145-1 Quantitative Myasthenia Gravis Scale Table 145-2 Myasthenia Gravis Activities of Daily Living Scale Box 145-1. Myasthenia Gravis Foundation of America (MGFA) Classification System

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146  Duchenne and Becker Muscular Dystrophies Kevin Flanigan

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. The muscular dystrophies comprise a clinically and genetically heterogeneous group of disorders, the most common of which are the allelic X-linked recessive disorders, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Both occur because of mutations in the DMD gene, encoding the dystrophin protein, and are thus known as dystrophinopathies. In general, the more severe DMD is associated with an absence of the dystrophin protein, whereas the milder BMD is associated with the presence of a partially functional dystrophin protein. Both states result in dystrophic changes in muscle, a term that refers to chronic and severe myopathic changes, including muscle fiber degeneration and regeneration but also fibrosis and fatty replacement of muscle fibers. The severity and tempo of these changes differs between DMD and BMD, but these features play a prominent role in the loss of muscle function, as noted by Guilliame Duchenne de Boulogne when he described paralysie musculaire pseudohypertrophique ou paralysie myosclérosique. Despite the association of his name with the syndrome, a compelling case has been made that the English physician Edward Meryon provided an earlier description of the syndrome in 1852, and claim has been made for the primacy of an even earlier description by the Italian physician Gaetano Conte in 1836. The German neurologist Peter Becker first proposed what we now know as BMD as a “benign variant” in 1952. The more severe DMD is also the more common dystrophinopathy. A DMD incidence of 1 in 3500 live male births is frequently cited, with a citation trail leading to a 1991 estimate of population frequency in a Northern English population. However, newborn screening studies have demonstrated an incidence ranging from around 1 : 3802 to 1 : 6391, with an incidence of around 1 : 5200 found in a recent U.S. study. BMD is about one third as common, with an estimated incidence of around 1 in 18,500 male births. Rarely, DMD mutations may result in a third form of dystrophinopathy: X-linked dilated cardiomyopathy (XLDC), in which skeletal myopathy may be entirely absent. As the DMD gene is found on chromosome Xp21, the dystrophinopathies typically affect only boys, although rare cases in females occur explained by unusual genetic mechanisms such as balanced chromosomal translocations; most often, carriers are asymptomatic, although exceptions can occur.

The Dystrophin Protein The dystrophin protein consists of multiple functional domains. In the 427-kDa muscle-specific isoform (Dp427m), the N-terminus contains an actin-binding domain (ABD1) canonically described as critical to dystrophin function, participating in binding to the filamentous F-actin of the cytoskeleton. A central rod domain consists of 24 spectrin-like repeats, and 4 hinge regions. Within this region are found a second actin-binding domain and a binding site for neuronal nitric oxide synthase (nNOS). A C-terminal cysteine-rich domain mediates binding to β-dystroglycan at the sarcolemmal membrane. Anchored by a complex of four sarcoglycan proteins (mutations in any of which cause a limb-girdle

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muscular dystrophy), β-dystroglycan binds the extracellular α-dystroglycan, which in turn is engaged in glycosylationdependent binding to extracellular matrix ligands and in particular to laminin α2. Distal to the dystroglycan-binding region are binding sites for additional proteins, including dystrobrevin and syntrophin. Based on this structure, a standard model of dystrophin function has been developed in which it plays a critical role as a stabilizer of the muscle membrane in the setting of significant deformational forces generated by muscle contraction. In the absence of dystrophin, the muscle membrane is damaged, as seen clinically by elevations of the muscle enzyme creatine kinase (CK) in serum. Elevated CK is typically the first biochemical sign of the disease detected by clinicians. Simultaneously, calcium influx into the muscle fiber leads to activation of calcium-dependent proteases, initiating myofiber degeneration, followed by cycles of regeneration and fibrosis and eventual loss of muscle contractile function. However, the presence of binding sites for nNOS, dystrobrevin, and syntrophin suggests that dystrophin has a significant signaling role as well. In contrast to the absence of dystrophin resulting in DMD, the protein resulting from BMD mutations retains some of these functions, resulting in the milder phenotype. Shorter isoforms utilize promoters found in intronic regions, but generally share the same C-terminal domains. Of particular clinical relevance are the dystrophin isoforms Dp140 and Dp71, which are predominant in brain; as discussed below, mutations that result in absent expression of these isoforms are related to increased cognitive impairment in DMD patients.

The “Reading Frame Rule” DMD is nearly always associated with an absence of dystrophin expression, whereas BMD is associated with expression of a partially functional protein (Figure 146-1). At the level of gene mutations, the difference between an absent or a partially functional dystrophin is explained by the concept of the “reading frame rule.” As discussed under Molecular genetic testing, the majority of mutations responsible for dystrophinopathies consist of exonic deletions. The reading frame rule states that the number of exons deleted is not the primary determinant of disease severity. Rather, mutations that disrupt an open reading frame—commonly termed “out-of-frame” mutations—lead to termination of translation, no protein expression, and DMD. In contrast, mutations that maintain an open reading frame—or “in-frame” mutations—lead to BMD (Figure 146-2). Most often, these are single or multiple exon deletions that result in internal deletions of some portion of the central rod domain, and allow translation of the protein that still binds F-actin and β-dystroglycan. As a result, some patients with quite large deletions, particularly of the spectrin repeat–containing central rod domain, can have relatively mild disease. This rule has proven useful in understanding phenotypic differences, with a sensitivity of 93% to 96% in predicting



DMD in large series (Flanigan et al., 2009). Importantly, it also provides a pathway for therapeutic approaches for DMD. Two examples discussed below include virally mediated microdystrophin gene therapy and antisense oligonucleotide exon-skipping therapy, both of which are directed toward expression of internally deleted dystrophin proteins from in-frame BMD-like transcripts. Exceptions to the rule occur, and are discussed in more detail in the Molecular Diagnostic section below.

Clinical Features Duchenne Muscular Dystrophy Boys with DMD typically present with symptoms between 2 and 5 years of age. Parents most commonly describe abnormal gait, often as toe walking immediately on gait acquisition, but gait onset may also be delayed. Recent studies show measurable differences in motor function in infants. Symptoms may only be obvious to parents in retrospect—sometimes noted only after a younger sibling is noted to show more rapid motor development—but delayed motor and developmental function can be demonstrated within the first years of life. Delayed language acquisition may be the presenting sign of DMD, and boys with language delay should have a CK level checked as part of their assessment. By the time of presentation to the specialist, proximal weakness is typically evident to an examiner. At ages when isolated strength testing is unreliable, examination shows difficulty in climbing stairs or hopping. Attempts to arise from the floor typically elicit the Gowers’ maneuver (Figure 146-3), which, although not specific (as it may be seen in the setting of any disease causing pelvic girdle weakness), is always eventually seen in DMD: a supine boy will roll over into quadruped, spread his base of support, raise his buttocks into the air before his trunk, and place one hand or both hands on his knees and walk his hands up his thighs to thrust into an upright position. Muscle enlargement is common, particularly in the calves. Originally termed “pseudohypertrophy” by Duchenne, such enlargement is often attributed to increased fibrosis and fatty replacement, but true hypertrophy of the contractile mass of muscle fibers also occurs. At presentation, heel cords are typically tight, and mild lordosis is present. Neck extension strength is often normal but the neck flexors are particularly weak, in contrast to BMD, in which neck flexor strength may be relatively preserved. Given their gait abnormalities, boys with DMD are often first referred to orthopedic physicians, or physical therapists rather than neurologists as part of their diagnostic odyssey. The clinical course in DMD after diagnosis is stereotyped. Strength may show improvement, and motor function typically improves into the sixth or seventh year, followed by a plateau in function that may last 12 to 18 months. Thereafter, weakness progresses and leads inexorably to wheelchair dependence. This loss of ambulation historically occurred, in the precorticosteroid treatment era, by the age of 12 years (although, steroid treatment has moderately altered the natural history of disease). Wheelchair dependence is followed by progressive arm weakness, which limits independent function. It is also followed by a progressively increased risk of ventilatory insufficiency, scoliosis, and cardiomyopathy, and without supportive ventilatory therapy, death historically occurred by the age of 20 years—a figure altered by current care standards. Arguably the best predictor of disease severity in an individual patient is the clinical course of an affected male relative carrying the same mutation. Such comparisons must take into

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account different treatment practices, but families with significant differences in severity between affected individuals are rare. Few clinical tests help provide prognostic information. Importantly, the level of CK elevation is not predictive of the severity of the phenotype, but rather reflects the phase of the disease process. In addition to motor symptoms, cognitive impairment is common in DMD patients. IQ is diminished by one standard deviation in comparison to normal controls and in general does not change with age. Language development is delayed, and although the verbal IQ does improve, difficulties with expression may occur. Combined with dysarthria because of tongue hypertrophy, this may make communication challenging with age. Boys with DMD are also at an increased risk of autism, attention-deficit/hyperactivity disorder, and obsessivecompulsive disorder. Measuring progression of skeletal muscle dysfunction is important both for clinical trials and to predict the loss of function in clinical care (see Ch. 137). In general, boys with DMD improved by most measures until the age of 7 years, after which their function begins to decline. Timed functional tests in common usage include the time to rise from the floor, the time to complete a 10-m walk/run, the time to climb a standard set of 4 stairs, and the distance covered during a 6-minute walk test (6MWT). Among these, the 10-m walk and time to rise from the floor are particularly useful in the clinic setting, as a boy taking greater than 12 seconds to walk 10 m or unable to rise from the floor is highly likely to lose the ability to ambulate independently within 1 year. The 6MWT has become the current de facto standard as both a stratification tool and an outcome measure in clinical trials. A 30-m change on the 6MWT is considered the minimal clinically significant change in the DMD population, and among DMD boys those walking less than 350 m are at a high risk for a significant functional decline within 1 year, and those walking less than 1000 U/L as a neonate, then typically rises to 20,000+ (>100× normal values) in childhood, but then declines as muscle mass is lost; as a result, the serum CK level may be normal in end-stage disease. No other clinical laboratory values besides serum CK is particularly useful in making the diagnosis. However, it is very important for clinicians to be aware that the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels are always elevated in dystrophinopathies, as these enzymes are found in muscle in addition to the liver. In the setting of unexplained transaminase elevations, the serum CK should always be checked before liver biopsy. The serum level of the liver-specific gamma-glutamyl transferase has proven to be a useful marker of liver injury in the dystrophinopathy population. In assessing renal function in the DMD patient, serum creatinine or creatinine clearance may be decreased because of diminished muscle mass, and cystatin C is a more appropriate clinical marker of renal dysfunction.

Molecular Genetic Testing DMD Mutation Analysis.  Mutation analysis of the DMD gene has largely replaced muscle biopsy as the first diagnostic test performed after serum CK testing. Testing of genomic DNA derived from lymphocytes is readily available. Detailed mutational analysis now represents the standard of care, not only because it may provide prognostic information, but also because it facilitates genetic counseling and potentially more importantly may determine suitability for specific novel therapies. Notably, DNA confirmation of an obligate carrier status is not required in the setting of a clear X-linked history consistent with that state. However, one third of DMD cases are de novo (consistent with the Haldane rule for an X-linked lethal disorder). Genetic counseling is essential, in part to address the risk of germline mosaicism in mothers whose lymphocyte DNA analysis is negative (up to 10%). The DMD gene is, in genomic terms, the largest gene identified. Because it consists of 79 exons spread over 2.2 million bases, mutation analysis has historically been challenging. Eight different promoters have been identified, resulting in a variety of isoforms that share the same C-terminal portion of the protein. The most abundant in muscle is 427 kDa (Dp427m), but other isoforms are found in brain, retina, and in a wide variety of tissues.

Around 65% of all dystrophinopathy mutations consist of a deletion of one or more exons, and because males are hemizygous at the DMD locus, a polymerase chain reaction (PCR)–based test can readily detect the absence of exons. As exon lesions are clustered around “hotspots” within the gene, a limited number of exons (25 to 28) could be tested to determine whether there was a deletion. This multiplex PCR test identified 98% of patients with deletions (Beggs et al., 1990), but did not necessarily identify the full extent of the deletion, nor could be used for determining carrier status or identifying duplications. In addition, it could not identify point mutations, such as nonsense mutations, missense mutations, or small insertion/deletion mutations. This now archaic test has been superseded by methods that interrogate all exons for copy number change, allowing complete characterization of the exon range of all duplication and deletions, as well as identification of carriers of these mutation classes. Several such methods exist, including multiplex ligation-dependent probe amplification, and comparative genomic hybridization. Clinically, the specific method used is not as important as the fact that these methods interrogate all exons, which not only confirms the extent of deletions or duplications but also has the additional benefit of allowing the identification of those rare patients with complex exon duplications or deletions (i.e., affecting noncontiguous blocks of exons). Such modern methods are typically paired with a reflex test for direct sequence analysis of all exons by either Sanger or next-generation sequencing in patients without an exon copy number change to detect point mutations. Nearly all point mutations are individually rare and random mutations, meaning that they do not occur in hotspots and sequencing must be performed across the entire coding region. The distribution of DMD mutation classes varies slightly in different cohorts, but in an unselected clinic cohort of 68 index cases, exonic deletions accounted for 65% of mutations and exonic duplications for 6%; nonsense mutations for 13%; missense mutations for 4%; and small insertions/deletions for 3%. Some reported cohorts are enriched for a single mutation class because of their recruitment design, but a similar distribution of mutation classes is seen in other large aggregate collections of patients. With these modern methods of mutation analysis, the sensitivity of mutation detection in the peripheral blood– derived genomic DNA samples is approximately 93% to 96%. Patients for whom there is a strong index of suspicion but no detectable mutation on genomic DNA analysis require muscle biopsy. This allows confirmation of the diagnosis of the dystrophinopathy (by analysis of dystrophin expression) and provides muscle tissue for mRNA extraction, necessary for detection of mutations that escape detection by current clinical blood-based assays. The standard mutational methods result in the sequencing of both exons and flanking introns, but many dystrophinopathy patients without detectable mutations within these regions have deep intronic mutations that activate cryptic splice sites and result in the inclusion of intronic sequence as a “pseudoexon” within the mRNA. Sequencing of cDNA generated by reverse transcription PCR is required for diagnosis of pseudoexon mutations and for clarification of other unusual mutations such as exon inversions, for which standard mutational analyses may prove inadequate. It is important for clinicians to recognize that exceptions to the reading frame rule do exist, and complicate prognostication based on mutation analysis alone. One such example consists of large in-frame deletions that encompass a large part of the ABD1 domain and extend the central rod domain, and may be associated with DMD. More commonly, predicted nonsense mutations—which, by definition, should result in no dystrophin expression—may instead alter exon splice



definition elements, including exon splice enhancer or exon splice suppressor sequences. Among predicted nonsense mutations, 14% are associated with BMD, nearly all of which affect pre-mRNA splicing. These mutations are found within the exons flanked by two exons that would maintain an openreading frame, typically with the regions spanning exons 23 to 42; the resulting mature mRNA includes some proportion that excludes the nonsense-containing exon, with resultant dystrophin expression. Particularly in the absence of an informative family history regarding the implication of a given mutation, prognostication or phenotypic classification cannot rely solely on the results of mutation analysis, but must take into account the entire clinical picture, including age at presentation, consistency of the examination with the predicted phenotype, and, if available, the results of any dystrophin expression studies on muscle biopsy.

Genotype-Phenotype Correlations All mutations that ablate expression of the Dp427m isoform result in skeletal muscle degeneration, and with the exception of some mutations in which some variability of splicing may result in low levels of reading frame restoration, the specifics of the mutation do not significantly influence skeletal muscle phenotype. However, in nonmuscle tissues, mutations may influence symptoms; for example, mutations that ablate expression of the shorter dystrophin isoforms that are expressed in brain (Dp140, Dp71) result in a higher frequency of cognitive impairment (Pane et al., 2012). When a mutation results in an open reading frame, allowing expression of a partially functional dystrophin, symptom severity may be related to the presence or absence of specific domains, such as in BMD because of in-frame rod domain mutations where cardiomyopathy onset occurs earlier in deletions affecting the amino-terminal portion of the rod domain than in those affecting the latter portion of the rod domain. Observations from patient mutations confirm the importance of the reading frame rule while providing templates for therapeutic approaches. The identification of a mildly affected BMD patient with a very large central rod domain deletion lends credence to the potential of mini- or microdystrophin approaches for viral gene therapies. The large in-frame deletion of exons 45 to 55 may result in X-linked dilated cardiomyopathy (XLDCM) without any significant limb weakness, or may result in relatively mild BMD; either outcome suggests the utility of a therapy directed at inducing exon skipping to result in the equivalent mRNA. Besides variation caused by underlying alternative splicing, notable exceptions to the reading frame rule can result from alternative translational initiation. Another is the only DMD founder allele mutation described in North American families.

Muscle Biopsy The histopathologic features in DMD and BMD are not specific to the dystrophinopathies. The degree of changes depends in part on age of the patient, the muscle sampled, and where the patient lies in the disease course. In DMD patients without dystrophin, myofiber necrosis, phagocytosis, and regeneration are present from an early age, along with fibrosis and fatty replacement leading eventually to end-stage pathology. NF-kB is upregulated in DMD in infancy, before fibrosis becomes evident. In BMD, the degree of pathology is often less severe, particularly in earlier phases of the disease, where more moderate variation in myofiber size may be seen, and fibrosis may be less prominent; however, with time many BMD muscles in older patients appear indistinguishable from

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DMD muscles, correlating with weakness rather than a specific clinical classification. The importance of muscle biopsy in the diagnosis of the dystrophinopathies has declined as robust and complete mutational analysis has become available. Nevertheless, absent or altered dystrophin expression can provide an unequivocal diagnosis, and as previously noted, muscle biopsy is still required to establish the specifics of the mutational mechanism in some patients. Dystrophin protein expression can be assessed by either immunofluorescent (IF) or immunohistochemical (IHC) staining of muscle sections, or by immunoblot analysis of homogenized tissue, or by Western blot (WB) analysis (see Figure 146-1). The standard clinical practice is to perform IF or IHC staining with three antibodies, with one directed to each of the N-terminal, C-terminal, and central rod domains, as utilization of a rod domain antibody alone may give a false result in patients with in-frame deletions of exons coding for the epitope. Reproducible and specific quantification of dystrophin expression is technically challenging, and is routinely performed only in research settings. In routine clinical practice, dystrophin expression is typically expressed qualitatively. Biopsies of DMD muscle frequently demonstrate revertant fibers—found in up to 50% of biopsies—which are clusters of fibers with significant dystrophin expression that occurs because of altered mRNA splicing resulting in some mRNA with an open reading frame, resulting in the expression of dystrophin. Western blotting can provide information regarding protein size, and quantitative estimates, although absolute values as cutoffs of DMD versus BMD have not been rigorously validated.

Management of DMD and BMD Although the dystrophinopathies commonly present because of skeletal muscle symptoms, multiple systems are affected. DMD uniformly progresses to include cardiomyopathy, impaired ventilation because of diaphragmatic and thoracic muscle weakness, diminished bone density (exacerbated by corticosteroid therapy), and gastrointestinal dysmotility. Once a boy is wheelchair dependent, cardiac and ventilatory dysfunction become more severe, scoliosis typically supervenes, and the need for adaptive therapies becomes more important. Management may be facilitated by provision of care within a multidisciplinary clinic, and published standards of care describe consensus recommendations (with an updated version in preparation) (Bushby et al., 2010a,b). At a minimum, DMD patients should be seen yearly by a neurologist or rehabilitation physician, a cardiologist, a pulmonologist, physical and occupational therapists, and a nutritionist (see also Ch. 152). Additional input may be required from endocrinologist, orthopedic surgeons, social workers, and palliative care specialists.

Pharmacologic Management Corticosteroids.  The mainstay of medical therapy for DMD is the corticosteroids prednisone and deflazacort. These are the only medications that have been shown to affect the clinical course, with a consensus that treatment with some corticosteroid regimen results in preservation of ambulation by up to 1 to 3 years. Their precise mechanism of their effect is unknown, but postulated effects include membrane stabilization, diminished fibrosis, and decreased inflammatory responses. A seminal randomized placebo-controlled trial of prednisone demonstrated that treatment with 0.75 mg/kg per day resulted in improved muscle strength by 6 months, whereas a dose twice that showed no additional benefit, with significantly more side effects. Deflazacort at an equivalent dose of 0.9 mg/ kg per day has equivalent efficacy but a potentially a less

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pronounced side effect profile, with less weight gain. However, both drugs are associated with significant side effects, including obesity, gastrointestinal bleeding, osteoporosis (leading to increased vertebral body and long bone fracture, with the latter leading to a risk of fat embolism syndrome), short stature, delayed puberty, Cushingoid features, hypertension, cataracts, glaucoma, and emotional lability. Alternative regimens have been utilized in an effort to minimize side effects, including dosing on a schedule of 10 days on/10 days off or for the first 10 days a month. A small study of weekend dosing at 10 mg/ kg per week divided on weekend days suggested efficacy roughly equivalent to daily dosing in terms of efficacy, but showed no significant decrease in side effects. These different regimens have not been well characterized in head-to-head clinical trials, but the ongoing NIH-sponsored multicenter, multiyear FOR-DMD randomized double-blinded trial will likely answer outstanding questions regarding relative efficacy and side effects among these alternate regimens. Despite decades of use, several issues regarding corticosteroid therapy exist. One is at what age to initiate corticosteroid therapy with treatment. Published recommendations suggest starting therapy between 2 and 5 years of age in boys whose strength has plateaued or is declining, but earlier treatment may be more beneficial. A second concern regards dose adjustments; in common practice most physicians do not adhere strictly to a 0.75-mg/kg dose of prednisone over years but instead allow the per-kilogram dose to drift down depending on tolerance and side effects. A third issue relates to the optimal use of corticosteroids after loss of ambulation, as there is increasing evidence that the use of low-dose steroids in nonambulant boys may result in diminished scoliosis and improved ventilation. Cardiac.  All patients with DMD eventually develop cardiomyopathy, the clinical importance of which is arguably increasing as ventilatory and orthopedic care continues to improve. Although a typical age of onset is often described as around 14 to 15 years, the incidence may be as high as 25% by age 6 years and 59% by 10 years. Screening echocardiograms are recommended at diagnosis or by age 6 years, then every 2 years up to age 10, and yearly thereafter. Cardiac MRI is increasingly available, and may demonstrate fibrosis and diastolic dysfunction before systolic dysfunction is noted. Cardiomyopathy is typically treated with afterload reduction, using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, with evidence that drugs should be initiated even before echocardiographic abnormalities are detected. Cardiac conduction disturbances are frequent, and the use of regular Holter monitoring may be helpful. In BMD, cardiomyopathy is also frequent, and may be severe, even necessitating cardiac transplantation, often when the skeletal muscle phenotype is more modestly affected. Pulmonary.  Pulmonary insufficiency remains the major cause of mortality, with impairment in vital capacity and airway clearance frequently leading to significant morbidity. Respiratory therapy and nocturnal ventilatory support have played key roles in extending life expectancy and improving quality of life in patients with DMD (LoMauro et al., 2015). The use of mechanical insufflator/exsufflator devices is associated with decreased pulmonary infections, and their use should be considered routine in this population. Loss of forced vital capacity becomes noticeable after loss of ambulation, and all patients in a wheelchair should be considered for yearly sleep studies and institution of bilevel positive airway pressure support.

Non-pharmacologic Management Spine/Scoliosis.  Scoliosis ultimately affects the majority of boys with DMD, accelerating after loss of ambulation.

Orthopedic consultation should be considered for boys with scoliosis notable on examination, with yearly progression assessed by x-rays. Historical retrospective data from a single clinic suggest that spine stabilization surgeries in appropriate patients, combined with nocturnal ventilation, are sufficient interventions to prolong survival into the fourth decade. Contractures.  Early institution of the use of nighttime anklefoot orthoses (AFOs) decreases the development and progression of heel cord contractures. Dynamic splints may be preferred over fixed AFOs, as they reduce contracture progression by stretching the ankle joint and maintaining ankle position over several hours. A dynamic splint has the potential to provide a passive muscle stretch throughout the night, whereas a solid brace will maintain the ankle in a 90-degree position. Use of daytime ankle bracing is generally not recommended, as they may interfere with gait deviations that are compensatory for pelvic girdle and the extensor weakness. Other muscle groups prone to contracture and targeted for passive stretching are the iliotibial band, hip flexors, hamstrings, and elbow and finger flexors. Surgical release of Achilles tendon contractures is generally not advised when the child is still ambulatory, and may even lead to premature loss of ambulation.

Recent Advances in Dystrophinopathy Therapeutics Multiple approaches toward correcting the pathologic features of dystrophinopathy are in development, and some are near or have reached clinical trials. These include therapies directed toward upregulation of the dystrophin surrogate utrophin, toward diminishing fibrosis, or toward modulating nNOS (which is mislocalized in muscle in the absence of dystrophin). Many of the most promising potential therapies that have already reached clinical trials are directed toward correcting the fundamental defect in DMD by inducing expression of a corrective (i.e., at least partially functional) version of the dystrophin protein (Figure 146-4). Nonsense suppression therapies alter ribosomal recognition of premature stop codons, as first demonstrated with gentamicin treatment in the mdx mouse, which carries a nonsense mutation in exon 23. Gentamicin treatment of nonsense mutation associated DMD patients—accounting for around 15% of all mutations—is not practical, despite a small proofof-principle study. The orally available nonsense suppression agent ataluren has demonstrated promising clinical efficacy into early phase clinical trials, and received conditional approval in Europe. Exon skipping therapies are based on the reading frame rule, and seek to alter pre-mRNA splicing such that an exon flanking an out-of-frame exonic deletion excluded from the mature mRNA resulted in an in-frame transcript encoding a BMD-like protein. Targeting of a given exon may restore the reading frame for several different out-of-frame mutations; for example, exclusion of exon 51 will restore the reading frame for deletions of 13 to 50, 29 to 50, 43 to 50, 45 to 50, 47 to 50, 48 to 50, 49 to 50, 50 alone, 52 alone, and 52 to 63. Because of the clustering of exon deletions around the central rod domain deletion hotspot, targeting a limited number of exons will allow restoration of an open reading frame for a relatively large number of patients. For example, skipping of only four exons would be beneficial to around 35% of patients, including exon 51 (13.0% of patients), exon 45 (8.1%), exon 53 (7.7%), and exon 44 (6.2%), and skipping of up to two exons corrects 83% of DMD mutations. Such skipping has been brought to human trials using antisense oligonucleotides based on two different chemistries,



2′O-methyl phosphorothioate (2′O-Me) antisense oligonucleotides or phosphorodiamidate morpholino oligomers (PMO), in each case with exon 51 as the lead target. Treatment of 12 patients with the PMO eteplirsen resulted, at 48 weeks, in a significant difference in the distance walked in the 6MWT between patients treated with the compound at the start of the study and those who initially received a placebo for 24 weeks before receiving active drug, and at 3 years in a difference between treated patients and historical controls. Similarly, treatment of 53 patients with the 2′O-Me drisapersen for 48 weeks resulted in a significant increase in 6MWT distance walked at 25 weeks in those patients treated with continuous treatment, rather than intermediate treatment or placebo. In 2016, the US Food and Drug Adminstration granted approval for Eteplirsen and denied approval for drisapersen. Studies targeting other exons are underway. Gene transfer is directed toward the delivery of a functional version of the gene to skeletal muscle, and ultimately as well to the heart and diaphragm. Delivery of the full-length DMD gene in naked plasmid form proved inefficient. In contrast, various serotypes of adeno-associated viruses (AAV) show significant tropism for muscle, and can deliver transgenes that remain in the cell as episomal DNA. Because AAVs are limited in the size of transgene they can encapsidate (with a maximum capacity of around 5 kb), microdystrophin transgenes lacking large portions of the central rod domain have been developed. Although an initial trial with an early microdystrophin vector version did not show significant dystrophin expression after intramuscular injection, improved AAV vectors are in development and are reaching clinical trials. Other approaches: In addition to these gene-directed therapies, a variety of other approaches are in or have reached clinical trials, although none have yet gained regulatory approval. Treatment with idebenone, a benzoquinone antioxidant that inhibits lipid peroxidation and stimulates mitochondrial electron flux and cellular energy production, has been shown to slow the decline in peak expiratory flow as percentage predicted, forced vital capacity, and peak cough flow in nonambulant DMD patients. Inhibition of myostatin has been shown to ameliorate disease severity in animal models of DMD. This has led to trials of myostatin inhibition by antibodies or by expression of a transgene expressing the competing protein follistatin, and studies have been published in BMD or are underway in DMD. Another approach is the use of phosphodiesterase type 5 (PDE5) inhibitors such as

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tadalafil or sildenafil to increase nNOS activity in skeletal muscle. Although this has been shown to be promising in animal models and can alter measures of muscle ischemia in DMD patients, it has not yet been shown to have a clinical benefit. Upregulation of the dystrophin paralog utrophin is beneficial in mouse models, and clinical development of a small-molecule upregulator is underway. Other new therapeutics are directed toward antiinflammatory pathways or membrane stabilization. Altogether the breadth of these approaches allows the clinician to offer some optimism to the parents of a child with a new diagnosis, and can appropriately claim that the dystrophinopathies are the subject of intense clinical research with the prospect of meaningful therapies on the horizon. SELECTED REFERENCES Beggs, A.H., Koenig, M., Boyce, F.M., et al., 1990. Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum. Genet. 86, 45–48. Bushby, K., Finkel, R., Birnkrant, D.J., et al., 2010a. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 9, 77–93. Bushby, K., Finkel, R., Birnkrant, D.J., et al., 2010b. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 9, 177–189. Cheuk, D.K., Wong, V., Wraige, E., et al., 2015. Surgery for scoliosis in Duchenne muscular dystrophy. Cochrane Database Syst. Rev. (10), CD005375. Flanigan, K.M., Dunn, D.M., von Niederhausern, A., et al., 2009. Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum. Mutat. 30, 1657–1666. Kamdar, F., Garry, D.J., 2016. Dystrophin-deficient cardiomyopathy. J. Am. Coll. Cardiol. 67, 2533–2546. LoMauro, A., D’Angelo, M.G., Aliverti, A., 2015. Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: current and emerging options. Ther. Clin. Risk Manag. 11, 1475–1488. Matthews, E., Brassington, R., Kuntzer, T., et al., 2016. Corticosteroids for the treatment of Duchenne muscular dystrophy. Cochrane Database Syst. Rev. (5), CD003725. Pane, M., Lombardo, M.E., Alfieri, P., et al., 2012. Attention deficit hyperactivity disorder and cognitive function in Duchenne muscular dystrophy: phenotype-genotype correlation. J. Pediatr. 161, 705–709 e701. Shieh, P.B., 2015. Duchenne muscular dystrophy: clinical trials and emerging tribulations. Curr. Opin. Neurol. 28, 542–546.

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147  Congenital, Limb Girdle and Other Muscular Dystrophies Richard S. Finkel, Payam Mohassel, and Carsten G. Bönnemann

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

Muscular dystrophies (MDs) are prototypic neuromuscular disorders that often present in childhood and are characterized by progressive weakness and loss of motor function. In addition, there is often related cardiac, pulmonary, and musculoskeletal morbidity, and survival may be shortened. All MDs are caused by mutations in genes responsible for the production of proteins essential for contractile, cytoskeletal, signaling, or enzymatic function within the muscle fiber or extracellular matrix. The explosion in molecular genetics over the past three decades has brought a greater understanding of the biologic basis for these disorders and the appreciation that multiple genes, when mutated, can cause a similar phenotype. Conversely, mutations in one gene can cause very different phenotypes. Chapter 135 discusses normal muscle development and the pathophysiologic processes involved in MDs. Common themes to MDs are features of muscle fiber degeneration with inadequate cellular repair, leading to atrophy of these fibers and replacement by fat and connective tissue. As a consequence, muscles lose contractile force and become flaccid, stiff, atrophic, or hypertrophied. This results in loss of function and joint contractures in skeletal muscle, and in some instances impaired cardiac and intestinal (smooth muscle) function. Each MD has distinctive features, for reasons not well understood, where some muscles are more vulnerable and others more resistant to the intrinsic pathologic processes that cause the progressive muscle fiber deterioration. As such, patterns of muscle involvement have been identified over nearly two centuries, and this has led to the current nomenclature. Figure 147-1 presents a classification of the MDs within the overall context of muscle disorders. Chapter 137 discusses more general principles of neuromuscular disorders and Figure 137-2 illustrates the more common MDs. Duchenne and Becker MD (“dystrophinopathies”) are discussed in Chapter 146. Myotonic dystrophies, a distinct category of muscle disease, are discussed in Chapter 151. This chapter discusses the other common MDs with an emphasis on pediatric presentation: • Limb-Girdle MD (LGMD): proximal > distal weakness involving the lower > upper extremities • Congenital MD (CMD): early onset dystrophic process, often with brain and ophthalmologic involvement, abnormal brain myelination, or extracellular matrix collagen abnormality • Facioscapulohumeral MD (FSHD): principal involvement of the facial, scapular, humeral, peroneal, and abdominal muscles • Emery-Dreifuss MD (EDMD): scapular, humeral, and peroneal involvement with early onset of joint contractures and often cardiac involvement • Oculopharyngeal MD (OPMD): ocular, bulbar, and variable proximal shoulder and hip girdle involvement (onset of OPMD is typically in the adult years) To grasp how these conditions are interrelated, it is useful to understand how the various genes and gene products (proteins) function within the muscle fiber as illustrated in

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Figure 147-2. Table 147-1 categorizes these disorders based on the clinical phenotype and related genes, mode of inheritance, and name of the gene product. Each subsection below will address the relevant genes, proteins, mechanisms, and pathophysiology. The inheritance patterns—autosomal dominant, autosomal recessive, and X-linked recessive—are also discussed. Three websites listed in the selected references are particularly useful when a focused search is desired. In addition, the Online Mendelian Inheritance in Man (www.omim.org) and the Orphanet (www.orpha.net) websites provide a broad overview of all genetic conditions. The Gene Tests website (www.genetests.org) provides a comprehensive resource of genetic testing laboratories, by country, where testing for these disorders can be pursued.

DYSTROPHINOPATHIES (DUCHENNE AND BECKER MUSCULAR DYSTROPHIES AND CLINICAL VARIANTS) The dystrophinopathies are reviewed in Chapter 146.

LIMB-GIRDLE MUSCULAR DYSTROPHIES Definition The limb-girdle MDs (LGMDs) consist of a diverse group of disorders within the broader field of genetic muscle diseases. LGMD is defined as a muscular dystrophy presenting with predominantly proximal weakness, sparing facial, extraocular, and distal extremity muscles (at least early in the course of the disease). Muscle biopsy is of great importance for inclusion into this group and shows dystrophic features, including degeneration and regeneration, increased internalized nuclei, fiber size variability, increased endomysial fibrosis, and fatty replacement. However, just mild, nonspecific myopathic changes may also be seen still be consistent with the diagnostic category. Autosomal-recessive LGMDs (type 2) are more common than the autosomal-dominant (type 1) counterparts and will be discussed first in this chapter. Currently, 8 forms of type 1 and 19 forms of type 2 have been described and assigned a number and are summarized in Table 147-1.

Autosomal-Recessive Limb-Girdle Muscular Dystrophies Classic autosomal-recessive LGMDs include the sarcoglycanopathies (LGMD 2C-F), calpainopathy (LGMD 2A), and dysferlinopathy (LGMD 2B). This order reflects their average age of onset from younger to older. Two additional more common autosomal-recessive LGMDs are attributed to mutations in the α-dystroglycanopathy gene fukutin-related protein (FKRP) (LGMD 2I), with a broad range of age of onset, and anoctamine-5 (LGMD 2L), a primarily adult-onset disease that resembles dysferlinopathy. There are a number of additional recessive LGMD forms.



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147 Collagen VI Bethlem Ullrich Myopathy

FKRP-LGMD2I

Laminin-2

POMT1-LGMD2K Fukutin-LGMD2M

LGMD2D LGMD2C

POMT2-LGMD2N

LGMD2F

POMGnT1-LGMD2O

LGMD2E

Caveolin-3 Anoctamin-5

Dysferlin

LGMD1C

LGMD2B LGMD2L

TRIM32

LGMD2H Dystrophin

Emerin

Myotilin LGMD1A

Calpain-3 LGMD2A

Telethonin LGMD2G

Lamin A/C LGMD1B

Titin LGMD2J

Myosin

Actin

Figure 147-2.  Schematic Schematic diagram illustrating a muscle fiber and the cellular localization of the gene products for the limb-girdle and congenital muscular dystrophies, with their associated disorders. DG, dystrophglycan; SG, sarcoglycan. (Reproduced, with permission, from Wicklund MP, Kissel JT. The limb-girdle muscular dystrophies. Neurol Clin 2014;32:729–49.)

Sarcoglycanopathies (LGMD 2C-F) Sarcoglycanopathies were first described as autosomalrecessive disorders resembling Duchenne muscular dystrophy (DMD). In addition to the autosomal-recessive pattern of inheritance, the immunohistochemical presence of dystrophin on muscle biopsy differentiated sarcoglycanopathies from DMD. While initially referred to as SCARMD (for severe childhood autosomal-recessive muscular dystrophy), many patients with milder presentations were subsequently identified and the term SCAMRD is no longer widely used. Sarcoglycanopathies account for 20% to 25% of all patients with muscular dystrophy but comprise roughly 50% to 60% of the more severe LGMDs as opposed to 10% to 20% of the milder forms. Pathophysiology.  See online chapter for discussion. Genetics and Mutations.  Mutations in all four major sarcoglycan genes cause four genetically separate forms of autosomal-recessive LGMD with almost indistinguishable clinical phenotypes. The majority of milder cases in sarcoglycanopathies are related to α-sarcoglycan mutation, including almost asymptomatic patients with high CK levels and lordosis. β- and γ-sarcoglycan mutations have a higher proportion of severe early childhood cases, although significant intrafamilial variability occurs. δ-Sarcoglycan mutations generally are more severe. Clinical Features.  Clinical features of the four sarcoglycanopathies overlap. They predominantly affect young children with a median age of onset around 6 to 8 years.

Time Course and Distribution of Motor Symptoms.  The first symptoms generally relate to pelvic muscle weakness, evidenced by a waddling gait, which limits running, getting up from the floor, or climbing stairs. Primary toe walking may be present. Muscle cramps, pain, and exercise intolerance with or without myoglobinuria can occur. The distribution of weakness is reminiscent of dystrophinopathies. However, unlike dystrophinopathies, anterior and posterior compartments of the thigh may be equally affected. Shoulder girdle weakness ensues. Deltoid, infraspinatus, and biceps muscles are involved early in the disease. Scapular weakness tends to be more pronounced compared with dystrophinopathies (Figure 147-3). Facial and extraocular muscles are spared. Late in the disease, distal muscles may be involved. In later stages and similar to DMD, neck flexor weakness may occur. Loss of independent ambulation may occur around 12 to 16 years of age, although there is variability. CK levels are elevated 10- to 100-fold early in the course of the disease. Cardiac Features.  Cardiac involvement occurs although clinically overt dilated cardiomyopathy is only seen in a minority of patients. Cardiac failure or sudden cardiac death may occur and cardiac transplantation may become necessary. Dilated cardiomyopathy may be more common in γ- and δ-sarcoglycanopathies but cardiac involvement is reported in all sarcoglycanopathies. Subclinical cardiac involvement is more common and noticeable on electrocardiography and echocardiography. Pulmonary Features.  Symptomatic respiratory failure is not an early feature of sarcoglycanopathies. Some patients with severe early onset muscle weakness develop severe restrictive

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lung disease. Clinically relevant respiratory failure does not manifest while the patient is still ambulant. Contractures and Other Signs and Symptoms.  Other associated signs include calf hypertrophy and macroglossia. Achilles tendon shortening tends to be the first sign of contractures and lordosis may occur early in the course, and so toe walking can be an early manifestation. Later, more contractures involving the hip flexors, lateral tractus, and knee flexors may develop. Progressive scoliosis may worsen respiratory compromise later in the disease. Intellectual impairment is not seen.

mild reduction of laminin α2. Although these are not specific, they can be helpful in suggesting appropriate genetic analysis of the FKRP gene.

Diagnosis.  Sarcoglycanopathies can be suspected based on clinical grounds. The probability of an autosomal-recessive LGMD in boys with a Duchenne-like phenotype is 6% to 8%. Definitive histologic diagnosis requires immunohistochemical stains with antibodies against muscle sarcoglycans and dystrophin (Figure 147-4). Histology usually shows marked degeneration and regeneration and severely dystrophic muscle. Dystrophin immunoreactivity is expected to be normal, although it can be reduced similar to BMD or female carriers of a dystrophin mutation. Western blot analysis usually shows dystrophin with a normal molecular weight and quantities within 10% of normal.

See online chapter for discussion.

Treatment.  No specific therapies are available for sarcoglycanopathies but unlike dystrophinopathies, sarcoglycanopathies are more amenable to gene therapy as discussed in the online chapter.

Disorders of α-Dystroglycan Glycosylation Limb-Girdle Muscular Dystrophy 2I: Fukutin-Related Protein Deficiency Fukutin-related protein (FKRP) belongs to the growing list of genes underlying the group of α-dystroglycanopathies, characterized by abnormal O-mannosyl glycosylation of αdystroglycan, which more typically are associated with forms of CMD (Congenital Muscular Dystrophies, below). Mutations in FKRP cause an extremely wide spectrum of phenotypes: ranging from severe Walker-Warburg syndrome (WWS), transitional phenotypes of CMD with variable central nervous system involvement or normal brain imaging, to less severe LGMDs with Duchenne to Becker MD-like like severities that are referred to as LGMD2I. LGMD2I is one of the more common forms of LGMD, representing from 11% to 19% of all cases of LGMD in different series. Clinical Features.  The LGMD phenotype of FKRP mutations can present with severity and distribution of muscle weakness similar to DMD, with early loss of ambulation even before 10 years of age. There is a pronounced predilection for axial muscles, neck flexors, and proximal limb muscles with prominent lordosis. Predominant weakness is typically seen in shoulder adduction and internal rotation, elbow flexion, hip flexion and adduction, knee flexion, and ankle dorsiflexion. Hamstrings are generally more involved than the quadriceps. Mild facial weakness can be seen. Scapular winging is not common. There can be tongue, calf, and brachioradialis hypertrophy. Dilated cardiomyopathy can occur even before the loss of ambulation, whereas respiratory failure necessitating nocturnal ventilatory support manifests after loss of ambulation. Diagnosis.  LGMD 2I may be clinically suspected based on features such as the peculiar hypertrophy of brachioradialis muscle and tongue and the pattern of muscle weakness. Muscle MRI may demonstrate a distinctive pattern of involvement, similar to LGMD2A (calpain-3 deficiency). Muscle biopsy shows prominently reduced α-dystroglycans and also

Management.  No specific treatments are available at this time. Similar to other MDs with a predilection for cardiomyopathy and respiratory failure, recognition, evaluation, and treatment of these complications is of utmost importance.

Other α-Dystroglycanopathies Calpainopathy (LGMD2A) Background and Epidemiology.  Calpainopathy or LGMD 2A is likely the most common juvenile onset form of LGMD and may account for 40% to 50% of all LGMD patients. Pathophysiology, Genetics, and Mutations.  CAPN3, the gene mutated in LGMD 2A, encodes calpain-3, a calciumactivated protease that localizes to the cytoplasm and nuclei of the cells. Clinical Features.  Calpainopathies have a characteristic clinical phenotype although variations and atypical presentations do occur. The age of onset is later than sarcoglycanopathies, between 8 and 15 years of age, with a wide range from 2 to 40 years. Time Course and Distribution of Motor Symptoms.  The first symptoms generally relate to pelvic girdle muscle weakness. Later, shoulder girdle and arm weakness becomes apparent. Minimal facial weakness is reported very late in the disease, and facial, extraocular, and pharyngeal muscles are otherwise spared. Overall, a rather thin-appearing muscle profile, with gluteus maximus and hip adductor weakness, scapular winging and high riding scapulae, wide stance, biceps atrophy, and lax abdominal muscles, is the most typical clinical appearance of patients with calpain-3 mutations (Figure 147-5). The course of the disease is progressive. Loss of independent ambulation occurs around 14 years of age or later. CK concentrations in the serum are significantly elevated. In comparison to sarcoglycanopathies or dysferlinopathies, CK levels tend to be lower on average. Cardiac Features.  No primary cardiac involvement has been attributed to CAPN3 mutations. However, right bundle branch block has been reported. Pulmonary Features.  Respiratory failure is rare, occurring only in patients with severe and very advanced disease. Mild restrictive lung disease evidenced by reduced forced vital capacity is quite prevalent and usually asymptomatic. Contractures and Other Signs and Symptoms.  Contractures appear in the Achilles tendons and may involve the elbows and spine. In some patients, contractures may be severe earlier in the course, mimicking EDMD. Early lordosis may be seen. Diagnosis.  The clinical features can strongly suggest calpainopathy but further studies are needed for confirmation. Muscle imaging may reveal the characteristic distribution of muscle disease with selective involvement of the posterior compartment of the thigh and hip adductors, but such testing should be interpreted with caution. Muscle biopsy may show dystrophic features and type 1 fibers may appear lobulated on the oxidative stains such as NADH. Direct immunohistochemistry for calpain-3 with the current antibodies is not reliable but Western blot analysis can be informative with the calpain-3 level reduced or absent in muscle biopsy immunoblots in most patients. Mutation analysis is the most specific test. Treatment.  No specific therapies are available for calpainopathies. Findings of eosinophilic inflammation in the muscle



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in some LGMD2A patients have raised some interest in the use of immunosuppressive therapies. In mouse models, adenovirus-mediated gene transfer has been successful.

a more specific diagnostic test and can also be attempted and yield diagnostic information. Mutation analysis is the most specific test.

Dysferlinopathy (LGMD 2B)

Treatment.  No specific treatments are available. Judicious use of orthotics can provide help in maintenance of ambulation in many patients.

Linkage studies have identified mutations in DYSF, the gene coding for dysferlin, the protein affected in LGMD 2B on chromosome 2p. DYSF mutations are associated with a number of distinct clinical phenotypes: a typical LGMD, a distal muscular dystrophy known as Miyoshi myopathy, and a third phenotype with early anterior tibial compartment weakness. Even in the limb-girdle phenotype, the phenotypic spectrum is broad. The majority of patients first develop weakness in late adolescence and early adulthood. However, some patients develop a congenital myopathy and some remain only mildly affected well into adulthood. Pathophysiology. (see online) Genetics and Mutations. (see online) Clinical Features.  Compared with sarcoglycanopathies and calpainopathies, dysferlinopathies begin later in life with weakness starting around 18 to 20 years of age but congenital disease or mild adult onset disease have been reported. Weakness is slowly progressive and ambulation is usually preserved typically into the fourth decade. Time Course and Distribution of Motor Symptoms.  In the limb-girdle dysferlinopathy (LGMD2B), the first motor symptoms occur in the pelvifemoral distribution, in particular the quadriceps, and later involve the arms. However, one can detect gastrocnemius and soleus muscle wasting and weakness early in the limb-girdle phenotype as well, causing early inability to walk on toes even in the LGMD phenotype. This unique feature, which can be demonstrated with muscle imaging, can be diagnostically helpful. The pattern of weakness in the arms is usually mild at first and involves the distal biceps. Deltoid and periscapular muscles are often spared and as a result, in contrast to sarcoglycanopathies and calpainopathy, scapular winging is not a usual feature. As in other LGMDs, facial and extraocular muscles are preserved. In the Miyoshi phenotype, the gastrocnemius and soleus muscles are affected first, manifesting as the inability to walk on toes. In the upper extremities, the muscles of the forearms are quite weak, yet the intrinsic muscles of the hand are spared. The proximal muscles are affected as the disease progresses. CK levels tend to be very high during the early, 20 to 150 times the upper limit of normal; in the presymptomatic patients it may only be mildly elevated. Cardiac and Pulmonary Features.  Dysferlinopathies do not feature conductive or functional cardiac disease or restrictive lung. Contractures and Other Signs and Symptoms.  Contractures are not a usual feature of dysferlinopathy. Diagnosis.  The characteristic clinical presentation includes the following features: age of onset around 18 to 20 years, highly elevated CK levels, proximal lower extremity weakness in conjunction with inability to walk on toes, relative sparing of the periscapular muscles, and early gastrocnemius muscle involvement on muscle imaging. However, the significant phenotypic variation, even among family members, can be misleading. Muscle biopsy usually shows dystrophic features but inflammation may be prominent and delay the accurate diagnosis by suggesting myositis. Immunostains for dysferlin are usually absent. However, secondary reductions and staining abnormalities for dysferlin in other dystrophic conditions are not uncommon. Likewise, calpain level may be secondarily reduced or absent in dysferlinopathy. Western blot analysis is

Anoctaminopathy (LGMD2L) Recessive mutations in ANO5 on chromosome 11, the gene encoding anoctamine-5, have recently been linked with a group of adult patients with limb-girdle muscular dystrophy. See online chapter for discussion.

Other Rare Autosomal-Recessive Limb-Girdle Muscular Dystrophies Telethoninopathy (LGMD 2G), LGMD 2H, and titinopathy (LGMD 2J) are rare forms of LGMD that may present in childhood. Further information on these disorders can be found on the resources listed at the beginning of this chapter.

Autosomal-Recessive Conditions Presenting as LGMD Partial Laminin α2 Deficiency.  This condition is allelic to primary laminin α2 deficiency, the form of CMD related to severe deficiency of laminin α2, the heavy chain of the heterotrimer laminin 211 (merosin). Primary mutations in the LAMA2 gene on chromosome 6q are responsible. In case of complete deficiency the clinical phenotype is that of a severe CMD. MRI of the brain may show supratentorial white matter T2 hyperintensities and some children develop seizures. The clinical presentation may be that of a milder CMD or may resemble LGMD with proximal weakness only, in which case, walking may be achieved. Joint contractures can be prominent and resemble EDMD. In these cases, only a partial deficiency of laminin α2 on muscle biopsy specimen is seen. Western blot analysis is a more sensitive measure. Patients with partial laminin α2 deficiency almost always show subtle alterations of white matter signal on T2-weighted MRIs. Patients with the LGMD phenotype usually have a missense mutation or an in frame deletion.

X-Linked Recessive Conditions Presenting as LGMD Some patients with emerin mutations, the protein mutated in classical X-linked EDMD, discussed below, may present with an LGMD-like presentation without cardiac involvement.

Autosomal-Dominant Limb-Girdle   Muscular Dystrophies Autosomal-dominant LGMDs are generally less common and constitute about 10% of LGMDs. They occur later in comparison to autosomal-recessive LGMDs and have a milder or moderate course. Commonly, a positive family history is evident; however, de novo mutations and germline and/or somatic mosaicism account for some patients. In this section we will divide autosomal-dominant LGMDs into two groups: one without cardiac involvement (LGMD 1A, 1C, and 1D) and the other with cardiac involvement (LGMD 1B).

Autosomal-Dominant LGMDs Without Cardiac Involvement Myotilinopathy-LGMD 1A.  Myotilinopathy LGMD 1A mutations have been implicated in myofibrillar myopathy-3—a distal, adult-onset, autosomal-dominant myopathy. Pathophysiology and Mutations.  (see online)

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Clinical Features.  Onset usually is in adulthood (late 20s) with slowly progressive symptoms involving proximal leg and arm weakness. Patients have a particular nasal speech quality and dysarthria. Achilles tendon contractures may be seen. CK values may be raised 1.6- to 10-fold the upper limit of normal. Cardiac and pulmonary involvement is not a typical feature. Diagnosis.  The peculiar clinical feature of nasal speech quality in the setting of an autosomal-dominant LGMD with mildly raised CK values can suggest this diagnosis. Muscle biopsy shows dystrophic features and in some cases autophagic vacuoles; Z-line streaming and disorganization as well as rod-shaped accumulations similar to nemaline myopathies have been reported on electron microscopy. Immunohistochemistry and Western blot analysis usually show normal levels of myotilin. Mutation analysis is usually necessary. Treatment.  No specific therapies are available. Caveolinopathy (LGMD 1C) Pathophysiology and Genetics.  Caveolin-3 mutations, the muscle-specific form of caveolin, result in LGMD 1C as well as other phenotypes. Caveolae contribute to sarcolemmal integrity, regulate ion channels, and play a role in signal transduction among other roles. Most mutations resulting in the limb-girdle phenotype are missense or microdeletions. There is significant reduction of caveolin-3 immunoreactivity in muscle biopsy specimens of heterozygous patients. Clinical Features.  Four different muscle disease phenotypes are recognized: LGMD, rippling muscle disease, asymptomatic CK elevation, and a distal myopathy. There is significant overlap. There is also significant intrafamilial variability without a typical clinical phenotype. Some patients develop weakness in early childhood, whereas others remain asymptomatic. Myalgias and cramping with exertion have been reported. Some patients have calf hypertrophy (Figure 147-6). Definite cardiac or pulmonary involvement is not typically seen. Diagnosis.  Immunohistochemistry of muscle biopsy tissue shows reduced caveolin-3 immunoreactivity. Genetic confirmation is necessary in suggestive cases. Treatment.  Supportive management can be helpful to patients. LGMD 1D.  This particular muscular dystrophy has been genetically linked to chromosome 7q in several families with DNAJB6 mutations. See online chapter.

Autosomal-Dominant LGMDs With Cardiac Involvement Autosomal-dominant LGMDs with cardiac involvement have a close relationship to autosomal-dominant EDMD. Desmin mutations can also present with LGMD-like phenotype (LGMD 1E) and cardiac involvement; however, they are better described as myofibrillar myopathy. Laminopathy (LGMD 1B).  This LGMD is allelic with autosomal-dominant EDMD. Pathophysiology and Genetics.  (see online) Clinical Features.  Whereas the EDMD and CMD forms have onset in earlier childhood, the LGMD presentation of laminopathy usually occurs in the late teens and early adulthood. Most patients develop weakness in the pelvic girdle muscles. Mild facial weakness and mild anterior tibial compartment weakness may be seen. Progression is slow, and biceps and Achilles tendon contractures may develop. CK values are usually mildly elevated, 1.5- to 3-fold. Cardiac Features.  Cardiac problems may manifest in the third and fourth decades with first-degree atrioventricular (AV) block that progresses to complete AV block. Similar to the EDMD and CMD presentations of LMNA mutations, sudden

cardiac death is a prominent risk and may be its first and only manifestation. Dilated cardiomyopathy only rarely occurs. Diagnosis.  Diagnosis is based on suggestive clinical features, the cardiac manifestations, as well as the presence of contractures and an autosomal-dominant hereditary pattern. Muscle biopsy evaluation is not particularly helpful as lamin A/C immunoreactivity appears normal even in the presence of mutations; however, it is helpful to rule out other causes of LGMD. Genetic analysis should be initiated when LGMD 1B is suspected. Treatment.  No specific treatments are available. Careful cardiac evaluation and monitoring is important to evaluate for the need for intracardiac defibrillator placement to prevent fatal cardiac arrhythmias.

Autosomal-Dominant Conditions That May Present as LGMD Facioscapulohumeral Dystrophy (FSHD, See Below).  FSHD is the single most important entity to consider in patients with an LGMD-like presentation, especially those with an autosomal-dominant pattern of inheritance. Myotonic Dystrophy (DM) Types 1 and 2.  Myotonic dystrophy, discussed in Chapter 152, is one of the most common MDs. Patients with myotonic dystrophy, especially DM type 2, may present with a limb-girdle pattern of muscle weakness. Collagen VI–Related Dystrophies.  Collagen VI–related dystrophies constitute a spectrum of severities from the mild Bethlem myopathy, via intermediate severity to the more severe Ullrich CMD. For the differential diagnosis of LGMD, Bethlem myopathy is the most important to consider. Bethlem myopathy is an autosomal-dominant and rarely also a recessive disorder caused by mutations in one of three genes coding for alpha chains of collagen type VI, COL6A1 and A2 on chromosome 21q22.3 or COL6A3 on chromosome 2q37. Ullrich CMD is characterized by severe weakness concomitant with joint hyperlaxity and contractures at birth. Respiratory insufficiency, which may begin before loss of independent ambulation, also worsens over time. As a result, early detection and treatment with noninvasive bilevel positive airway pressure ventilation may be required. There are also patients presenting with phenotypes of intermediate severity (Figure 147-7). Patients in this intermediate phenotype also experience progressive respiratory insufficiency, frequently leading to the need for nighttime noninvasive ventilator support. Diagnosis is clinically suspected based on congenital weakness and concomitant severe contractures and joint laxity. Skin findings with prominent keratosis pilaris of the extensor surfaces of the arms and legs and abnormal keloid formation may be seen (Figure 147-8). Muscle imaging may show a characteristic pattern of muscle degeneration beginning adjacent to the fascia, resulting in the typical rimming of muscles and the “central cloud” in the rectus femoris along its central fascia. Molecular testing is similar for all collagen VI–related phenotypes. Most patients with Bethlem myopathy develop symptoms in childhood and some may have congenital weakness/ hypotonia, torticollis, or foot deformities. Weakness is usually more predominant in the proximal muscles. Early on, there may be no contractures, and joint hyperlaxity may be present. Contractures usually occur at the end of the first decade, involving the deep finger flexors and proximal joints (Figure 147-8), and when absent or minor, the phenotype can resemble LGMD. Diagnosis is usually secured by showing mutations in one of the three genes encoding one of the alpha chains of collagen type VI. Sanger sequencing as well as nextgeneration sequencing is available to screen for mutations in the collagen type VI genes and arrive at a specific diagnosis.



EMERY-DREIFUSS MUSCULAR DYSTROPHY Emery-Dreifuss MD (EDMD) is characterized by a clinical triad of early contractures, muscle wasting, and weakness in a humeroperoneal distribution, and cardiomyopathy. Considerable phenotypic variability exists regarding age at onset and rate of progression. X-linked transmission and autosomaldominant transmission are recognized. Five genes have been identified (Table 147-1). EDMD is included in this section on LGMD because of the phenotypic similarity. Mutations in FHL1 or STA genes also cause EDMD (see online chapter).

Pathophysiology and Genetics Both X-linked and autosomal-dominant EDMD result from mutations in genes coding for nuclear envelope proteins. See online chapter. Autosomal-dominant EDMD and, very rarely, autosomalrecessive EDMD result from mutations of the LMNA gene, located on 1q21, which encodes two nuclear envelope proteins, lamins A and C, discussed above.

Clinical Features Although X-linked EDMD and autosomal-dominant EDMD usually share a similar phenotype, wide clinical variation with poor genotype-phenotype correlation has been documented in both. The onset of contractures occurs early in the disease, in the first or second decade, and often precedes weakness. Contractures are most prominent at the elbows, Achilles tendons, and posterior cervical muscles. Upper-extremity contractures often precede axial and lower extremity deformities. The arms are held in a semiflexed position. The feet are set in talipes equinus, often in association with toe walking. Posterior cervical contractures preclude full neck flexion (Figure 147-9). Contractures usually remain disproportionate to the degree of weakness and may be the major factor in functional impairment. Muscle weakness is relatively mild and slowly progressive. The distribution of motor deficits is humeroperoneal, with upper-extremity weakness (in biceps, triceps, and spinatus muscles) occurring earlier than leg weakness (in tibialis anterior and peroneal muscles). Pseudohypertrophy is not seen, and its absence helps differentiate X-linked EDMD from dystrophinopathy (BMD) clinically. Cardiac symptoms may include palpitations, syncope, and diminished exercise tolerance. Supraventricular dysrhythmias, AV conduction block, ventricular dysrhythmias, and restrictive or dilated cardiomyopathy may evolve.

Diagnosis The diagnosis of EDMD is suspected based upon the clinical phenotype, especially the early onset of joint contractures relative to the degree of weakness, and confirmed by genetic testing for mutations in the LMNA, FHL1, or STA genes.

Management Treatment is based largely on symptoms. The high incidence of cardiac dysfunction mandates early and regular cardiology evaluations. ICD rather then pacemaker should be considered for the arrhythmogenic component of the cardiomyopathy. Mothers and sisters of males with X-linked EDMD should also receive cardiology consultation. Orthopedic interventions may be helpful in addressing limb contractures. In the late stage of EDMD, respiratory aids, including cough-assistive devices and noninvasive nocturnal respiratory support, may be helpful.

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Summary and Approach to LGMD Patients Clinical Features Because of the significant genetic and phenotypic variability of the different LGMDs, a careful family history and examination of family members that may or may not be aware of symptoms can play an important role in narrowing the differential diagnosis. Certain diagnostically helpful clinical features need to be evaluated fully: 1. Age of onset and speed of progression may provide an important clue in patients with suspected LGMD. Earlier onset and a more severe course with elevated CK are suggestive of mutations in the sarcoglycan complex or FKRP. With later childhood-onset symptoms, calpainopathy become more likely. If symptoms first appear in adolescence or early adulthood, a dysferlinopathy should be suspected, especially if the CK levels are extremely elevated. Adult-onset symptoms that are mild with significantly elevated CK may suggest anoctaminopathy, or myotilinopathy if the CK is close to normal. 2. The distribution of muscle weakness, presence or absence of contractures, or muscle groups that are spared can be important clues. Radiologic imaging such as MRI can be helpful in discerning the distribution of myopathy. For a summary of the specific clinical features in the commonly encountered LGMDs, please refer to Table 147-2. 3. The presence or absence of cardiac features can be an important clue, especially in autosomal-dominant LGMDs.

Muscle Biopsy and Protein Studies In LGMD patients, muscle biopsy with routine histochemical stains usually shows dystrophic features with fiber size variability, increased endomysial fibrosis, fatty replacement, as well as myofiber degeneration and regeneration. Immunohistochemistry, in addition to Western blot analysis, can be helpful in many cases. Although assessment against many antibodies can be done, these methods are at best semiquantitative and should be interpreted with caution. Major patterns of immunohistochemical reduction of expression in different LGMDs are summarized in Table 147-2.

Molecular Genetic Testing It is preferable that all diagnoses of genetic LGMDs be confirmed by molecular genetics when available. Availability of whole-exome sequencing and simultaneous sequencing of multiple genes at relatively low cost using next-generation technology has recently provided an alternative to traditional methods and costly panels. However, some mutations with large deletions or duplications are not amenable to detection using this approach. In addition, variations of unknown significance complicate the interpretation of the results in the absence of functional data. As a result, these approaches should be used as a complement to the clinical findings and the molecular and clinical features carefully correlated. It is always important to adequately consider metabolic etiologies, for example, Pompe disease, and acquired muscle diseases as the treatment and genetic implications are so different.

Diagnostic Algorithm The American Academy of Neurology published an evidencebased guideline in 2014 for the diagnosis and treatment of LGMD and distal MDs. The three algorithm tables for autosomal-dominant, autosomal-recessive, and X-linked LGMDs and distal MDs are reproduced as Figure 147-10.

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TABLE 147-2  Characteristic Clinical and Biopsy Findings in the Limb-Girdle Muscular Dystrophies Helpful Clinical Features

Immunohistochemistry and Western Blot

A. Autosomal-Dominant LGMD LGMD 1A (myotilinopathy)

Late onset and milder disease Nasal speech quality Early contractures of the Achilles tendons

Usually normal

LGMD 1B (laminopathy)

Contractures mimicking EDMD but can be minimal Conductive cardiac disease and AV block Early childhood onset possible Common de novo mutations

Usually normal

LGMD 1C (caveolinopathy)

Highly variable May present with isolated elevated CK with none to minimal weakness

Majority of cases with reduced or absent protein

LGMD 2A (calpainopathy)

Juvenile onset (~10 yrs) Early periscapular weakness Muscle wasting and atrophy Hamstrings weakness Sparing of the hip abductors

IHC is not available but WB shows reduction in the majority of cases. Secondary reduction in dysferlin occurs. Eosinophilic myositis has been reported.

LGMD 2B (dysferlinopathy)

Late adolescent onset (~18 yrs) Can present with proximal and/or distal weakness Early gastrocnemius involvement, esp. on MRI Spared periscapular muscles CK levels extremely high

Possible by IHC but WB is more specific. Secondary reductions in calpainopathy occurs. Intramuscular vessels may show amyloid deposits.

LGMD 2C-F (sarcoglycanopathies)

Early childhood onset (6–8 yrs) Similar pattern to DMD/BMD except early scapular weakness Calf hypertrophy very common CK levels very high Cardiomyopathy in a subset

IHC and WB are possible. Pattern of absence of all sarcoglycan proteins may be helpful.

LGMD 2G (telethoninopathy)

Variable clinical phenotype Early anterior tibial weakness and foot drop

IHC and WB are possible.

LGMD 2H

Variable clinical phenotype LE > UE weakness Trapezius and deltoid affected

Not possible

LGMD 2I

Typically mild but early childhood onset seen Weakness in the neck flexors and axial muscles UE > LE weakness Brachioradialis, tongue, and calf hypertrophy Cardiopulmonary disease possible

IHC may show reduced α-dystroglycan and laminin α2 but not specific.

LGMD 2L (anoctaminopathy)

Adult onset Knee flexor and extensor weakness Medial gastroc, hamstring, and quadriceps atrophy, esp. vastus medialis

Not possible Intramuscular vessels may show amyloid deposits.

B. Autosomal-Recessive LGMD

AV, atrioventricular; BMD, Becker’s muscular dystrophy; DMD, Duchenne’s muscular dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; IHC, immunohistochemistry; LE, lower extremity; LGMD, limb-girdle muscular dystrophy; UE, upper extremity; WB, Western blot.

The Jain Foundation website (www.jain-foundation.org) provides a computer-based “automated LGMD diagnostic assistant,” which is a useful resource to narrow the focus of diagnostic considerations in an individual patient.

weakness of the facial muscles, fixators of the scapula, and dorsiflexors of the ankle. Although skeletal muscle symptoms dominate the clinical picture, other systems are often involved, which implies a more widespread developmental/degenerative process.

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

Molecular Genetics

Facioscapulohumeral MD (FSHD) is inherited as an autosomal-dominant disorder with high penetrance and variable expression. Between 10% and 30% of cases represent new mutations. Prevalence is estimated at 2 to 4.5 × 10−5 (refer to Table 137-2 in Chapter 137). Clinical signs and symptoms are usually present before age 20 years and are manifested by

FSHD maps to chromosome 4q35. More than 95% of patients with FSHD have a reduced number of 3.3-kilobase tandem repeat sequences termed D4Z4. See online chapter for additional discussion. Testing for the number of D4Z4 tandem repeats on chromosome 4q35 is the most specific and sensitive diagnostic test for FSHD. Subtelomeric translocations



between chromosomes 4q35 and 10q26 occur relatively frequently in the general population and may complicate molecular diagnosis.

Clinical Features Clinical diagnostic criteria have been established by the Facioscapulohumeral Muscular Dystrophy Consortium. Inclusion criteria specify autosomal-dominant inheritance; bifacial weakness; and weakness of the scapular stabilizer muscles, ankle dorsiflexor muscles, or both. Supporting criteria include asymmetry of motor deficits (a finding far more common in FSHD than any other muscular dystrophy); sparing of deltoid, neck flexor, and calf muscles; and involvement of wrist extensors and abdominal muscles. Hearing loss involving high frequencies and retinal vasculopathy (Coats disease) are additional supportive findings. Exclusion criteria include eyelid ptosis, extraocular muscle weakness, skin rash, elbow contractures, cardiomyopathy, sensory loss, neurogenic changes documented in muscle biopsy, and myotonia or neurogenic motor unit potentials documented on needle electromyography. Weakness is usually appreciated first in the facial muscles. Patients have difficulty with puckering the lips, whistling, sipping through a straw, or blowing up balloons because of weakness of the orbicularis oris muscle. Most patients have a transverse smile and limited facial expression. Weakness of the orbicularis oculi is usually asymptomatic, but the examiner can recognize facial muscle weakness by observing incomplete burying of the eyelashes with forced eyelid closure and the ease with which the closed eyelids can be pried apart. A history of sleeping with the eyes open may be offered by a parent or spouse. Facial weakness may be asymmetric (Figure 147-11). Weakness of scapular fixation is evidenced by scapular winging, accentuated by arm extension. The scapulae ride high on the back, producing the illusion of hypertrophied trapezius muscles. Arm abduction is impaired in the presence of normal power and bulk of the deltoid muscles. Wasting of the biceps and triceps with preservation of deltoid and forearm muscles yields a “Popeye” configuration to the arms. Wasting of the clavicular head of the pectoral muscles produces a reversal of the axillary folds with a deep upward slope. Weakness of lower abdominal muscles may result in a “pot belly” when standing and a positive Beevor sign (cephalad movement of the umbilicus with neck flexion) when the patient lies supine. Lower-extremity weakness is usually evident first in the ankle dorsiflexors, with compromised heel walking or overt footdrop. Atrophy is most prominent in the tibialis anterior muscle. Preservation or hypertrophy of the extensor digitorum brevis muscle clinically excludes a neurogenic etiology of the footdrop. Axial paraspinal muscle weakness may result in marked lumbar lordosis, especially in patients with childhoodonset FSHD. Motor deficits are slowly progressive. Most patients remain functionally independent throughout life. Sensorineural hearing loss is frequently documented, especially in children presenting before 10 years of age, and can often be asymptomatic. Retinal vasculopathy with telangiectasia and retinal detachment (Coats disease) may develop. Symptomatic cardiac disease is infrequently encountered. Restrictive lung disease may be seen in patients with more severe FSHD. Congenital onset of FSHD has been associated with mental retardation and epilepsy in children with the largest D4Z4 deletions. The congenital-onset, or infantile, phenotype is often severe and rapidly progressive, accompanied by sensorineural hearing loss and Coats disease. Profound weakness of facial muscles is typical (Figure 147-11).

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Laboratory Findings Creatine kinase determinations are either normal or slightly elevated; creatine kinase levels exceeding five times the laboratory norms are suggestive of an alternative diagnosis. Genetic testing has largely replaced electrodiagnostic and muscle biopsy evaluations in persons with suspected FSHD.

Diagnosis The American Academy of Neurology published an evidencebased guideline in 2015 for the evaluation, diagnosis, and treatment of FSHD (reference below) (Figure 147-12).

Treatment There is no definitive treatment for FSHD. Results of therapeutic trials of corticosteroids and the β-adrenergic agonist albuterol have been disappointing. Trials of the calcium blocker diltiazem and an industry-sponsored trial of monoclonal antibody directed against human myostatin failed to increase strength or function.

OCULOPHARYNGEAL MUSCULAR DYSTROPHY Oculopharyngeal MD (OPMD) is an adult-onset, autosomaldominant disorder, manifesting after 50 years of age, that maps to chromosome 14q11.2 and is caused by a small trinucleotide GCG repeat expansion. See online chapter.

CONGENITAL MUSCULAR DYSTROPHIES The CMDs are a diverse group of genetically based disorders characterized by early onset of progressive hypotonia, weakness, and a variable degree of muscle contractures. There may be associated dysmorphic or dysmyelinating brain abnormalities and structural eye abnormalities. Signs and symptoms are typically evident in the neonatal period, but may present within the first year of life, before ambulation is achieved. Serum creatine kinase levels are usually elevated. Muscle biopsy abnormalities typically show features of a dystrophic process, with variation in muscle fiber size, degenerating and regenerating fibers, and an increase in endomysial and perimysial connective tissue (refer to Chapter 135). Milder myopathic changes can also be seen initially. Biopsies are also useful to exclude congenital structural or metabolic myopathies. Biopsies from suspected CMD patients should be analyzed in specialized muscle histopathology laboratories that can perform the detailed immunohistochemical staining and interpretation necessary to identify features of dystroglycanopathies, merosinopathy, and collagen type VI disorders. The CMDs are autosomal recessive, with the exceptions of de novo dominant mutations in the lamin A/C gene, and the majority of cases of Ullrich CMD. There is no clear separation of the CMDs from the LGMDs. The latter, in a general sense, have onset after ambulation has been achieved and after 24 months of age. Different mutations within genes causing CMD can also cause LGMD (i.e., allelic heterogeneity). Additional mutations and range of related phenotypes are likely to be discovered that will blur the boundary between the CMDs and the LGMDs. The CMDs are rare disorders, having an estimated overall prevalence of approximately 0.8 to 5.46 × 10−5 (refer to Table 137-2 in Chapter 137). The CMD syndromes have been classified in several ways. An earlier classification of CMDs into two groups of “merosinnegative” and “merosin-positive” is no longer used as the latter group has been better characterized by the identification

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of several genes that comprise this clinical cluster. CMDs can be considered as those with dysmorphic brain and eye changes (“syndromic”) and those with a pure muscle phenotype (“nonsyndromic”). Current classification schema combine clinical features and cellular localization of the gene product into five categories, discussed in more detail below and summarized in Table 147-1: 1. Dystroglycanopathies: 15 glycosyltransferase genes that affect glycosylation of α-dystroglycan, and DAG1 2. Basil lamina disorders: 4 genes—laminin α2 (merosinopathy), integrins α7 and α9, and also incorporating the dystroglycanopathies 3. Extracellular matrix (collagenopathies): 3 collagen type VI genes 4. Nuclear envelope proteins: 2 genes—lamin A/C (LMNA) and nesprin 5. Endoplasmic reticulum: selenoprotein 1 (SEPN1)

Abnormalities of α-Dystroglycan The dystroglycan complex, discussed above in the LGMD section, structurally links the intracellular dystrophincytoskeleton complex to the extracellular matrix (Figure 147-2). Here the discussion will focus on α-dystroglycan (ADG) and its role in CMD. CMD patients with mutations in the dystroglycan gene (DAG1) are extremely rare, as it believed that most of these mutations result in an embryologic lethal condition. The vast majority of ADG-related CMDs are caused by mutations in glycosyltransferase genes responsible for the glycosylation of ADG and are termed dystroglycanopathies. Fifteen such genes have been identified to date (Table 147-1).

Clinical Presentations of the Dystroglycanopathies Current classification in OMIM divides the dystoglycanopathies into three syndromic categories: 1. Muscle-eye-brain phenotypes. This includes WWS, muscleeye-brain (MEB) disease, and Fukuyama CMD. Brain abnormalities involve migrational disorders of the cortex (lissencephaly, polymicrogyria, pachygyria), gross structural defects (absence of the corpus callosum, or vermis of the cerebellum, ventriculomegaly without hydrocephalus), and posterior fossa defects (cerebellar cysts, cerebellar and brainstem hypoplasia). Eye abnormalities range from microphthalmia, retinal degeneration, cataracts, glaucoma, and anterior chamber malformation to mild myopia. 2. CMD with posterior fossa abnormalities but having normal supratentorial structures. These CMD patients may have intellectual disability. 3. LGMD and CMD phenotypes with normal brain MRI.

for fukutin, a protein localized to the basement membrane of muscle. Fukutin deficiency is associated with decreased immunostaining for α-dystroglycan and merosin, with preservation of the dystrophin-related complex. Hypotonia and generalized muscle weakness are usually present before 9 months of age, and 50% of affected infants manifest a poor suck and weak cry. Facial weakness and a tented upper lip are frequent findings. Calf hypertrophy is often present. Gross motor milestones are severely delayed. Affected children often achieve independent sitting, but never gain independent ambulation. Contractures are not marked at birth, but develop by 1 year of age and involve the hips, knees, ankles, and elbows. Mental retardation is often severe. Seizures occur in approximately 40% of affected children. Ocular abnormalities are common but not universal, and include myopia, cataracts, optic disc pallor, and retinal detachment. Creatine kinase levels are increased. Electrodiagnostic studies reveal myopathic potentials on electromyography; nerve conduction velocities are normal. Brain imaging studies and postmortem studies reveal brain malformations, including polymicrogyria, pachygyria, and agyria of the cerebrum and cerebellum (type II cobblestone lissencephaly), with a lack of normal lamination of the cerebral cortex.

MDC1C (Fukutin-Related Protein Deficiency) MDC1C is allelic to LGMD2I, discussed above, caused by mutations in the FKRP gene coding for fukutin-related protein. Symptoms usually manifest at birth or in the first few weeks of life, with hypotonia and leg muscle hypertrophy. Creatine kinase values are greatly increased (1000 to 10,000 IU/L). Children follow a regressive course that may include cardiomyopathy. Routine histochemical analysis of muscle biopsy specimens does not differentiate these patients from children with merosin-negative CMD, but immunohistochemical staining reveals partial merosin deficiency and severely reduced glycosylated α-dystroglycan.

Muscle-Eye-Brain Disease

See online chapter.

The first description of patients with the muscle-eye-brain phenotype were from Finland but the syndrome has now been seen worldwide. Initial reports suggested that POMGNT1 was the gene causing muscle-eye-brain disease. It is now evident that this phenotype may be the result of mutations in other genes along the α-dystroglycan O-mannosyl-glycosylation pathway (Table 147-1). The clinical phenotype may be severe, dominated by neonatal hypotonia, profound developmental delay with psychomotor retardation, and ocular abnormalities. Affected children may attain independent ambulation by age 4 years. Visual failure is in the form of severe myopia, followed by retinal degeneration, glaucoma, and cataracts. Seizures are common. Central nervous system dysgenesis includes lissencephaly type II (cobblestone complex), frontal pachygyria, cerebellar hypoplasia, and occipital micropolygyria. There is severe disorganization of the cerebral and cerebellar cortices. The associated myopathy may be overshadowed by central nervous system and ocular abnormalities. Creatine kinase levels are increased, especially after the first year of life, and electromyography studies show myopathic abnormalities.

Fukuyama Congenital Muscular Dystrophy

Walker-Warburg Syndrome

Fukuyama CMD is the second most common form of muscular dystrophy in Japan, where the carrier frequency is estimated at 1 in 90. The disease is uncommon outside of Japan. Fukuyama CMD is caused by mutations in the FKTN gene coding

WWS has no ethnic predominance. The clinical stigmata are dominated by the most severe brain malformations seen in any CMD syndrome, including lissencephaly type II, hydrocephalus, occipital encephalocele, fusion of the cerebral

Unlike several of the other CMDs and LGMDs, the responsible gene cannot be inferred from the phenotype as many of these glycosyltransferase genes can present with a similar phenotype. Conversely, some of these genes can present with a broad range of phenotypes; for example, FKRP can cause CMD with a severe WWS phenotype or a milder LGMD type 2I.

Muscle Biopsy Features



hemispheres, absence of the corpus callosum, and hypoplasia of the cerebellum and brainstem. Ocular findings have included congenital cataracts, microphthalmia, buphthalmus, and Peter’s anomaly. At birth, affected children are blind, markedly hypotonic, and poor feeders. Myopathy is manifest by mild elevations of the creatine kinase level and variable abnormalities on muscle biopsy. All affected infants manifest profound psychomotor retardation, and the median length of survival is only 4 months. Epilepsy is a common comorbidity. It is now felt that WWS and muscle-eye-brain disease represent a clinical spectrum secondary to multiple mutations in multiple genes rather than distinct diseases.

MDC1D: LARGE CMD caused by LARGE1 gene mutations (MDC1D) is a very rare disorder and is discussed in the online chapter.

Congenital Muscular Dystrophy With Integrin α7 Deficiency Integrins are transmembrane heterodimeric (α/β) receptors crucial in establishing linkages between the extracellular matrix and muscle cytoskeleton. Deficiency of integrin α7 is a very rare disorder and is discussed in the online chapter.

Abnormalities of Extracellular Matrix Proteins MDC1A: Laminin-α2 (Merosin)–Negative Congenital Muscular Dystrophy (“Nonsyndromic Congenital Muscular Dystrophy”) Genetics.  The LMNA gene encodes the extracellular matrix protein lamin α2 (merosin). Laminin α2–negative CMD (MDC1A) is the most commonly diagnosed of the CMD disorders and accounts for about one-quarter of cases of nonsyndromic autosomal-recessive CMDs. Clinical Features.  Patients with complete absence of merosin present as neonates with significant hypotonia and generalized trunk and limb weakness, and may have multiple joint contractures. The upper limbs are often more affected than the lower limbs, which may exhibit muscle hypertrophy. Feeding and respiratory function is usually preserved initially. Small, slow gains in motor function are expected over the first year or two, with maximal milestones usually no better than independent sitting, and occasionally standing with support, but independent ambulation would be exceptional. Flexion contractures develop initially and are followed by a progressive rigid kyphoscoliosis that often necessitates surgical correction. Feeding tubes and noninvasive ventilation support are often needed because of development of dysphagia with aspiration and respiratory insufficiency, respectively. Most patients exhibit normal brain structure, although cystic lesions have been described, and cognitive development is generally preserved. Epilepsy occurs in approximately 30% of patients. Diagnosis.  Serum creatine kinase levels are usually elevated in the neonatal period in excess of 1000 U/L but tend to decrease over years. Characteristic changes are seen in brain MRI scans of merosin-negative CMD patients. These findings may not be evident at birth but invariably become evident by age 6 months. White-matter hyperintensity is most prominent on T2-weighted images and principally involve the centrum semiovale, while sparing other myelinated structures in the corpus callosum, internal capsule, cerebellum, and brainstem. These MRI scans are often misinterpreted as a leukodystrophy. Focal cortical dysplasia of the occipital lobes occurs in some

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cases with concurrent intellectual impairment, but the extensive neuronal migration abnormalities characteristic of patients with syndromic CMD are not seen. Electrodiagnostic studies yield nonspecific myopathic findings on electromyography. Nerve conduction studies reveal slowing of conduction velocity. Muscle biopsy demonstrates changes consistent with a dystrophic process. Absence of immunohistochemical staining for the laminin α2 chain on frozen muscle biopsy or skin biopsy tissue provides confirmation of the diagnosis of merosin deficiency. Genetic testing is necessary to confirm the diagnosis. Partial merosin deficiency has been reported in patients with a less severe childhood-onset or young adult-onset LGMD phenotype. See online chapter.

Merosin-Positive, Nonsyndromic Congenital Muscular Dystrophies This category is no longer used.

Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy They are allelic disorders caused by mutations in any of three collagen 6 genes (COL6A1, COL6A2, and COL6A3). Ullrich CMD and Bethlem myopathy are discussed above in the LGMD section.

Congenital Muscular Dystrophy With Early Rigid Spine Syndrome Rigid spine syndrome (RSS) is characterized by contractures of the paraspinal muscles, which limit spine flexion, especially in the thoracolumbar segments. Onset of RSS in infancy is caused by mutations in the SEPN1 gene. Rigid spine can be seen in other muscle disorders, including EDMD and Ullrich CMD. Infants with SEPN1-related CMD present initially with mild hypotonia and weakness, followed by development of rigid spine and joint contractures, especially the Achilles tendons (Figure 147-13). Despite the spine rigidity, scoliosis typically evolves and may need surgical correction. A thin body habitus with generalized decrease in muscle bulk is typical. Motor milestones are delayed but most children with SEPN1-related CMD eventually achieve and maintain independent ambulation. Restrictive lung disease evolves later in the course and cardiac involvement has not been described. Diagnosis.  Classic features of SEPN1-CMD can lead the clinician directly to request genetic testing for mutations in the SEPN1 gene. The creatine kinase level is typically normal and the muscle biopsy can have subtle dystrophic features or have multiminicores, fiber-type disproportion, or myofibrillar changes with Mallory body–like inclusions. These findings may erroneously focus attention on other congenital myopathies. Treatment.  Management of SEPN1-CMD is supportive.

Lamin A/C-Associated Congenital   Muscular Dystrophy The broad spectrum of neuromuscular and nonneuromuscular disorders caused by mutations in the lamin A/C gene (LMNA) has been outlined earlier in the section describing Emery– Dreifuss MD. A CMD phenotype has also been identified with de novo mutations of the LMNA gene. See online chapter for further discussion.

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Nesprin-Associated Congenital   Muscular Dystrophy This entity is discussed in the online chapter.

Approach to the Patient With an LGMD,   FSHD, EDMD, and CMD Clinical Assessment The following clinical features should be considered when evaluating the patient with a suspected MD: age at symptom onset, distribution and extent of weakness, contractures, rigid spine, muscle atrophy or hypertrophy, microcephaly, eye abnormalities, and seizures. Feeding, respiratory, and cardiac status also should be evaluated. It is important to obtain a careful family history.

Diagnostic Studies Diagnostic testing to consider includes creatine kinase level, electromyography, and nerve conduction studies; muscle biopsy, MR brain, and muscle imaging; and ophthalmology evaluation. The algorithms presented here and in Chapter 137 (Figure 137-1) can then be used to help focus on a small number of diagnoses and guide confirmatory genetic testing.

Treatment Management of these patients is supportive and discussed in more detail in the online chapter. Chapters 152 and 160 provide additional information on these issues. As the molecular genetic basis and related cellular pathophysiology of these disorders become better understood, targeted treatment strategies are likely to be developed. The age of precision medicine for the MDs as with other childhood neurologic disorders is now emerging and offers some hope to these patients. Acknowledgments Drs. Diana M. Escolar and Robert T. Leshner contributed the chapter on muscular dystrophies to the prior edition of this textbook. We thank them for use of portions of their chapter and some figures that have been retained here. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bonne, G., Quijano-Roy, S., 2013. Emery-Dreifuss muscular dystrophy, laminopathies, and other nuclear envelopathies. Handb. Clin. Neurol. 113, 1367–1376. Bonnemann, C.G., Wang, C.H., Quijano-Roy, S., et al., 2014. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul. Disord. 24, 289–311.

Bushby, K.M., Collins, J., Hicks, D., 2014. Collagen type VI myopathies. Adv. Exp. Med. Biol. 802, 185–199. Gene Reviews. Resource from the University of Washington. . Narayanaswami, P., Weiss, M., Selcen, D., et al., 2014. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 83, 1453–1463. Tawil, R., Kissel, J.T., Heatwole, C., et al., 2015. Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 85, 357–364. The Gene Table. Comprehensive compendium of genes identified to cause neuromuscular disorders. . The Washington University neuromuscular center searchable compendium website. . Wang, C.H., Bonnemann, C.G., Rutkowski, A., et al., 2010. Consensus statement on standard of care for congenital muscular dystrophies. J. Child Neurol. 25, 1559–1581. Wicklund, M.P., Kissel, J.T., 2014. The limb-girdle muscular dystrophies. Neurol. Clin. 32, 729–749.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 147-1. Classification of the muscular dystrophies. Fig. 147-3. Two patients with γ-sarcoglycanopathy (LGMD2C). Fig. 147-4. Sarcoglycan immunohistochemistry in a muscle biopsy from a patient with α-sarcoglycanopathy. Fig. 147-5. Calpainopathy (LGMD 2A) in a 14-year-old boy. Fig. 147-6. Calf hypertrophy in a woman and her 7-year-old daughter with caveolinopathy (LGMD1C). Fig. 147-7. Features of Ullrich congenital muscular dystrophy in a 22-month-old boy. Fig. 147-8. Features of Bethlem myopathy with a limb-girdle phenotype. Fig. 147-9. (A) A 16-year-old male with X-linked Emery– Dreifuss muscular dystrophy. (B) Significant neck extensor contractures severely limit neck flexion. Fig. 147-10. Diagnostic algorithms for limb-girdle muscular dystrophy. Fig. 147-11. Features of facioscapulohumeral muscular dystrophy. Fig. 147-12. Diagnostic algorithm for facioscapulohumeral muscular dystrophy. Fig. 147-13. SEPN1-related rigid spine congenital muscular dystrophy is illustrated in this 4-year-old girl. Table 147-1. Classification of the muscular dystrophies Table 147-3. Clinical features of the congenital muscular dystrophies

148  Congenital Myopathies

Jahannaz Dastgir, Hernan D. Gonorazky, Jonathan B. Strober, Nicolas Chrestian, and James J. Dowling

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Congenital myopathies are a clinically and genetically heterogeneous group of neuromuscular diseases. The most common clinical presentation is in the neonatal period as the floppy infant. However, congenital myopathies can present at essentially all life stages, making them an important diagnostic consideration in all individuals with muscle weakness. The prevalence of congenital myopathies is incompletely defined. The most accurate pediatric estimate (from a North American study) is approximately 1 : 26,000, though this is likely a significant underestimation given the increasing recognition of the condition and the delineation of an expanded range of clinical phenotypes considered under the congenital myopathy umbrella (North et al., 2014). Historically, congenital myopathies have been diagnosed and defined based on features observed on muscle biopsy. The first congenital myopathy described, central core disease (CCD), was by Shy and Magee in 1956. The most common histopathologic subtypes are nemaline myopathy (NM), centronuclear myopathy (CNM), core myopathy, and congenital fiber-type disproportion (CFTD). With significant improvements in the cost, availability, and diagnostic accuracy of genetic testing, a gene-based definition of congenital myopathies has recently taken shape. At present, the most accurate and parsimonious categorization for congenital myopathies incorporates clinical features, muscle biopsy findings, and genetic information. All congenital myopathies, with very rare exceptions, are assumed to have a genetic underpinning. To date, mutations in 20+ genes have been identified as causes of congenital myopathies (Table 148-1). These genes explain disease in approximately two thirds of all cases; in other words, about one third of the genetic burden of disease remains to be solved (Colombo et al., 2015). Inheritance can be autosomal dominant, autosomal recessive, and X-linked. Although a positive family history is often elicited, many cases are sporadic, and dominant mutations in particular often present (because of the severity of symptoms) as de novo. At present, no therapies have been defined for congenital myopathies that have been tested in controlled clinical trials (Wang et al., 2012). Therefore management has largely been symptomatic, with a strong focus on respiratory management, surgical correction of orthopedic complications, and application of physical and occupational therapy services to maximize motor function. For a select few congenital myopathies, cardiac management is also necessary. A handful of drugs, all of which seem to provide modest clinical benefit at best, have hinted at efficacy based on case-controlled studies. In addition, several candidate therapeutics have been developed in preclinical studies and are now on the cusp of assessment in the clinical arena. Efforts to evaluate these drug targets will hopefully usher in a new era of therapy for a group of previously untreatable and devastating diseases.

DIAGNOSTICS In general, congenital myopathies are considered in the setting of low muscle tone, depressed or absent reflexes, and extremity

muscle weakness, often of a long-standing nature, that exhibits limited active progression. Facial weakness is often a key additional clue (Fig. 148-1). Ultimately, the diagnosis of congenital myopathy, regardless of clinical presentation, is established through a compatible muscle biopsy result and/ or through positive genetic testing. The diagnostic strategy for assessing patients with neonatal hypotonia in whom congenital myopathy is suspected follows logically from the differential diagnoses (spinal muscular atrophy (SMA) DM1, congenital myasthenic syndromes, congenital muscular dystrophies, and Prader-Willi syndrome). Studies should include serum CPK levels (typically normal to maximum two to three times elevated in congenital myopathies), chromosomal microarray, genetic testing for SMA and congenital DM1, and (where available) electromyography and nerve conduction studies (EMG/NCS) (with repetitive stimulation) to evaluate for congenital myasthenic syndrome. Muscle magnetic resonance imaging (MRI) can also provide useful data in many cases. As mentioned, the diagnosis of congenital myopathy is only truly established through a consistent muscle biopsy and/or via positive genetic testing (see below under muscle biopsy and genetics sections). Similar strategies for diagnosis should be considered in the older child, keeping in mind that there will be a shift in consideration of potential alternative diagnoses based on age. A diagnostic algorithm that highlights some discriminative clinical and biopsy features is presented in Figure 148-2.

DIAGNOSTIC TESTING FOR   CONGENITAL MYOPATHIES Muscle Biopsy The muscle biopsy has long been the definitive diagnostic study for congenital myopathies. In fact, congenital myopathies are defined and named by the characteristic observations seen by muscle pathology analysis. Each subtype of congenital myopathy is defined as follows (Dowling et al., 2015): Centronuclear myopathy (Jungbluth et al., 2008): The basic definition of CNM is the presence of centrally located nuclei in >25% of the muscle fibers. This number can be quite variable, and truly there is no specific threshold for establishing CNM. Central nuclei are best seen with hematoxylin/eosin (H/E) staining (Fig. 148-3, A), though can also be appreciated with Gomori trichrome. The diagnosis of CNM is thus usually established not only by the presence of central nuclei but also by other histopathologic features. These features include myofiber hypotrophy, type I fiber predominance, and central accumulation of staining product with oxidative stains. Nemaline myopathy: NMs are defined on biopsy by the presence of nemaline rods or nemaline bodies. Rods are composed primarily of proliferations of Z-band lattices. By light microscopy, rods are best visualized on Gomori trichrome staining, where they appear as eosinophilic aggregates (Fig. 148-3, B). The signature rod-like appearance from which the disorder derives its name is best appreciated by electron microscopy. In most cases, light microscopy is sufficient for

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TABLE 148-1  Classification of Congenital Myopathies by Genes Gene

Subtype

ACTA1

• Nemaline myopathy (NM) • Cap disease (NM variant) • Zebra body myopathy (NM variant) • Congenital fiber-type disproportion

TPM3

Inheritance Pattern

Protein

Features

AD, AR AD AD AD

Actin, alpha1, skeletal muscle

Onset; variable within families with variable severity. Could present severe arthrogryposis or fetal akinesia. Severe respiratory involvement out of proportion to muscle weakness rarely cardiomyopathy. One patient described with hypertonia.

• Nemaline myopathy (NM variant) • Cap disease (NM variant) • Congenital fiber-type disproportion

AD, AR AD AD

Tropomyosin 3

Onset at birth to early adolescence. Distal leg involvement with later involvement of proximal muscle. Slow progression. Respiratory involvement out of proportion to muscle weakness. Could present mild ptosis and mild facial involvement.

TPM2

• Nemaline myopathy(NM) • Cap disease (NM variant)

AD AD

Tropomyosin 2 (beta)

Onset at birth to early childhood. Distal leg weakness, severe arthrogryposis, fetal akinesia. Cardiac involvement (bifascicular ventricular block with right bundle block and left anterior hemiblock).

TNNT1

• Nemaline myopathy (NM)

AR

Troponin T type 1 (skeletal, slow)

Older order Amish and rare Dutch and Hispanic patients. Onset at birth, 1 month of age usually starts with tremor on the jaw and lower limbs (resolves by 3 months of age). Proximal weakness with mild proximal contractures, rigid chest wall severe respiratory involvement, death usually at the age of 2 years.

NEB

• Nemaline myopathy (NM)

AR

Nebulin

Variable onset, classic form, birth onset with dysmorphic features (high-arched palate, micrognathia, lower facial weakness with marked bulbar involvement chest deformities, nasal voice, and distal leg weakness respiratory involvement out of proportion to muscle weakness).

LMOD3

• Nemaline myopathy (NM)

AR

Leiomodin 3

Onset; prenatal. Polyhydramnios, multiple joint contractures, proximal distal and lower facial weakness with marked bulbar involvement, and ophthalmoplegia. Usually neonatal death.

KBTBD13

• Nemaline myopathy (NM)

AD

Kelch repeat and BTB (POZ) domain containing protein 13

Onset; childhood. Proximal and axial involvement, slow movements, high-arched palate, and thorax deformities.

CFL2

• Nemaline myopathy (NM)

AR

Cofilin 2 (muscle)

Onset at birth to early childhood. Proximal and axial weakness, prominent neck extensors involvement. Severe scoliosis.

KLHL40

• Nemaline myopathy (NM)

AR

Kelch-like family member 40

Onset; prenatal. Polyhydramnios, severe arthrogryposis and fetal akinesia, dysmorphic faces, severe respiratory and limb involvement, ophthalmoplegia usually death at the age of 5 months.

KLHL41

• Nemaline myopathy (NM)

AR

Kelch-like family member 41

Onset; prenatal. Fetal akinesia hip and knee dislocation with severe respiratory involvement early death. Missense mutations could present with mild forms with a survival into late childhood or early adulthood.

RYR1

• Central core myopathy • Multiminicore myopathy • Core rod myopathy • Nemaline myopathy • Congenital fiber-type disproportion • Centronuclear myopathy • Congenital neuromuscular disease with uniform type 1 fiber

AD, AR AR AD, AR AR AR AR AD

Ryanodine receptor I

Variable onset and severity. Proximal weakness, ptosis, ophthalmoplegia, hyperlaxity, congenital hip dislocation, scoliosis, moderate respiratory involvement, exercise induce myalgia, MHS. Could present rigid spine syndrome, and severe arthrogryposis.



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TABLE 148-1  Classification of Congenital Myopathies by Genes (Continued) Gene

Subtype

Inheritance Pattern

STAC3

• Native American myopathy

SEPN1

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Protein

Features

AR

SH3 and cysteine rich domain containing protein 3

Lumbee Indians in North Carolina. Congenital onset, dysmorphic features (telecanthus, cleft palate, downslating palpebral fissures, low ear set, ptosis), short stature, arthrogryposis proximal weakness, MHS.

• Multiminicore myopathy • Congenital fiber-type disproportion

AR AR

Selenoprotein N1

Onset birth to childhood. Predominant axial muscle involvement, poor head control, rigid spine, scoliosis at the age of 10 years, nocturnal hypoventilation central apnea during paradoxical sleep.

CCDC78

• Centronuclear myopathy

AD

Coiled coil domain containing protein 78

Congenital onset, distal involvement with slow progression, excessive fatigue mild to moderate cognitive impairment.

BIN 1

• Centronuclear myopathy

AR, AD

Amphiphysin

Variable onset. Severe forms present at birth or childhood. Proximal and lower facial weakness with marked bulbar involvement, ophthalmoparesis and ptosis, could present cardiomyopathy (dilated)

DNM2

• Centronuclear myopathy

AD

Dynamin 2

Variable onset. Distal muscle weakness, exercise induce myalgias, ophthalmoparesis, ptosis, lower facial weakness and marked bulbar involvement, slow progression hypertrophy of paravertebral muscles absent or reduce tendon reflexes, distal limb, contractures, scoliosis cardiomyopathy.

MTM1

• Myotubular myopathy

XR

Myotubularin 1

Onset; prenatal. Polyhydramnios, macrosomia, proximal and distal weakness with severe respiratory involvement at birth, lower facial weakness with marked bulbar involvement, usually early death, other features, bleeding diathesis, liver and gastrointestinal complications.

SPEG

• Centronuclear myopathy with dilated cardiomyopathy

AR

SPEG complex locus

Onset at birth, proximal weakness with lower face and bulbar involvement, ophthalmoplegia, hip contractures cardiomyopathy.

PTPLA (= HCDA1)

• Congenital myopathy related to PTPLA

AR

Protein tyrosine phosphatase-like (3-hydroxyacyl CoA dehydratase)

Onset birth. Lower facial and proximal weakness. Absent or reduce deep tendon reflexes. Severe presentation at onset with progressive improvement.

TTN

• Centronuclear myopathy • Congenital myopathy with fatal cardiomyopathy

AR AR

Titin

Onset, birth or infancy. Proximal and distal weakness with facial involvement. Could present asymmetric ptosis. Some with scapula-peroneal syndrome. Pseudohypertrophy of thighs and calves. Ambulation could be achieved in most of the cases. Scoliosis and absent reflexes. Cardiomyopathy (dilated)

MYH7

• Myosin storage myopathy • Myosin storage myopathy with cardiomyopathy • Congenital fiber-type disproportion

AD AR AD

Myosin, heavy chain 7, cardiac muscle

Onset at infancy or early childhood, distal weakness predominant, and week toe extensor (hanging big toe), scapular winging, mild facial involvement, cardiomyopathy (dilated or hypertrophic)

MYH2

• Myosin IIa myopathy

AD, AR

Myosin, heavy chain 2, skeletal muscle

Onset at birth, contractures, ophthalmoplegia, ptosis, mild to moderate proximal weakness

MEGF10

• Early onset myopathy, areflexia respiratory distress and dysphagia • Minicores

AR AR

Multiple EGF-like domains 10

Prenatal onset with reduced fetal movements. Proximal and distal weakness, distal contractures, scoliosis, areflexia, bulbar involvement, respiratory distress.

AD, autosomal dominant; AR, autosomal recessive; XR, X linked. (Adapted from Kaplan JC, et al. The 2015 version of the gene table of monogenic neuromuscular disorder. Neuromuscul Disord 2014;24:1123–53.)

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A

B

C

Figure 148-1.  The “myopathic” facies. One of the characteristic clinical observations in many children with congenital myopathies is the so-called “myopathic” facial appearance. This can include both upper and lower facial weakness, as illustrated in these photomicrographs. Left panel: The patient depicted demonstrates ptosis, ocular misalignment caused by ophthalmoparesis, an inverted C-shape to her upper lip, and prominent lower facial weakness resulting in an open mouth appearance. The ultimate diagnosis in this case was nemaline myopathy caused by recessive mutation in the LMOD3 gene. Patients with nemaline myopathy often have particularly striking lower facial weakness. Middle panel: This individual has ptosis, ophthalmoparesis, and moderate lower facial weakness. He has DNM2-related centronuclear myopathy. Note also the muscle atrophy present in his chest and shoulders. Right panel: Photograph of a young boy with myotubular myopathy caused by MTM1 mutation. He has the characteristic long face with bilateral ptosis and ophthalmoparesis.

NEB

ACTA1

Muscle disease suspected (weakness, hypotonia, delayed motor miIestones)

Other NM

MTM1

Congenital myopathy suspected

CK normal or mildly elevated

RYR1

SEPN1

TTN

MYH7

Contractures Myopathic face

DNM2

Neck or Axial weakness

DNM2

Hip dysplasia/ scoliosis

Yes

Severe hypotonia NEB

Muscle MRI (Fig. 4)

MYH7

SPEG

Cardiomyopathy

Genetic testing (gene panel)

TTN

DNM2

LMOD3

EOM restricted

And\or

SEPN1

EO respiratory dysfunction

Physical Exam

Other diagnosis CMD Or repeat CK

RYR1

DNM2

Ptosis

No

Other CNM

And\or

ACTA1

Other NM

MTM1

Other CNM

Muscle biopsy Rods Cores Central nuclei

Confirmed Genetic diagnosis

Rods and cores Caps CFTD

Figure 148-2.  Clinical approach to congenital myopathy, practical algorithm. ACTA1, ACTA1 nemaline myopathy; CFTD, congenital fiber-type disproportion; CK, creatine kinase; CMD, congenital muscular dystrophy; CNM, centronuclear myopathy; EO, early onset; EOM, extraocular movements; MM, mitochondrial myopathy; MYH7, MYH7 myopathy; NEB, nebulin mutation; NM, nemaline myopathy; Other NM, LMOD3, TPM2, TPM3, KBTBD13, TNNT1, KLHL40, KLHL41, and large spectrum of clinical presentation from mild to severe; RYR1, ryanodine receptor myopathy; SEPN1, SEPN1 myopathy; TTN, Titin myopathy.



establishing the diagnosis; however, there are instances where the rods are either poorly appreciated or else not seen at the light level and only revealed through electron microscopic analysis. In addition, there are histopathologic variants that are included within the nemaline umbrella. These include cap myopathy (where there is an accumulation of myofibrillar material sitting as a cap at the periphery of the myofiber) and zebra body myopathy (Dowling et al., 2015). Core myopathy (Jungbluth, 2007a,b): Core myopathies are typically subdivided into CCD and multiminicore myopathy. Cores are best appreciated on light microscopy with oxidative stains such as SDH and NADH (Fig. 148-3, C). They are defined as areas devoid of reactivity for these enzymes and reflect areas in the myofibers that lack mitochondria. Central cores are longitudinal and often traverse the entire length of the myofiber. Minicores are typically transverse in location and usually small. Core myopathies are often also seen in the context of type I fiber predominance and type I fiber hypotrophy, both features best seen with ATPase staining. Electron microscopy is often required for evaluation of core myopathies. This is because there are other conditions that can result in absence or change of SDH/NADH staining. Most prominent among them is the targetoid staining pattern seen with neurogenic lesions. On EM, cores appear as areas of myofibril disorganization that lack mitochondria. At times there will be a ring of mitochondria around the area of disorganization (referred to as a structured core). Congenital fiber-type disproportion: CFTD is defined by two biopsy features. The first is relative hypotrophy of type I fibers compared with type II fibers. The second is numerical predominance of type I fibers over type II fibers. The general criterion for calling CFTD is a 25% reduction in type I fiber size. Such a reduction is relatively nonspecific and can be seen in a range of disease, many of which are not primary myopathies. “True” CFTD, or CFTD caused by mutations in congenital myopathy genes, is usually characterized by much more significant reduction in type I fiber size (to 75% of fibers). CFTD can be seen by H/E staining, but is best diagnosed and evaluated using stains for fiber type (Fig. 148-3, D). These include enzymatic reactions (ATPase at acid pH [4.3 to 4.6] to stain type I fibers and at basic pH [9.4 to 10.2] to mark type II fibers) or immunostaining with myosin antibodies (slow myosin for type I and fast myosin for type II).

Genetics All pediatric-onset (and most adult-onset) congenital myopathies are considered to have a genetic underpinning. It is important to establish a genetic diagnosis, even when a child has a consistent muscle biopsy, because knowledge of the specific genetic subtype greatly contributes to understanding of specific clinical features, anticipatory care requirements, and prognostication (Wang et al., 2012; North et al., 2014). Mutations in congenital myopathies span the range of inheritance patterns (X-linked, autosomal recessive, autosomal dominant) and often are caused by sporadic/de novo variants. To date, mutations in 20 genes have been identified as causal in patients with congenital myopathy (see Table 148-1). The interplay between clinical presentation, biopsy diagnosis, and genetic subtype is complex. In particular, there are several genetic causes for each histopathologic grouping (e.g., mutations in 10 genes are associated with NM), and each genetic cause can result in a variety of clinical presentations and histopathologic diagnoses (e.g., RYR1 mutations have been described in every histopathologic subtype) (North et al., 2014). Of note, it is critically important that genetic counseling be offered to all patients with congenital myopathies and to their families,

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ideally starting at the time that genetic testing is first considered (Wang et al., 2012).

Muscle Imaging (MRI or Ultrasonography) Muscle imaging is an emerging modality for the diagnosis and care of patients with a range of neuromuscular disorders. For congenital myopathies it is used primarily as an adjunct diagnostic tool, though in the future may aid in assessment of disease status and progression. Muscle ultrasonography is the fastest and least expensive technique and offers the potential of application in the outpatient clinic and/or inpatient setting, though requires an experienced user for interpretation. Muscle MRI is widely available and does not require any particular advanced training to obtain or analyze; the downside is expense and the fact that some children (particularly those under age 5 years) may require sedation. The diagnostic value of muscle imaging lies in the fact that different genetic subtypes of myopathy present with different imaging patterns of muscle involvement. The pathognomonic patterns are best characterized with lower extremity imaging, though the value of whole-body MRI for diagnosis (particularly in the young child) is increasingly being recognized. Representative examples of muscle MRI and a diagnostic flow chart describing its application are presented in Figure 148-4.

SPECIFIC SUBTYPES OF CONGENITAL MYOPATHY Centronuclear Myopathies Centronuclear myopathies, even though clinically heterogeneous (particularly in terms of symptom onset and severity), often feature prominent eye muscle weakness (ptosis and ophthalmoparesis) in addition to lower facial and extremity weakness (Jungbluth et al., 2008). In infancy and childhood, these features can appear like those seen in congenital myasthenic syndromes. The extremity weakness may have significant distal involvement, including distal predominance in some individuals. There are six established genetic causes of CNM. Mutations in myotubularin (MTM1) are associated with the distinctive, severe, neonatal-onset X-linked condition myotubular myopathy (XLMTM or MTM) (Das et al., 1993). Mutations in dynamin-2 (DNM2) are the most common cause of dominant CNM; patients typically present either in the first year or two of life (with de novo mutations) or in late childhood. Recessive causes of CNM include mutations in RYR1, BIN1, TTN, and SPEG. RYR1 mutations are the most common and can present in infancy in a manner resembling MTM. BIN1 mutations typically cause childhood-onset CNM, though one particular homozygous splice mutation results in a rare, rapidly progressive form. There is also a late-onset CNM in some families with dominant BIN1 mutations. SPEG mutations cause a rare, severe form of CNM that also includes cardiomyopathy. There are currently no therapies that have been proven to be efficacious for CNM. There is mounting evidence, however, including several case reports and compelling preclinical data, that acetylcholinesterase inhibitors such as pyridostigmine provide modest but definitive improvement in clinical symptomatology. Patients with mutations in RYR1, DNM2, and MTM1 have all been reported in these case series. In terms of experimental therapies, there is considerable excitement concerning both gene therapy and enzyme replacement therapy for MTM. These strategies have shown robust disease correction in the MTM mouse model, and gene therapy

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additionally has been effective in a spontaneous dog model of the disease.

Nemaline Myopathies NMs are characterized in general by the presence of significant bulbar dysfunction (because of lower face and neck flexor weakness) in the setting of additional and variable extremity weakness (North et al., 2014). The disease is noted to have significant clinical variability and has thus been classically subdivided into groups based on age of onset and clinical severity: (1) severe congenital NM (16% of NM cases), (2) intermediate congenital NM (20%), (3) typical congenital NM (46%), (4) childhood-/juvenile-onset NM (13%), and (5) adult-onset NM (4%) (North and Ryan, 1993). There is considerable overlap between the groups, though the distinctions can be helpful (e.g., individuals with severe congenital NM have a high risk of death in infancy, whereas those with typical congenital NM tend to show stabilization and even improvement). There are 10 known genetic causes of NM. Mutations in ACTA1 are the most common dominant/de novo cause (25% of all NM), whereas those in nebulin (NEB) are the most common autosomal-recessive cause (~50% of all NM). Mutations in ACTA1 are associated with a tremendous variability in age of presentation and clinical expression, not only between different mutations in the gene but also among family members with the same mutation. They are the most common cause of severe congenital NM (severe weakness, reduced or absent fetal/neonatal movements, respiratory failure, and often death in infancy). Mutations in NEB are most frequently encountered with typical congenital NM (neonatal hypotonia, weakness, feeding difficulties, ability to eventually ambulate, static/slowly progressive course). The specific breakdown in terms of relative prevalence of the other genetic subtypes is otherwise not well established. Some are associated primarily with specific clinical groupings. LMOD3 and KLHL40 mutations are seen almost exclusively with severe congenital NM. Dominant mutations in TPM2 and TPM3 are associated with symptoms ranging from typical congenital to mild childhood (with TPM2 mutations usually milder), whereas rare recessive mutations in TPM3 are associated with severe disease. TPM2 mutations can additionally been seen in the absence of overt weakness with distal arthrogryposis syndromes. Dominant mutations in KBTBD13 are seen with childhood-onset NM and characteristic slowness of movements. Recessive mutations in TNNT1 (Amish NM) and CFL2 (severe or typical congenital) are extremely rarely encountered. Of note, ophthalmoparesis is infrequently observed in NM (with the exception of LMOD3 mutations), and may serve as a means of distinguishing NM from other congenital myopathies. At present, there are no specific therapies that have proven efficacious for NM. L-tyrosine has been examined in a mouse model of Acta1 and shown to increase muscle strength; a limited patient case series examining L-tyrosine found that it improves some bulbar symptoms and specifically sialorrhea. Its impact on disease course is likely limited, and true efficacy awaits more systematic clinical study. There are no other therapies currently in the clinical pipeline, though a few are at the stage of preclinical assessment.

Core Myopathies Core myopathies can be subdivided into CCD and multiminicore disease (MmD). CCD is caused by RYR1 mutations (usually dominant/de novo) in approximately 90% of cases (Jungbluth, 2007a). The other well-described cause

is dominant MYH7 mutation. Minicore disease, along with the more general categorization of myopathy with cores, has several genetic causes (Jungbluth, 2007b). Most classically, it is caused by mutations in either SEPN1 (MmD without ophthalmoparesis) or RYR1 (MmD with ophthalmoparesis). Other genetic causes include ACTA1, TTN, MEGF10, and CCDC78; biopsies in these settings typically include additional histopathologic abnormalities (such as rods or protein aggregates). In addition, there can be both cores and rods in the same biopsy (termed “core-rod” myopathy), with known causes, including TPM2, NEB, RYR1, ACTA1, and KBTBD13.

RYR1-Related Myopathies Myopathies caused by mutations in the skeletal muscle ryanodine receptor (RYR1) are the commonest group of nondystrophic muscle conditions. These are also termed “RYR1-related myopathies,” and encompass a broad clinical spectrum that spans the entire gamut of histopathologic subtypes. RYR1related myopathies are subdivided primarily either by mode of inheritance (recessive vs. dominant/de novo) or by histopathology (CCD, MmD, CNM, etc.), though there are distinctive clinical conditions that do not classically fall into a specific grouping (e.g., axial myopathy, malignant hyperthermia, exertional rhabdomyolysis, isolated ophthalmoparesis). CCD associated with RYR1 mutation is almost entirely caused by dominant mutations (Jungbluth, 2007a). The typical pediatric presentation for CCD is one of neonatal hypotonia, muscle hypotrophy, and extremity muscle weakness, often accompanied by significant skeletal abnormalities such as chest wall deformities, scoliosis, joint contractures, and hip dysplasia. Respiratory failure is present in some instances, though rarely requires tracheostomy and often improves. The course of disease is typically quite stable, and, although delayed, individuals often acquire all motor developmental milestones. Of note, there may be some mild facial muscle involvement, including ptosis and lower facial weakness, but ophthalmoparesis is rarely encountered. There is also a milder CCD presentation that includes minimal weakness that may only be recognized in adulthood; there are also several cases of dominant mutations causing late-onset axial myopathy. Rarely, heterozygous de novo mutations can present with extreme weakness in the perinatal period that results in death in infancy. The mutations in RYR1 that cause CCD are enriched in the C-terminal aspect of the gene. Some are additionally associated with malignant hyperthermia susceptibility (MHS), a pharmacogenetic condition of hypermetabolism and muscle breakdown in response to exposure to volatile anesthetics. The other histopathologic subtypes (MmD, CNM, core-rod myopathy, and CFTD) are most commonly seen with recessive RYR1 mutations. The most frequently encountered recessive subtype is minicore disease, which typically presents with diffuse weakness in combination with ophthalmoparesis. Onset is usually in the neonatal period or in early childhood, and can be severe enough to result in respiratory failure with chronic ventilator support and wheelchair dependence. As with CCD, skeletal abnormalities (particularly joint contractures and scoliosis) are quite frequently encountered. These are often accompanied by severe facial weakness that can include ophthalmoparesis. Axial muscle involvement can also be quite pronounced. At present, there are no specific treatments for RYR1-related myopathies. Salbutamol has been shown in a small casecontrol series to improve strength and motor function. This result has not been followed up with additional clinical trials, and the medication is not widely used in RYR1 patients. An intriguing candidate drug class is the RyCals; RyCals interact with RyR1 and augment its ability to release calcium. RyCals



have yet to be tested for efficacy in patients, and have not been examined in any preclinical models of RYR1 myopathy. One drug that has shown promising results in animal models and in patient cells is the antioxidant N-acetylcysteine (NAC). NAC is currently being evaluated in a placebo-controlled clinical trial in ambulant RYR1 myopathy patients. Of note, dantrolene is the standard therapy for treating MH. It has yet to be tested in other dynamic RYR1-related phenotypes such as rhabdomyolysis. Because it reduces RyR1 calcium release, it is unlikely to be effective in the majority of instances of RYR1 mutations that cause static muscle weakness.

SEPN1-Related Myopathies Recessive mutations in SEPN1 were first described in a rare muscular dystrophy subtype called rigid spine muscular dystrophy. However, SEPN1 mutations are most typically found associated with multiminicore disease; they are also seen with other histopathologic patterns, including CFTD and Mallory Body myopathy. Regardless of histopathologic phenotype, patients with SEPN1 mutations present a relatively uniform clinical picture. This picture includes early onset hypotonia and axial muscle weakness with relative sparing of the extremity muscles. It also includes spinal rigidity; severe, progressive scoliosis; and potentially lethal, progressive respiratory failure. These severe axial symptoms are not matched by corresponding limb weakness, with the resulting appearance often one of an ambulant patient with ventilator dependence. Patients do not have ophthalmoparesis, a distinguishing feature from RYR1 mutations. SEPN1 encodes selenoprotein N1 (SelN1), a selenocysteinecontaining protein located in the endoplasmic reticulum. The functions of SelN1 in relation to muscle structure and function have been relatively elusive, though it seems clear that one of its major roles is to regulate oxidative stress. Based on this, the consequences of SEPN1 mutations (which in general result in loss of SelN1 expression and/or function) are predicted to be increased basal oxidative stress, susceptibility to the consequences of oxidative species, and ultimately impaired redox related RyR1 function. As with RYR1 myopathies, the antioxidant NAC protects SEPN1-patient-derived myotubes from oxidant-related death, and is now being considered for clinical trial in SEPN1-related myopathy patients.

Congenital Fiber-Type Disproportion CFTD is a diagnosis applied in the context of clinical symptoms of myopathy and fiber-type disproportion on biopsy (significantly smaller type I fibers, usually type I predominance) (Clarke, 2011). The biopsy observation of CFTD often precedes or is accompanied by other pathologic features (rods, cores, etc.); in such cases, the individual is typically described as having the diagnoses corresponding to the other biopsy features (e.g., NM when rods are present). Some individuals, however, do have “pure” CFTD (usually considered when type I fibers are >40% smaller). When this occurs, the recognized genetic causes are mutations in TPM3, TPM2, RYR1, SEPN1, and ACTA1. The clinical presentations in these cases are primarily dictated by the underlying genetic cause; for example, patients with CFTD caused by TPM3 mutations resemble those with similar mutations and NM on biopsy.

GENERAL MANAGEMENT OF CONGENITAL MYOPATHIES General management guidelines for congenital myopathies are based on practical experience, expert opinion, and inferences from other similar neuromuscular conditions. These

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guidelines are summarized here, and also found in extensive detail in the recently published standards of care for congenital myopathies (Wang et al., 2012).

Respiratory Respiratory dysfunction is the likeliest cause of morbidity and mortality in children with congenital myopathies. This relates to the fact that the diaphragm and intercostal muscles are often weakened in these conditions, leading to poor rib excursion, impaired mucus expectoration and airway clearance, and sleep apnea. The recognition of early respiratory compromise (often identified via sleep study or pulmonary function testing in both the seated and supine positions) leads to early intervention via noninvasive ventilation, typically first at night and then during daytime in more severe or progressive cases. Identifying a weak cough in patients is also an important predictor of how a child may respond to an upper respiratory infection. A weak cough can predispose to mucus plugging and bronchiectasis and hence cause risk for fatal pneumonias. This can be prevented with the use of a cough assist device (either while sick or best also when healthy) as a form of pulmonary physical therapy. A thairvest, which employs chest vibration to loosen mucus, may also be used, though it is imperative that this treatment is followed by cough assist regimen. This is so that the mucus that is loosened as a result of this procedure can actually be expectorated and not actually make things worse by being left to plug the airways.

Nutrition, Gastrointestinal, and   Oromotor Management Nutritional management guidelines for congenital myopathies are essentially nonexistent despite the fact that poor nutrition and growth are inherent to many of these conditions. Weakness in oromotor function is a contributing factor, particularly in nemaline and centronuclear myopathies. Efforts should be made to monitor patient weight and height (either erect or via ulnar length) in conjunction with calorie intake. If calorie intake is limited, or the risk of aspiration pneumonia is high, the placement of a gastrostomy tube should be discussed with families early in the disease course. Improved nutritional status has been related to improved growth and decreased respiratory problems. Yearly assessments of calcium and vitamin D levels should also be made in order to address bone health, as osteopenia is a concern in any individual with long-standing muscle weakness. Gastrointestinal dysmotility is also a frequent problem in children with congenital myopathies. Dysmotility may present as gastroesophageal reflux, which can be managed with medication (e.g., proton pump inhibitors, H2 blockers, and antacids), nonpharmacologically (e.g., thickening of formula and adjusting feeding positions), and/or surgically (e.g., with Nissen fundoplication). Dysmotility can also present with delayed gastric emptying and constipation, symptoms that can be treated with diet modification, stool softeners/ laxatives, and the use of prokinetic drugs (erythromycin or metaclopromide). Excessive oral secretions are often a significant problem in congenital myopathies. This is related to bulbar and facial weakness and particularly seen in nemaline and CNM. Speech and occupational therapy can be used to address this, primarily through facial muscle–strengthening exercises. If this is not successful, anticholinergic drugs may be administered systemically (e.g., robinul and scopolamine), though they are not without systemic side effects (e.g., constipation). A small study has also found evidence that L-tyrosine supplementation may

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be helpful with sialorrhea in NM. Botulinum toxin injections and surgical management are considered in very rare circumstances when secretions are particularly debilitating, though such strategies are controversial.

Cardiac The majority of congenital myopathy subtypes are not associated with primary cardiac involvement. Baseline and periodic follow-up cardiac evaluations, however, should be provided to all patients with congenital myopathy until the specific genetic cause has been identified. This is because certain gene mutations, such as those in TTN, MYH7, SPEG, and (more rarely) ACTA1, can cause cardiomyopathy. In addition, continued cardiac screening is indicated in settings (SEPN1related myopathy, for example) where secondary right-sided heart failure is of concern because of chronic respiratory compromise.

Orthopedic Scoliosis is a pervasive problem in these conditions and should be monitored from the initial presentation of symptoms. This can initially be done via clinical examination (with the patient assessed in forward flexion at the hip), but once any curvature is noted, routine x-rays should be obtained. Once scoliosis has been diagnosed, patients should be referred to orthopedics for the management of the progressive curvature with either a conservative (e.g., bracing/casting) or invasive/surgical approach. The management of scoliosis is essential for maintaining respiratory function. Joint contractures are a concern for the majority of congenital myopathy patients, and may in fact be the presenting sign of patients in some individuals. Ankle contractures are typically managed with physical therapy, passive stretching, and ankle-foot orthoses, which are used in the ambulant patient to slow contracture progressive and to improve gait, and in the nonambulant patient to aid in comfort and wheelchair positioning. Surgery to release contractures is rarely indicated, as it often does not appreciably improve range of motion and can potential worsen muscle weakness. Exceptions include contractures that significantly hinder ambulation (in the setting of relatively preserved strength) and those that cause considerable discomfort (in the nonambulant patient).

Physical Therapy/Exercise Physical therapy is mainstay of management in children with congenital myopathy. It helps with strengthening and improves range of motion. It should be utilized regularly and in a manner that matches the child’s pattern of weakness. Assist devices can complement therapy services, and include gait trainers and stationary bikes. The impact of exercise on muscle strength and motor function in congenital myopathies has yet to be formally addressed, though there is anecdotal evidence that exercise in children with myopathies is safe and potentially of benefit. Further work is necessary to establish this as a formal recommendation.

SUMMARY Congenital myopathies represent a clinically and genetically heterogeneous group of childhood muscle disorders. With

improvements in clinical recognition and genetic testing, it is now clear that these disorders represent a significant portion of childhood genetic neuromuscular disease. The availability of gene panels and whole-exome sequencing has improved diagnostics, has enabled the discovery of new myopathy genes, and has greatly broadened the genotype-phenotype spectrum of these disorders. It has also presented challenges related to disease classification and genetic variants of unknown clinical significance; in addition, the genetic cause in many individuals still remains elusive. Currently there are few, if any, therapies available for these often devastating disorders; however, work using preclinical model systems has identified several promising candidates for translation into the clinical arena. One of the key challenges in the future will be effectively translating these drugs, and factors related to disease natural history and clinical trial readiness are becoming of paramount importance as the field moves forward toward hopefully identifying meaningful therapies. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Clarke, N.F., 2011. Congenital fiber-type disproportion. Semin. Pediatr. Neurol. 18, 264–271. Colombo, I., et al., 2015. Congenital myopathies: natural history of a large pediatric cohort. Neurology 84, 28–35. Das, S., Dowling, J., Pierson, C.R., 1993. X-Linked centronuclear myopathy. In: Pagon, R.A., et al. (Eds.), GeneReviews® [Internet]. University of Washington–Seattle, Seattle, WA, pp. 1993–2016. Dowling, J.J., et al., 2015. Congenital and other structural myopathies. In: Darras, B.T., et al. (Eds.), Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Elsevier, New York, pp. 502–537. Jungbluth, H., 2007a. Central core disease. Orphanet J. Rare Dis. 2, 25. Jungbluth, H., 2007b. Multi-minicore disease. Orphanet J. Rare Dis. 2, 31. Jungbluth, H., Wallgren-Pettersson, C., Laporte, J., 2008. Centronuclear (myotubular) myopathy. Orphanet J. Rare Dis. 3, 26. North, K.N., Ryan, M.M., 1993. Nemaline myopathy. In: Pagon, R.A., et al. (Eds.), GeneReviews® [Internet]. University of Washington– Seattle, Seattle, WA, pp. 1993–2016. North, K.N., et al., 2014. Approach to the diagnosis of congenital myopathies. Neuromuscul. Disord. 24, 97–116. Wang, C.H., et al., 2012. Consensus statement on standard of care for congenital myopathies. J. Child Neurol. 27, 363–382.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 148-3. The common congenital myopathy subtypes by histopathology. Fig. 148-4. Muscle MRI in congenital myopathies. Fig. 148-5. MTM- and DNM2-related centronuclear myopathy. Fig. 148-6. ACTA1- and NEB-related nemaline myopathies. Fig. 148-7. RYR1-related myopathy.

149  Metabolic Myopathies Ingrid Tein

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

UTILIZATION OF BIOENERGETIC SUBSTRATES IN EXERCISE Symptoms in muscle energy defects are directly related to a mismatch between the rates of adenosine triphosphate (ATP) utilization (energy demand) relative to the capacity of the muscle metabolic pathways to regenerate ATP (energy supply). This energy supply-demand mismatch impairs energydependent processes that power muscle contraction (weakness, exertional fatigue), mediate muscle relaxation (muscle cramping, tightness), and/or maintain membrane ion gradients necessary for normal membrane excitability (fatigue, weakness) and muscle cell integrity (muscle pain, injury, myoglobinuria). In metabolic myopathies, the specific metabolic mediators of premature fatigue, cramping, pain, and muscle injury are complex and vary among the different metabolic disorders. Disorders of glycogen, lipid, or mitochondrial metabolism may cause two main clinical syndromes in muscle: (1) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps), for example, mitochondrial disorders, and (2) progressive weakness, for example, fatty acid oxidation (FAO) defects and mitochondrial enzyme deficiencies (Box 149-1). Progressive weakness and recurrent myoglobinuria can also occur together in a given disorder. Defects of energy metabolism may profoundly disrupt the function of muscle and other highly energy-dependent tissues, such as brain, nerve, heart, kidney, liver, and bowel. The limits of energy utilization in skeletal muscle are set by the adenosine triphosphatases (ATPases) that couple muscle contraction (myosin ATPase) and ion transport (calcium and sodium, potassium ATPases) to the hydrolysis of ATP to adenosine diphosphate (ADP) and inorganic phosphate (Pi). ADP and Pi in turn activate energy-producing reactions that regenerate ATP. Without this, ATP stores would be exhausted in seconds. The substrates that are used to replenish ATP are determined by the intrinsic properties of these fuels and by the intensity and duration of exercise that modulates fuel selection. The creatine kinase (CK) reaction and anaerobic glycogenolysis are the major anaerobic sources of ADP phosphorylation. Increases in ADP and AMP that occur in heavy exercise are primarily buffered by the coupled adenylate kinase (myokinase), adenylate deaminase (myoadenylate deaminase) reactions. Anaerobic glycogenolysis and phosphocreatine hydrolysis support muscle energy production with two- to fourfold higher rates than those supported by oxidative metabolism. Anaerobic energy is crucial for rapid bursts of exercise and to fuel the transition from rest to exercise. The acceleration to high rates of energy production occurs instantly for ATP, in less than a second for phosphocreatine, and within seconds for anaerobic glycogenolysis. In contrast, maximal oxidative power requires from 3 minutes (with glycogen as the oxidative substrate) to 30 minutes (for peak FAO). Anaerobic fuels are rapidly depleted and lead to the accumulation of metabolic end products such as protons and Pi that promote fatigue.

If exercise needs to be sustained for more than a few minutes, then oxidative phosphorylation is necessary and provides the most abundant source of ATP synthesis. Glycogen is the major endogenous oxidative fuel of skeletal muscle, whereas blood glucose and free fatty acids (FFA) are the major exogenous fuels. A small percentage of muscle energy needs are supplied by amino acids, predominantly branched chain amino acids, which are oxidized to a limited extent. Oxidative metabolism provides higher yields of ATP per mole of substrate, rising from 2 to 36 for glucose and from 3 to 37 per glycosyl unit of glycogen metabolized anaerobically versus oxidatively. Furthermore, the metabolic end products of oxidative metabolism, namely, CO2 and water, are easily removed from working muscle and do not promote fatigue. The most abundant and critical fuel for the support of prolonged, moderate exercise is lipid. Carbohydrate stores in the form of muscle and hepatic glycogen and blood glucose (derived mainly from hepatic glycogenolysis) are limited and can support highintensity exercise for only 1 to 2 hours. However, carbohydrate, particularly muscle glycogen, is critical for normal oxidative metabolism. Glycogen supports a peak rate of oxidative phosphorylation that is about twofold greater than fat. Though incompletely understood, this may be based upon a requirement for glycogen-derived pyruvate to support optimal function of the tricarboxylic acid cycle. The proportion of carbohydrate relative to lipid oxidation progressively increases as the intensity of the aerobic exercise increases until carbohydrate is the exclusive fuel of maximum oxidative metabolism. Second, glycogen is able to accelerate to maximal oxidative power output rapidly compared with other fuels. Third, the molar ratio of ATP produced to O2 consumed is higher for glycogen (6.17) and glucose (5.98) than for fatty acids (5.61). The importance of this point lies in the fact that peak O2 utilization in healthy humans is limited by O2 delivery. The combustion of fuels in oxidative metabolism involves the generation of reducing equivalents in β-oxidation, glycolysis, and the tricarboxylic acid cycle that are oxidized via the respiratory chain, where the phosphorylation of ADP is coupled to the reduction of molecular oxygen to water. Normal oxidative metabolism requires a highly integrated physiologic support system to regulate the flow of oxygen from the lungs to the respiring muscle mitochondria as well as functional mitochondria that can efficiently extract the available oxygen from blood. Muscle oxygen utilization in oxidative phosphorylation may increase 50-fold or greater from rest to peak exercise. This increase is achieved by increases in the level of oxygen extraction from oxyhemoglobin in red blood cells and in the rate of delivery of oxygenated blood to working muscle by the circulation. The primary source of energy for resting muscle is derived from FAO. At rest, glucose utilization accounts for 10% to 15% of total oxygen consumption. Both slow and fast twitch fibers have similar levels of glycogen content at rest. The choice of the bioenergetic pathway in working muscle depends on the type, intensity, and duration of exercise (Gollnick et al., 1974), but also on diet and physical conditioning. In the first 5 to 10

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BOX 149-1  Heritable Causes of Myoglobinuria I. Biochemical abnormality known A. Glycolysis/glycogenolysis 1. Phosphorylase* 2. Phosphofructokinase 3. Phosphoglycerate kinase* 4. Phosphoglycerate mutase* 5. Lactate dehydrogenase* 6. Phosphorylase b kinase 7. Debrancher 8. Aldolase A deficiency* B. Fatty acid oxidation 1. Carnitine palmitoyltransferase II* 2. Long-chain acyl-CoA dehydrogenase 3. Very long-chain acyl-CoA dehydrogenase 4. Medium-chain acyl-CoA dehydrogenase 5. Short-chain L-3-hydroxyacyl CoA dehydrogenase* 6. Trifunctional protein deficiency* 7. Medium-chain 3-ketoacyl CoA thiolase* 8. Acyl-CoA dehydrogenase 9 (ACAD9)*,** C. Pentose phosphate pathway 1. G6PDH* D. Purine nucleotide cycle 1. Myoadenylate deaminase E. Respiratory chain 1. Complex I deficiency* 2. Coenzyme Q deficiency 3. Complex II and aconitase* 4. Complex III deficiency (cytochrome b) 5. Complex IV deficiency (cytochrome oxidase deficiency)* 6. Multiple mitochondrial DNA deletions* II. Ryanodine receptor 1 (RYR1) abnormality 1. Malignant hyperthermia 2. Central core disease 3. Minicore myopathy with external ophthalmoplegia 4. King-Denborough syndrome III. Biochemical abnormality incompletely characterized A. Impaired long-chain fatty acid oxidation* B. Impaired function of the sarcoplasmic reticulum (?) (predisposition in myotonic dystrophy, myotonia congenita, Schwartz-Jampel syndrome) IV. Abnormal composition of sarcolemma A. Abnormal composition of the sarcolemma in Duchenne and Becker muscular dystrophy* B. Muscle-specific phosphatidic acid phosphatase deficiency (LPIN1 mutations)* V. Biochemical abnormality unknown A. Familial recurrent myoglobinuria* B. Repeated attacks in sporadic cases* *Etiologies that have been documented to cause recurrent myoglobinuria beginning in childhood. **ACAD9 deficiency also leads to mitchondrial complex I deficiency. (Modified with permission of Tein I, DiMauro S, Rowland LP. Myoglobinuria. In: Rowland LP, DiMauro S, editors. Handbook of clinical neurology, vol. 18 (62). Myopathies. Amsterdam: Elsevier Science Publishers; 1992, pp. 553–93.)

minutes of moderate exercise, high-energy phosphates are used to first regenerate ATP. This is followed by muscle glycogen breakdown, which is indicated by a sharp rise in lactate during the first 10 minutes. Blood lactate levels then drop as muscle triglycerides and blood-borne fuels are used. After 90 minutes, the major fuels are glucose and FFAs. During 1 to 4 hours of mild to moderate prolonged exercise, muscle uptake

of FFAs increases approximately 70%, and after 4 hours, FFAs are used twice as much as carbohydrates. The disorders discussed here have a genetic basis. The inheritance pattern, gene, gene product, and function are summarized in the following sections for each disorder. More detailed and current molecular genetic information can be obtained from the Online Mendelian Inheritance in Man (omim.org), Gene Table of Neuromuscular Disorders (musclegenetable.fr), Gene Cards human gene database (genecards.org), and MitoMap.com websites. A fuller discussion of the history, genetic, biochemistry, and pathophysiologic aspects of these disorders can be obtained from the online version of the chapter.

MYOGLOBINURIA Myoglobinuria is a clinical syndrome, not just a biochemical state. In the alert patient, myalgia and limb weakness are the most common presenting symptoms. Urine color is usually brownish rather than red, and the urine tests positive for both albumin and heme (a concentration of at least 4 µg/mL). There are few or no red blood cells. Myoglobin can be identified by immunochemical methods. The sarcoplasmic enzymes, including serum CK, are usually elevated to more than 100 times normal. Inconstant features include hyperphosphatemia, hyperuricemia, and hypocalcemia. If renal failure occurs, serum potassium and calcium levels may rise. If the patient is comatose or if the presenting disorder is one of acute renal failure, there may be no muscle symptoms or signs. Under these conditions, the diagnosis can be made if (1) there is renal failure and (2) the serum content of sarcoplasmic enzymes is 100 times normal. The potentially life-threatening hazards of an attack of myoglobinuria include renal or respiratory failure and cardiac arrhythmias. The etiologies of heritable myoglobinuria differ in adults compared with children. In a study of 77 adult patients aged 15 to 65 years, Tonin et al. (1990) identified the enzyme abnormality in 36 patients (47%) as follows: CPT deficiency in 17 patients; glycolytic defects in 15 patients (including PPL in 10, PPL b kinase in 4, and PGK in 1); myoadenylate deaminase in 3; and combined CPT and myoadenylate deaminase in 1. In contrast, in 100 cases of recurrent childhood-onset myoglobinuria, a lower percentage of children have been diagnosed biochemically (24%): 16 with CPT deficiency, 1 with SCHAD deficiency, and 7 with various glycolytic defects, including 2 PPL, 1 PGK, 3 PGAM, and 1 LDH deficiency. These children could be divided into two groups: a type I exertional group, in which exertion was the primary precipitating factor (56 cases), and a type II toxic group, in which infection and/or fever and leukocytosis were the primary precipitants (37 cases). The type II toxic childhood group was distinguished from the type I exertional childhood- and adult-onset groups by its etiologies, which were limited to FAO defects, as well as its slight female predominance, which contrasted with the marked male predominance in the latter two groups. The type II toxic group was further distinguished by the earlier age at onset of myoglobinuria, the presence of a more generalized disease (e.g., ictal bulbar signs, seizures, encephalopathy, developmental delay), and a higher mortality rate. Currently the most common etiology for recurrent myoglobinuria in both adults and children is CPT II deficiency (Tein et al., 1992).

GLYCOGENOSES Only glycogenoses affecting skeletal muscle, alone or in association with other tissues, are discussed in this section (Figure 149-1). Molecular genetic analysis has led to the cloning of genes encoding the enzymes involved in the glycogenoses,



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TABLE 149-2  Clinical Presentation of Muscle Glycogenoses Type

Enzyme Defect

Affected Tissues

Clinical Presentation

II Infancy

Acid maltase

Generalized

Cardiomegaly, weakness, hypotonia, death 12 months to 3 years, 4 hours in the daytime, 10 (to 12) hours at night; 4 to 7 years, 4 hours during day, 10 (to 12) hours at night (Spiekerkoetter et al., 2009). These fasting periods apply under healthy, steady-state conditions, when on a normocaloric diet, glycogen sores can be built up during the day and used for glucose production during longer fasting intervals at night. In the event of progressive lethargy or obtundation or an inability to take oral feedings because of vomiting, the child should be taken immediately to the emergency room for intravenous glucose therapy. Intravenous glucose should be provided at rates sufficient to prevent fatty acid mobilization (8 to 10 mg/kg/

Specific treatments for individual FAO disorders may include consideration of medium-chain triglyceride (MCT) oil for long-chain FAO disorders, riboflavin for the multiple acyl-CoA dehydrogenase deficiencies, carnitine for OCTN2 deficiency, and docosahexaenoic acid (DHA) for TFP/LCHAD deficiency, and prednisone, triheptanoin, PPAR agonists (bezafibrate), resveratrol, premature stop codon read-through drugs (gentamicin and ataluren), and gene therapy approaches for selected disorders, as discussed in more detail in the online version.

High-Carbohydrate, Low-Fat Diet In general, it is advisable to institute a high-carbohydrate, low-fat diet with frequent feedings throughout the day, which would be commensurate with the nutritional needs of the child given his or her age. This goal is best achieved with the aid of a dietitian, aiming toward approximately 60% of calories from carbohydrate sources, 15% from protein, and approximately 25% to 30% from fat. Long-chain fat intake in healthy infants is 40% to 45% of total energy, and in children of school age it is 30% to 35%. Monitoring of essential fatty acid levels is important to ensure that the child is receiving adequate essential fatty acids, as these may require supplementation. See the online version for additional details.

Uncooked Cornstarch

Clinical Monitoring On a chronic basis, clinical monitoring of individuals with FAO disorders is very important. This should include evaluation of growth, development, neurologic examination, and diet as well as reinforcement of the prevention of risk factors and management of acute crises. Yearly ophthalmologic examinations are important for long-chain FAO disorders (e.g., pigmentary retinopathy in TFP/LCHAD deficiency) and



GA II. ECG and echocardiography are important to monitor cardiac function in long-chain disorders and OCTN2 defects. Liver ultrasonography may be important in LCHAD/TFP deficiency. Biochemical follow-up should include serum carnitine total and free and serum acylcarnitines to monitor metabolic control, and CK. Essential fatty acid and DHA status should be monitored in long-chain defects. Regular follow-up and education of the child and family is important throughout life to help prevent morbidity and mortality.

Genetics and Presymptomatic Recognition All known FAO disorders are inherited as autosomal-recessive conditions. The inclusion of FAO disorders in newborn screening programs with comprehensive and consistent long-term follow-up is highly desirable to prevent morbidity and mortality, to implement preventative measures and treatment strategies, and to reduce the cost of care of affected patients.

MITOCHONDRIAL ENCEPHALOMYOPATHIES   (also refer to Chapter 42) Though all of the mitochondrial encephalomyopathies that are expressed in muscle are at potential risk for the development of myopathy and exercise intolerance, the specific defects in which acute episodes of myoglobinuria have been documented to date include defects of complexes I, II, III, and IV activities as well as multiple mtDNA deletions, mtDNA depletion syndromes, and Coenzyme Q10 (CoQ10) deficiency. Mitochondrial myopathy commonly manifests with exercise intolerance and premature fatigue, which is often out of proportion to the degree of muscle weakness. The myopathy may selectively involve the extraocular muscles (progressive external ophthalmoplegia [PEO]) and/or may extend to bulbar, limb (usually proximal but may be distal), and axial muscles. Onset may occur at any age, although more severe phenotypes present earlier in life and milder phenotypes present later in life. As there is an entire chapter dedicated to the detailed discussion of the individual mitochondrial disorders (see Chapter 42), the following sections will serve to briefly summarize and highlight the key clinical, morphologic, biochemical, genetic, and physiologic features of this group of disorders.

Morphologic Considerations Although the finding of ragged-red fibers (RRF) or ultrastructural alterations of mitochondria in muscle biopsy specimens suggests the possibility of a mitochondrial disorder, there are important limitations. These have been articulated by DiMauro (2001) as follows: 1. Nonmitochondrial disorders, such as muscular dystrophies, polymyositis, and some glycogenoses, may demonstrate RRF or ultrastructural mitochondrial abnormalities in which they likely represent secondary changes. 2. Conversely, many primary mitochondrial diseases, such as enzyme defects in metabolic pathways other than the respiratory chain (e.g., the pyruvate dehydrogenase complex [PDHC], CPT, beta-oxidation, and fumarase deficiencies), do not have RRF. In addition, there are defects of the respiratory chain, such as Leigh syndrome secondary to cytochrome c oxidase (COX) deficiency, that tend not to have RRF. RRF are often COX negative, although not all COX-negative fibers are RRF.

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A global decrease in the activity of COX is usually suggestive of a nuclear mutation in an ancillary protein required for COX assembly such as SURF1 but can also be associated with some homoplasmic mt-tRNA defects. A mosaic appearance of COX-negative fibers generally suggests an mtDNA mutation because of the variable degrees of heteroplasmy between muscle cells. There may be increased numbers of mitochondria (pleoconial myopathy), increased size (megaconial myopathy), disoriented or rarefied cristae, or osmiophilic or paracrystalline inclusions on electron microscopy. The paracrystalline inclusions are deposits of mitochondrial CK. There may also be lipid or glycogen storage on muscle biopsy, signifying a defect of terminal oxidation. It should be noted that muscle histochemistry and/or electron microscopy may be normal even in the context of genetically proven mitochondrial syndromes, particularly early in the disease course or when the biochemical abnormality does not involve complex IV (COX).

Clinical Considerations Mitochondrial diseases are clinically heterogeneous. There may be variation in the age at onset, course, and distribution of weakness in pure myopathies. On average, the age of onset reflects the level of mutation and the severity of the biochemical defects; however, other factors, including nuclear genetic and/or environmental factors, can also affect the expression of disease. Additional features may include exercise intolerance and premature fatigue. Mitochondria and mtDNA are ubiquitous, which explains why every tissue in the body can be affected by mtDNA mutations. The most common presenting clinical features include short stature, sensorineural hearing loss, migraine headaches, opthalmoparesis, myopathy, axonal neuropathy, diabetes mellitus, hypertrophic cardiomyopathy, and renal tubular acidosis. Additional features may include stroke-like episodes, seizures, myoclonus, retinitis pigmentosa, optic atrophy, ataxia, and gastrointestinal pseuoobstruction. In the case of mtDNA mutations, there may be a diverse spectrum of associated syndromes, even in a single pedigree, because of heteroplasmy and the threshold effect whereby different tissues harboring the same mtDNA mutation may be affected to different degrees or not at all. Furthermore, the same mutation can cause different syndromes (e.g., the T8993G mutation can cause either neuropathy, ataxia, retinitis pigmentosa [NARP] or maternally inherited Leigh syndrome [MILS]) and different mutations can cause the same phenotype (e.g., A3243G mutation, single deletion, and multiple deletions of the mtDNA can all cause progressive external ophthalmoplegia [PEO]). Thus the diagnosis of mtDNA-related disorders often requires a careful synthesis of the clinical history, signs, mode of inheritance, laboratory data, neuroradiological findings, exercise physiology, muscle biopsy, muscle biochemistry with measurement of respiratory chain enzyme activities in fresh or snap-frozen muscle samples, and molecular genetics.

Biochemical Classification Mitochondrial encephalomyopathies can be classified into five groups according to the area of mitochondrial metabolism specifically affected: (1) defects of transport, (2) defects of substrate utilization, (3) defects of the Krebs cycle, (4) defects of the respiratory chain, and (5) defects of oxidation/ phosphorylation coupling (Figure 149-3) (see Chapter 42). Limitations of this classification scheme relate to the respiratory chain defects that can result from genetic defects of

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mtDNA, which are usually heteroplasmic, and to deletions of mtDNA or point mutations in tRNA, which affect mtDNA translation as a whole and may lead to multiple respiratory chain defects and from genetic defects of nDNA.

Physiologic Considerations (see online version of this chapter for details) Standard exercise physiology tests, such as cycle ergometers or treadmills, can be used to detect alterations of oxidative metabolism. Maximal oxygen uptake is the most useful indicator of a patient’s capacity for oxidative metabolism. Typical physiologic responses in patients with defects in oxidative metabolism are as follows (Taivassalo et al., 2003): 1. The increase of cardiac output during exercise is greater than normal relative to the rate of oxidative metabolism. 2. Oxygen extraction per unit of blood remains almost unchanged from rest to maximal exercise. 3. Ventilation is normal at rest but increases excessively relative to oxygen uptake. 4. Venous lactate, which is usually elevated at rest, increases excessively relative to workload and oxygen uptake.

Genetic Classification (see Chapter 42) Specific defects of mtDNA and nuclear DNA with myopathy as a feature are discussed in detail in the online version (Tables 149-6 and 149-7).

Therapeutic Approaches in   Mitochondrial Diseases Overall the therapy of mitochondrial respiratory chain disorders is highly inadequate, though there are currently multiple new emerging therapeutic strategies that may hold promise for the future. The therapeutic approaches have been comprehensively reviewed. Palliative therapy: Palliative therapy includes anticonvulsants, treatment of endocrinopathies (e.g., thyroxine, insulin), adequate nutrition (enteral feeding via gastrostomy is frequently needed), pancreatic enzyme replacement, electrolyte replacement in patients with severe renal tubulopathy, renal dialysis and/or transplantation, hearing aids, blood transfusions for sideroblastic anemia, psychological support for patients and families, and surgical procedures, for example, cochlear implants for hearing loss, pacemakers for cardiac conduction blocks, surgery for cataracts and for ptosis, and liver and cardiac transplantation for related organ failure. Valproic acid should be avoided because it inhibits cellular carnitine uptake and mitochondrial OXPHOS. Valproic acid should be absolutely avoided in Alper’s disease. Other medications to be used cautiously or to be preferentially avoided include statin medications, where there should be careful monitoring of symptoms and serum CK and antiretroviral agents, which are known to cause reversible and dosedependent mitochondrial toxicity. General anesthesia: General anesthesia may be needed in individuals with mitochondrial disorders and requires special perioperative, intraoperative, and postoperative care. It is important to maintain normothermia, normoglycemia, and normal electrolytes. Given the impairment in lactate metabolism, lactated Ringer’s solution should be avoided. It has been suggested that volatile inhalational anesthetics and depolarizing muscle relaxants should be avoided and that some individuals fail to tolerate local anesthetics. A listing of anesthetic recommendations from different investigators is provided by Rivera-Cruz (2013).

Removal of noxious metabolites: Other strategies include removal of noxious metabolites, including lowering the lactic acidosis. Though dichloroacetate (DCA) lowers serum lactic acid, a double-blind, placebo-controlled, randomized, crossover trial of DCA in a cohort of MELAS patients with the A3243G mutation had to be terminated because of significant peripheral nerve toxicity. Therefore DCA should not be used long-term in mitochondrial patients prone to peripheral neuropathy. Attempts to bypass respiratory chain blocks through the administration of electron acceptors have been disappointing. Cofactor and metabolite supplementation: Cofactor and metabolite supplementation has been the mainstay of therapy, particularly in disorders of primary deficiencies, for example, CoQ10 deficiency and primary carnitine deficiency caused by OCTN2 deficiency. Supplementation with oral CoQ10 (10 to 30 mg/kg/day in children and 1200 to 3000 mg/day in adults) has been effective in patients with COQ2 mutations, especially for the neurologic and renal manifestations of this disorder. In contrast, poor responses to CoQ10 supplementation have been observed in patients with PDSS2 and COQ9 mutations. Other agents used include riboflavin, thiamine, folic acid, and creatine. Antioxidants and reactive oxygen species scavengers are an area of increasing interest, particularly in complex I and III deficiencies. Agents used have included vitamin E, CoQ10, idebenone, and dihydrolipoate. Aerobic endurance and resistance exercise and physical therapy: Aerobic endurance and resistance exercise and physical therapy help to prevent deconditioning and disuse muscle atrophy and have been shown to improve exercise tolerance in patients with mtDNA mutations through mitochondrial proliferation and gene shifting, respectively, as outlined in the online version. In a recent Cochrane review of trials with vitamin, antioxidant, and nutrient supplements (CoQ10, lipoic acid, creatine, whey-based supplement, dimethylglycine), pharmacologic agents (dichloroacetate), and exercise therapy used in mitochondrial disorders, out of 1335 abstracts, only 12 studies fulfilled criteria for randomized controlled trials (including cross-over studies) (Pfeffer et al., 2012). It was concluded that, though there were some improvements in secondary outcome measures, there was no clear evidence supporting the use of any of these interventions in mitochondrial disorders. The ideal clinical trial should be adequately powered, statistically valid, and randomized, double-blinded, placebo-controlled and include a large group of homogenous patients in terms of clinical presentation, biochemical findings, and genetic defect, ideally at a similar stage of disease progression. However, this is very difficult for mitochondrial disorders because of the marked heterogeneity of diseases with different clinical manifestations and problems, the vast number of different genetic causes that may be individually rare, and the unpredictable course of the disease. There are a number of emerging approaches that may hold future promise. Antioxidants: The accumulation of reactive oxygen species (ROS) is generally accepted as a major cause of mitochondrial disease pathogenesis, leading to depletion of glutathione (GSH). Therapeutic strategies have included analogs of CoQ10. Though CoQ10 in high doses is of proven value in CoQ10 biosynthesis defects, its use in other mitochondrial disorders is less certain. Other analogs of interest include idebenone, which has reportedly better blood-brain barrier penetration. Another synthetic analog is EPI-743, which has had some potentially encouraging results in open-label studies in Leigh disease and other progressive mitochondrial disorders, but the unpredictable course of the disease makes the interpretation of results challenging. A summary of ongoing or recent



completed clinical trials in mitochondrial disease is provided by Rahman. N-acetylcysteine combined with metronidazole has been suggested as beneficial in ethylmalonic encephalopathy arising from mutations in the ETHE1 gene. Stem cells: In mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome, the loss of thymidine phosphorylase (TP) activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which in turn cause mtDNA instability. Allogenic hematopoietic stem cell transplantation to restore TP activity and to eliminate the toxic metabolites is a promising therapy for MNGIE. Mitochondrial biogenesis: Newer pharmacologic approaches have sought to upregulate mitochondrial biogenesis. Bezafibrate, a PPAR panagonist, has been used to activate mitochondrial proliferation enhancing oxidative phosphorylation capacity per muscle mass in a murine model of mitochondrial myopathy because of cytochrome c oxidase deficiency. Other pharmacologic agents that increase mitochondrial biogenesis and are under investigation include resveratrol, which activates the sirtuin SIRT1, which in turn is responsible for NAD +-dependent deacetylation of multiple proteins, including PGC1α and the mitochondrial transcription factor TFAM. Additional agents include 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), which is a pharmacologic activator of the adenosine monophosphate kinase (AMPK)-PGC1α axis, and nicotinamide riboside, which is able to stimulate mitochondrial biogenesis by increasing NAD+ availability, leading to NAD+-dependent activation of SIRT1. Dietary approaches: Dietary approaches include the ketogenic diet as a potential treatment, particularly for the associated epilepsy, though evidence in patients remains anecdotal. Future pharmacologic approaches: A comprehensive review of future pharmacologic approaches to restore mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics (fission and fusion), mitophagy, and the mitochondrial unfolded protein response, is given by Andreux et al. (2013). New and powerful phenotypic assays in cell-based models as well as multicellular organisms have been developed to explore these different aspects of mitochondrial function for the development of new drugs. Translating the emerging therapies to the bedside remains challenging because of the lack of large cohorts of clinically, biochemically, and genetically homogenous individuals; natural history data; and validated meaningful outcome measures for use in clinical trials. However, the recent development of national and international mitochondrial disease consortia and several large natural history studies will lay the groundwork for these trials. Gene therapy: Gene therapy is a highly challenging area because of heteroplasmy and polyplasmy, but approaches have been developed to decrease the ratio of mutant to wild-type mitochondrial genomes (gene shifting), converting mutated mtDNA genes into normal nuclear DNA genes, and importing cognate genes from other species. Emerging approaches in gene therapy, currently largely experimental, include the use of restriction endonucleases with mitochondrial targeting sequences, zinc finger nucleases to selectively degrade mtDNA mutations, transcription activator–like effector (TALE) nuclease and CRISPR/Cas9 mutant gene editing, rescue by overexpression of aminoacyl tRNA synthetases, and gene therapy for nuclear-encoded mitochondrial disorders. Germline therapy: Germline therapy raises ethics issues, but may be considered in the future for prevention of maternal transmission of mtDNA mutations. Preventive therapy through genetic counseling and prenatal diagnosis is important for nuclear DNA-related disorders.

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MYOADENYLATE DEAMINASE DEFICIENCY Clinical Presentation Myoadenylate deaminase (mAMPD) deficiency is detected in 1% to 3% of all muscle biopsies and may be characterized by exercise-related myalgia and cramps. However, the pathogenetic significance of this defect is controversial because (1) in patients with unexplained myopathy, symptoms are generally mild, ill-defined, and often subjective, and (2) more than 50% of patients had either well-defined myopathies, such as Duchenne or Becker muscular dystrophy, McArdle’s disease, spinal muscular atrophy, or amyotrophic lateral sclerosis. Therefore Fishbein divided mAMPD into the following two forms: (1) a primary (hereditary) mAMPD deficiency characterized by myopathy alone with exercise intolerance, myalgia, and cramps; very low residual activity ( 2000; normal 5–37 repeats

Chromosome 3q21.3, intron 1; CCTG expansion affecting the CNP (previously zinc finger 9 protein) gene; repeat sizes vary from 75 > 11,000; normal < 75 repeats

Age of onset

Broad range of ages (infancy to adulthood), with infant onset in most severe cases; approximately 10% begin in childhood

Broad range of ages (late childhood to late adulthood)

Myopathy

Face, eyes, forearm, hands, and legs, with generalized weakness and hypotonia in affected infants

Mild; thighs, hips, neck flexors, abdominal muscles; occasional calf muscle hypertrophy

Myotonia

Primarily affects hand and forearm muscles and tongue; often absent on clinical testing in infants and young children; occasionally affects respiratory muscles and smooth muscle, such as intestine or uterus; myotonia improves with heat and exercise; myotonia results from a decrease in chloride channel protein

Mainly in hands and thighs; varies; frequently hard paraspinal muscles detect; pain occurs sometimes with and without myotonia; myotonia improves with repeated contractions; myotonia results from a decrease in chloride protein

Provocative stimuli

Myotonia worsened by rest and cold; myotonia is relatively constant in severity and muscles affected once it develops

Myotonia worsened by rest but varies in severity, occasionally being absent on clinical examination; hand grip and thigh stiffness are usual sites

Therapy for symptoms

Bracing; cataract removal; monitoring dysrhythmias and respiratory insufficiency; pacemaker; antimyotonia therapy (mexiletine); avoid depolarizing muscle relaxants, opiates, and barbiturates with surgery

Cataract removal; occasional need for pacemaker; antimyotonia therapy often not necessary (mexiletine); monitor carefully during and after surgery for muscle rigidity and rhabdomyolysis

Early in the presentation of DM2 there is only mild weakness of hip extension, thigh flexion, and finger flexion. Myotonia of grip and thigh muscle stiffness vary from minimal to moderate severity over days to weeks. Direct percussion of forearm extensor and thenar muscles is the most sensitive clinical test for myotonia in DM2 but may be absent. Myotonia of grip is sometimes prominent and often has a jerky quality that seems to differ from that in DM1 and the nondystrophic myotonias. Myotonia is often less apparent in DM2 compared with patients with DM1. In cases of late-onset DM2, myotonia may only appear on electromyographic testing after examination of several muscles. Facial weakness is mild in DM2, as is muscle wasting in the face and limbs. Weakness of neck flexors is frequent. Trouble arising from a squat is common, especially as the disease progresses. Calf muscle hypertrophy occasionally is prominent. Other manifestations, such as excessive sweating, hypogonadism, glucose intolerance, dysphagia, cardiac conduction disturbances, and cognitive/ neuropsychologic alterations may also occur and worsen over time. A higher rate of premature labor and preterm deliveries has also been reported. In contrast to DM1, respiratory insufficiency or failure and cardiac conduction disturbances are less common in DM2. Difficulty swallowing, gastrointestinal dysfunction, and cognitive disturbances do occur in DM2, but they appear to be less frequent. At present there is no clear evidence of a congenital form of DM2 (Moxley et al., 2015). When symptoms occur in childhood, they typically are transient and relate to grip myotonia in the hands and thighs (Moxley et al., 2015). Proximal weakness, muscle pain, cataracts, and occasional cardiac dysrhythmias usually do not develop until mid or late adult life.

DM1 and DM2: Genotype–Phenotype Correlations In general, the greater the length of the abnormal CTG expansion in circulating leukocytes, the more severe are the disease manifestations and the earlier is the onset (Moxley et al., 2015). There are important exceptions to this generalization. In DM2 there is no clear relationship between disease onset

and severity and the length of the abnormal CCTG repeat in circulating leukocytes (Udd and Krahe, 2012). See the online chapter for a more detailed and helpful explanation of genotype–phenotype correlations.

DIAGNOSTIC APPROACH The major problem in making the diagnosis of DM1 and DM2 is the tendency of clinicians to ignore these entities in their practice. DM1 can present as a floppy infant or as child with delayed motor and cognitive development (Figures 151-3 and 151-4 show the workup of an infant with congenital DM1 and the workup of a child suspected to have childhood DM1, respectively). There are long lists indicating more common causes for these presentations in infants and in childhood than DM1. If there is a low diagnostic suspicion of DM1, the clinician may not probe the family history sufficiently and may not examine the parents of the patient using a focused approach to search for characteristic features of DM1 (Tables 151-1 and 151-2). The failure to consider DM1 is the principal contributor to the diagnostic odyssey and delays DNA testing, family counseling, and appropriate management and treatment (Moxley et al., 2015). DM1 and DM2 present primarily in adult life. The core clinical features and the multisystem manifestations can occur in isolation or combination and usually develop gradually (Moxley et al., 2015). Muscle stiffness, muscle pain, intermittent trouble with clear speech and swallowing, dropping of items, gait instability, and trouble seeing are frequent initial symptoms (Udd and Krahe, 2012). Early-onset cataracts (typically, iridescent posterior capsular cataracts) and cardiac arrhythmias are examples of multisystem manifestations that can occur early in DM1 and DM2. In contrast, patients with other hereditary myotonic disorders, such as chloride or sodium channel myotonias, do not have cardiac arrhythmias or posterior capsular cataracts. DM1 patients occasionally present with prolonged apnea or delayed-onset apnea following general anesthesia. These complications can occur in individuals with only mild clinical signs of DM1. The risk of

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complications after general anesthesia in DM2 patients appears to be low, but until more long-term data are available, it is prudent to monitor both DM2 and DM1 patients closely during and 24 hours or more following general anesthesia (Moxley et al., 2015). The current gold standard to establish the diagnosis is DNA testing to identify the abnormally expanded CTG repeat in the DMPK gene for DM1 and the abnormally expanded CCTG repeat in the CNBP gene for DM2 (Kamsteeg et al., 2012; Udd and Krahe, 2012). If a patient suspected of having DM1 or DM2 has negative DNA testing, performance of a muscle biopsy may help establish the diagnosis of another myotonic disorder. However, if the muscle biopsy findings are typical for DM1 (increased central nuclei, atrophy of type-1 fibers, ringed fibers, subsarcolemmal masses) or DM2 (very small fibers, type-2 nuclear clumps, type-2 fiber atrophy), further genetic analysis, including bidirectional triplet-primed polymerase chain reaction (TP-PCR), may provide evidence of a mutation variant (Kamsteeg et al., 2012). The diagnosis of congenital or childhood DM1 usually involves DNA testing for abnormal CTG repeat enlargement in the DMPK gene and usually prompts additional DNA testing of family members. Immediate counseling of the family is necessary to provide an understanding of current management of DM1 at its different stages. Parents need to know that preventive therapy and in vitro fertilization are available, along with the important supportive and symptomatic treatments (Table 151-2).

LABORATORY TESTING FOR DM1 AND DM2 DM1 Testing Identifying the abnormally expanded CTG repeat in the DMPK gene isolated from circulating leukocytes establishes the diagnosis of DM1. Electromyography to detect myotonia is helpful in older children, but myotonia may be absent in infancy and early childhood. Slit-lamp examination is helpful in older children to identify the typical iridescent spokelike posterior capsular cataracts that develop early in the disease. Muscle biopsy is not necessary to diagnose DM1. Careful examination of the mothers of patients with congenital DM1 may reveal clinical signs of the disease. Creatine kinase levels are often normal or only mildly elevated in children and adults with DM1, whereas gamma glutamyltransferase levels are often high normal to significantly elevated, two- or threefold over the upper limit of normal.

DM2 Testing Leukocyte DNA testing is also available for DM2 (Kamsteeg et  al., 2012). Slit-lamp examination to detect early cataract formation and electromyography, especially of the first dorsal interosseous, anterior tibialis, and anterior thigh muscles, are useful. Grip myotonia varies in severity and may be absent. Some patients have an elevation (twofold to eightfold) in creatine kinase and gamma glutamyltransferase levels. Muscle biopsy in DM1 and DM2 is rarely necessary for diagnosis.

TREATMENT OF DM1 AND DM2 DM1 Treatment Table 151-2 summarizes treatment of the typical multisystem problems that occur in congenital and childhood-onset DM1. Treating patients with congenital myotonic dystrophy involves ventilatory support, use of a feeding tube, bracing for clubfoot deformities when present, and occasional corrective surgery

for foot deformities (Moxley et al., 2015). Speech problems and abdominal pain may improve with antimyotonia treatment. Mexiletine is sometimes helpful in alleviating some of the symptoms, especially in later childhood or adolescence when patients may have recurrent dislocation of the mandible and pain and muscle spasm in the masseter muscles. Electrocardiographic monitoring is necessary on a regular basis, particularly during treatment with mexiletine, to search for covert dysrhythmias. Treatment should be coordinated with the child’s school to ensure that cognitive deficiencies and hearing deficits are monitored. The increased risk for cardiac dysrhythmia and apnea after administration of general anesthesia for surgery requires overnight hospitalization with monitoring. Apnea can develop several hours after a patient has been extubated. No specific limitation on physical activity is necessary during childhood provided the child has gained sufficient strength and coordination to carry out activities requested in the school environment.

DM2 Treatment In general, the management of DM2 is similar to that of DM1, but there is less need for supportive care, such as bracing, scooters, or wheelchairs (Moxley et al., 2015). Cataracts require monitoring, and serial monitoring with an electrocardiogram (ECG) is necessary to check for covert dysrhythmia. Disturbances in cardiac rhythm are less frequent in DM2, but abnormalities do occur. Hypogonadism and insulin resistance need monitoring as in DM1. Myotonia tends to be less marked and less troublesome in DM2, but in specific circumstances antimyotonia therapy is helpful, especially if muscle stiffness is frequent and persistent or if pain is prominent. Cognitive difficulties also occur in DM2 as in DM1, but the changes are less severe than in DM1. Management of these brain symptoms is similar to that for DM1. A frequent and difficult problem in DM2 is the peculiar muscle pain described earlier. Carbamazepine or mexiletine along with nonsteroidal antiinflammatory medications or Tylenol ameliorate this pain in some patients.

AUTOSOMAL-DOMINANT AND AUTOSOMALRECESSIVE MYOTONIA CONGENITA Thomsen’s disease (autosomal-dominant myotonia congenita) and Becker’s disease (autosomal-recessive myotonia congenita) represent two forms of chloride channelopathies (Heatwole et al., 2013; Statland and Barohn, 2013; Suetterlin et al., 2014; Jurkat-Rott et al., 2015) (Table 151-3). The chloride channelopathies that produce myotonia as their primary symptom resemble the sodium channel disorders without periodic paralysis and may resemble mild forms of DM1 and DM2. Other causes of muscle stiffness or poor coordination, including central nervous system diseases affecting the frontal lobes, brainstem, and cerebellum, require initial consideration but are rarely confused with these channelopathies.

Clinical Features Generalized myotonia is the major clinical symptom in dominant and recessive forms of chloride channel myotonia congenita. Recent studies indicate pain occurs in almost 30% of patients with chloride channel myotonia, and as many as 75% have mild generalized muscle weakness that is slightly greater proximally. Symptoms develop in the first or second decade of life. Myotonic stiffness occurs with sudden physical exertion after a period of rest. Repeated muscle contractions ameliorate the stiffness. This response is the “warm-up phenomenon,”



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TABLE 151-3  Chloride Channel Myotonias Clinical Features

Autosomal-Dominant Myotonia Congenita of Thomsen

Autosomal-Recessive Generalized Myotonia of Becker

Inheritance

Dominant

Recessive

Gene defect

Chromosome 7; mutation in skeletal muscle chloride channel

Chromosome 7; mutation in skeletal muscle chloride channel

Age of onset

Infancy to early childhood

Late childhood, occasionally starts earlier or begins in teens

Myopathy

Muscle hypertrophy frequent; no myopathy, although variants uncommonly develop weakness

Occasional muscle wasting and weakness can occur late; hypertrophy of muscles frequently occurs in legs

Myotonia

Generalized stiffness, especially after rest; improves with exercise; prominent myotonia of eye closure, but not paradoxical myotonia

Generalized stiffness, especially after rest; transient weakness is prominent after complete relaxation for several minutes; myotonia occurs in eyes; no paradoxical myotonia

Provocative stimuli

Prolonged rest or maintenance of the posture

Prolonged rest or maintenance of the same posture

Therapy for symptoms

Exercise; antimyotonia therapy (e.g., mexiletine); Achilles’ tendon stretching helps prevent need for heel cord– lengthening surgery

Exercise; especially avoiding prolonged rest; antimyotonia therapy (e.g., mexiletine); transient weakness does not improve after mexiletine

which helps distinguish chloride channel myotonia congenita from certain forms of sodium channel myotonia that display increasing muscle stiffness with repeated contractions, a paramyotonic response. DM1 and DM2, like chloride channel myotonia, demonstrate the typical warm-up response. In contrast to Thomsen’s disease, patients with autosomalrecessive myotonia congenita (Becker’s disease) have transient proximal muscle weakness. The transient weakness appears for a few seconds during the initial attempt at a specific movement after a period of inactivity. Muscle strength improves to normal after several strong contractions. Patients have prominent muscle hypertrophy, especially in the legs, in both the autosomal-dominant and autosomalrecessive forms of myotonia congenita. Tendon reflexes, cerebellar function, sensation, and strength are normal. Myotonia can be noted with hand contraction or after eye closure. If patients lie supine for 5 to 10 minutes and suddenly arise, generalized myotonic stiffness in the proximal and paraspinous muscles becomes apparent. The estimated prevalence of autosomal-dominant myotonia congenita is 0.14/100,000, and the prevalence for autosomal-recessive myotonia congenita is 0.12/100,000.

Genetics Point mutations in the gene for the skeletal muscle chloride channel cause both autosomal-dominant and autosomalrecessive forms of myotonia congenita (Jurkat-Rott et al., 2015). Over 100 mutations of the CLCN1 gene have been associated with myotonia congenita.

Pathophysiology See the online chapter for commentary on pathophysiology.

Clinical Laboratory Tests Evaluation of patients with suspected myotonia congenita should include consideration of other myotonic disorders, such as DM1, DM2, paramyotonia congenita, sodium channel myotonias of other types, and chondrodystrophic myotonia (Schwartz–Jampel syndrome). Distinguishing patients with chloride channel myotonia, either the autosomal-dominant or autosomal-recessive form, from those with sodium channel myotonic disorders is often difficult. Both cause myotonic

stiffness and muscle hypertrophy, especially in the legs. One distinguishing feature of sodium channel myotonia is the paradoxical myotonia of the eyelids that develops with repeated forceful eye closure. In contrast, patients with autosomal-dominant and autosomal-recessive forms of chloride channel myotonia exhibit warm-up after repeated contractions. Patients with chloride channel myotonia do not have a worsening of myotonic stiffness or paralysis after prolonged exposure of muscle to cold. To search for cold-induced paralysis, it is necessary to soak the hand or forearm muscles in cold water (15° C) for 15 to 20 minutes. If there is weakness with exercise after this cold exposure, this observation strongly favors sodium channel myotonia rather than chloride channel disease (Heatwole and Moxley, 2007). Electrodiagnostic studies should be considered in every patient suspected of having a myotonic disorder or channelopathy. Short and long exercise tests can identify differentiating patterns associated with specific channelopathies or myotonic conditions.

Treatment Antimyotonia treatment with mexiletine is often helpful (Heatwole and Moxley, 2007). Before initiating treatment with mexiletine, a baseline ECG is necessary to identify patients with unsuspected cardiac conduction abnormalities. Side effects of mexiletine, which are usually mild and dose related, include dysgeusia, light-headedness, and diarrhea. Carbamazepine is an alternative antimyotonia medication to consider for myotonia congenita. Children with moderately severe myotonia develop heel cord shortening and contractures at their elbows. If these contractures do not respond to stretching and other physical therapy exercises, it is appropriate to initiate antimyotonia treatment even when patients do not complain of stiffness.

ACETAZOLAMIDE-RESPONSIVE   SODIUM CHANNEL MYOTONIA AND   MYOTONIA FLUCTUANS Two disorders that mimic myotonia congenita and are forms of sodium channel myotonia without periodic paralysis are acetazolamide-responsive sodium channel myotonia and myotonia fluctuans (Heatwole and Moxley, 2007) (Table 151-4).

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TABLE 151-4  Sodium Channel Myotonias Without Periodic Paralysis Clinical Features

Acetazolamide-Responsive Sodium Channel Myotonia

Myotonia Fluctuans

Inheritance

Dominant

Dominant

Gene defect

Chromosome 17; mutation in skeletal muscle sodium channel

Chromosome 17; mutation in skeletal muscle sodium channel

Age of onset

First decade

First or second decade

Myopathy

Rare

Rare, muscle hypertrophy common

Myotonia

Face, paraspinal muscles, paradoxical myotonia of eyelids, grip limbs; varies in severity and often there is pain with myotonia

Face, limbs, eyelids; frequently fluctuates in severity; especially after exercise

Provocative stimuli

Fasting, cold, oral potassium, infection

Exercise–rest–exercise, oral potassium

Therapy for symptoms

Acetazolamide, mexiletine; avoid high-potassium diet; monitor during and after surgery for rigidity and rhabdomyolysis

Mexiletine; avoid high-potassium diet; monitor during and after surgery for rigidity and rhabdomyolysis

Clinical Features

Pathophysiology

Acetazolamide-responsive sodium channel myotonia often initially presents to the pediatrician rather than the neurologist with common complaints, such as clumsiness causing frequent falls, a lazy eye, growing pains, back muscle spasm, or stridor. Parents may observe that after prolonged crying, an infant or young child will have “their eyes stuck.” This symptom is a manifestation of paradoxical eyelid myotonia that develops with repeated bouts of forceful closure of the eyes during crying. Myotonia is most apparent in the face, eyes, and larynx in very young patients. Stiffness in the hands, proximal limb muscles, and paraspinous muscles is more apparent in middle childhood. Muscle hypertrophy, especially in the legs, is frequent. Cerebellar function, sensory testing, tendon reflexes, and muscle strength are normal. Grip and percussion myotonia, and lid lag, are present. The severity of these complaints varies both in affected individuals within the same kindred and between kindreds. Episodes of painful muscle spasm occur in some patients, usually during or immediately after exercise. Pain is relatively infrequent in recessive and dominant chloride channel myotonias. In contrast, pain is common and can be severe in acetazolamideresponsive sodium channel myotonia and in DM2. The clinical findings in myotonia fluctuans are similar to those described previously for acetazolamide-responsive sodium channel myotonia, with one important additional finding. The severity of the muscle stiffness fluctuates to a greater degree in this illness. On “good days” the myotonia can vanish. The fluctuating myotonia also has an interesting relationship with prolonged exercise. A phenomenon termed exercise-induced delayed-onset myotonia occurs. Patients report that after a period of rest following vigorous exercise, if they resume exercise “at the wrong time,” severe muscle stiffness may develop. The time interval between the period of rest and the resumption of exercise is critical. If it is only a few minutes or an hour or more, stiffness does not occur. During the intermediate time interval, the fluctuation and provocation of severe myotonia happen. The myotonic symptoms in both acetazolamide-responsive sodium channel myotonia and myotonia fluctuans tend to persist throughout a patient’s lifetime. Some individuals note a lessening in severity in middle to late adulthood. This finding may represent only an adjustment to the illness and a decrease in physical activity.

See the online chapter for commentary on pathophysiology.

Genetics See Table 151-4 and the Genetics section in the online chapter for more information.

Clinical Laboratory Tests Laboratories may screen for known mutations in the gene for the sodium channel in selected patients (Jurkat-Rott et al., 2015; Statland and Barohn, 2013; Suetterlin et al., 2014). The remainder of the laboratory evaluation is as described previously for chloride channel myotonia.

Treatment Acetazolamide often controls myotonic stiffness and pain in acetazolamide-responsive sodium channel myotonia (Heatwole and Moxley, 2007). This treatment usually ameliorates the muscle pain. Annual ultrasound of the abdomen is useful to detect early formation of kidney stones, which are a common complication of acetazolamide. Dysesthesia and dysgeusia typically occur. For attacks of severe muscle spasm and pain, cyclobenzaprine can be tried. Patients undergoing surgery require monitoring during and after the procedure for signs of worsening muscle stiffness. Maintaining plasma potassium levels between 3.8 and 4.2 mEq/L helps to decrease perioperative muscle stiffness. Stress, muscle tissue damage, and bleeding all elevate plasma potassium levels and worsen myotonia. Postoperatively, intravenous diazepam or lorazepam may be necessary to decrease myotonic stiffness, especially if patients are unable to take medications by mouth. Mexiletine is an effective alternative to acetazolamide, and, if necessary, these drugs can be used in combination (Heatwole and Moxley, 2007). The management of myotonia fluctuans is similar to that of acetazolamide-responsive sodium channel myotonia. Careful attention to the pattern and timing of exercise helps to decrease episodes of severe muscle stiffness. Intraoperative and postoperative monitoring is important, as noted previously.

THE PERIODIC PARALYSES This section focuses on those disorders listed in Tables 151-5 and 151-6, which are associated with periodic paralyses, including channelopathies affecting the sodium, potassium, and calcium channels in skeletal muscle. See the online chapter for commentary on general classification and features of the periodic paralyses.



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TABLE 151-5  Sodium Channel Myotonias With Periodic Paralysis Clinical Features

Paramyotonia Congenita

Paramyotonia Congenita With Hyperkalemic Periodic Paralysis

Hyperkalemic Periodic Paralysis With Myotonia

Inheritance

Dominant

Dominant

Dominant

Gene defect

Chromosome 17; mutation in skeletal muscle sodium channel

Chromosome 17; mutation in skeletal muscle sodium channel

Chromosome 17; mutation in skeletal muscle sodium channel

Age of onset

First decade

First decade

First decade

Myopathy

Very rare

Rare

Infrequent

Myotonia

Especially paradoxical myotonia of the eyelids, and grip

Especially paradoxical myotonia of the eyelids, and grip

Especially paradoxical myotonia of the eyelids

Provocative stimuli

Cold exposure followed by exercise leads to focal paralysis; occasionally exercise provokes stiffness

Oral potassium load, rest after exercise mainly in morning (hyperkalemic weakness), cold exposure followed by exercise (focal paralysis)

Rest after exercise, cold, oral potassium

Therapy for symptoms

Mexiletine, mild exercise, keep patient warm

Mild exercise, thiazides, mexiletine

Thiazides, acetazolamide, sodium restriction

TABLE 151-6  Channelopathies With Hypokalemic Periodic Paralysis Clinical Features

Andersen’s Syndrome: Periodic Paralysis With Cardiac Dysrhythmia

Calcium Channel Periodic Paralysis

Sodium Channel Periodic Paralysis

Potassium Channel Periodic Paralysis

Periodic Paralysis With Thyroid Disease

Inheritance

Dominant

Dominant

Dominant

Dominant

Sporadic-occasionally dominant

Age of onset

First or second decade

First to third decade

First to third decade

Not yet determined

Third decade (males 20 : 1)

Myopathy

Typical; also short stature; dysmorphic features; prolonged QT interval on electrocardiogram; ventricular dysrhythmias

Moderately common late; vacuoles frequently seen on biopsy

Not yet determined

Not yet determined

Infrequent

Myotonia

No

No

No

No

No

Provocative stimuli

Rest after exercise, oral glucose

High-carbohydrate meals, rest after exercise, cold, emotional stress/ excitement

High-carbohydrate meals, rest after exercise, cold, emotional stress/ excitement

Usually by strenuous exercise followed by rest; less consistent provocation after high carbohydrate intake

High-carbohydrate meals, rest after exercise, acetazolamide

Therapy for symptoms

Mild exercise, glucose, high sodium intake, acetazolamide, dichlorphenamide

Acetazolamide, dichlorphenamide, potassium, spirolactone

Acetazolamide, dichlorphenamide, potassium, spirolactone

Acetazolamide

Propranolol, restoration of euthyroid state, oral potassium, spironolactone

Hyperkalemic Periodic Paralysis Clinical Features Table 151-5 outlines the major clinical and diagnostic features of hyperkalemic periodic paralysis and important issues in management. All three forms are autosomal dominant with high penetrance in both sexes (Cannon, 2002). Attacks begin in childhood and are usually brief, being shorter and more frequent than attacks in hypokalemic periodic paralysis. The attacks can occur with or without myotonia; in certain families, hyperkalemic paralysis occurs in combination with coexisting paramyotonia congenita (Jurkat-Rott et al., 2015; Statland and Barohn, 2013; Cannon, 2002; Heatwole and Moxley, 2007). At the onset of an attack, myalgia may develop. Patients with hyperkalemic periodic paralysis plus myotonia frequently develop muscle stiffness and prominent paradoxical myotonia of the eyelids during attacks. Similar symptoms occur in patients with hyperkalemic periodic paralysis in association with paramyotonia congenita (Jurkat-Rott et al.,

2015; Statland and Barohn, 2013). Most patients with hyperkalemic attacks manifest signs of myotonia and notice increasing muscle tension, especially in the paraspinous muscles. The estimated prevalence of hyperkalemic periodic paralysis is 0.13/100,000.

Genetics See Table 151-5 and the Genetics section in the online chapter for more information.

Pathophysiology See the online chapter for commentary on pathophysiology.

Clinical Laboratory Tests The primary laboratory evaluation involves monitoring of serum electrolytes during attacks to identify hyperkalemia or hypokalemia and monitoring the ECG to search for any evidence of dysrhythmia or other conduction disturbance, such

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as the ECG changes that occur in Andersen–Tawil syndrome. A dominant family history helps to limit additional laboratory testing to search for secondary forms of hyperkalemia, which might lead to muscle weakness. Laboratory evaluation for secondary hyperkalemic weakness should include a search for hormonal disturbances, such as insulin deficiency or adrenal insufficiency, or toxic effects of medications, such as betaadrenergic antagonists, alpha-adrenergic agonists, digitalis intoxication, or the use of succinylcholine. Full gene screening can be performed for mutations in the skeletal muscle sodium, chloride, calcium, and potassium channel genes to search for a mutation to account for one of the forms of nondystrophic myotonia or one of the forms of periodic paralysis (Jurkat-Rott et al., 2015; Statland and Barohn, 2013; Suetterlin et al., 2014). In patients not observed during a spontaneous attack of weakness or posing a continuing problem in definite classification of the form of periodic paralysis, it may be necessary to perform provocative testing with oral potassium loading or exercise followed by potassium challenge. Electrodiagnostic testing including short and long exercise tests may also provide diagnostic utility (Statland and Barohn, 2013).

Treatment Attacks of weakness in hyperkalemic periodic paralysis are seldom severe enough to require emergency room evaluation. Oral glucose hastens recovery. Severe attacks usually respond to oral glucose and crystalline insulin subcutaneously. Occasionally, severe attacks may fail to respond to these treatments. Calcium gluconate is sometimes effective. Inhalation of betaadrenergic agents, such as metaproterenol, every 15 minutes for three doses has also been utilized. Preventive treatment includes avoidance of fasting, exposure to cold, and overexertion. A prudent consumption of frequent meals high in carbohydrate content is helpful. Diuretics that promote kaluresis, such as hydrochlorothiazide and carbonic anhydrase inhibitors, are good primary therapies (Heatwole and Moxley, 2007).

Paramyotonia Congenita Clinical Features Symptoms develop usually during the first decade of life and have a predilection for facial, lingual, neck, and hand muscles (see Table 151-5) (Jurkat-Rott et al., 2015; Heatwole and Moxley, 2007). Attacks of increased muscle stiffness followed by paralysis occur on exposure to cold followed by exercise. The hallmark clinical sign is paradoxical myotonia or paramyotonia, that is, stiffness that worsens with repeated muscle contraction. This sign is most prominent in the muscles of eye closure. Clinical myotonia may be restricted to the eye muscles and not be apparent in grip or after percussion. Some patients experience lid lag and diplopia. See the online chapter for commentary on rare severe variants. The estimated prevalence of this paramyotonia congenita is 0.17/100,000.

Genetics Mutations in the gene for the skeletal muscle sodium channel in several locations cause paramyotonia congenita (Jurkat-Rott et al., 2015; Matthews et al., 2010). See the online chapter for more details.

Clinical Laboratory Tests Standardized testing using immersion of the hand and forearm in cold water for 15 minutes followed by exercise is effective in provoking paramyotonic stiffness and paralysis in most patients. Most cooperative children can tolerate this testing. If

no clear evidence of cold-induced muscle stiffness and weakness is apparent, further laboratory testing as indicated previously under hyperkalemic periodic paralysis and as noted under laboratory tests for chloride channel myotonia may be necessary. Repetitive nerve stimulation of the ulnar nerve at the wrist as a short exercise test before and after cold exposure helps to identify certain forms of sodium channel myotonia, including paramyotonia congenita, but it is uncomfortable and has been standardized only in adults. DNA analysis to search for known mutations in the gene for the sodium channel is available (Jurkat-Rott et al., 2015; Statland and Barohn, 2013; Matthews et al., 2010).

Pathophysiology See the online chapter for commentary on pathophysiology.

Treatment Mexiletine is usually effective in preventing attacks of coldinduced weakness (Heatwole and Moxley, 2007). Patients having the combination of paramyotonia congenita plus hyperkalemic periodic paralysis require additional treatment with either a thiazide diuretic or acetazolamide.

Hypokalemic Periodic Paralysis Hypokalemic periodic paralysis is an autosomal-dominant disorder caused most commonly by mutations in the alpha subunit of the skeletal muscle calcium channel gene Cav1.1 (Jurkat-Rott et al., 2015; Statland and Barohn, 2013). A clinically identical form of hypokalemic periodic paralysis can also result from specific mutations of the alpha subunit of the Nav1.4 skeletal muscle sodium channel associated with hyperkalemic periodic paralysis (Jurkat-Rott et al., 2015; Statland and Barohn, 2013). Approximately 60% of cases are caused by missense mutations of the calcium channel gene, Cav1.1, and 15% to 20% of cases are caused by mutations in the sodium channel gene, Nav1.4. The estimated prevalence is 0.17/100,00.

Clinical Features Attacks of hypokalemic periodic paralysis usually have their onset in the first or second decade, and about 60% of patients are affected before the age of 16 years (Jurkat-Rott et al., 2015; Statland and Barohn, 2013). Rarely, attacks occur in infancy. Initially, attacks tend to be infrequent but eventually may recur daily. Diurnal fluctuations in strength may develop so that patients demonstrate greatest weakness during the night or early morning hours and gradually gain strength as the day passes. During major attacks, the serum potassium level decreases but not always to below normal. There is urinary retention of sodium, potassium, chloride, and water. Oliguria or anuria develops during such attacks, and patients tend to be constipated. Sinus bradycardia and ECG signs of hypokalemia appear when the serum potassium falls below normal. Usually during the fourth and fifth decades of life, attacks become less frequent and may cease. However, repeated attacks may leave the patient with permanent residual weakness (Jurkat-Rott et al., 2015). Treatment with acetazolamide can aggravate hypokalemic periodic paralysis caused by sodium channel mutations in some but not all kindreds.

Genetics In most kindreds familial hypokalemic periodic paralysis results from missense mutations at charged residues of the S4 voltage-sensing segments in either the L-type voltage-gated calcium channel Cav1.1 encoded by the CACNA1S gene or in the voltage-gated sodium channel Nav1.4.



Pathophysiology See the online chapter for commentary on pathophysiology.

Clinical Laboratory Tests Evaluation of serum electrolytes and ECG during attacks of weakness is essential to diagnosis and treatment. Muscle biopsy is usually not necessary but may reveal vacuoles, especially in patients with fixed weakness. In patients not observed during attacks of weakness, it may be necessary to undertake careful provocative testing if DNA analysis does not identify the responsible mutation. This testing requires hospitalization and continuous monitoring of the ECG, as indicated in previously published protocols. Occasionally, hypokalemic paralysis develops from acquired, secondary causes. Causes for secondary hypokalemic weakness include the following: hypokalemia in association with hyperthyroidism, betaadrenergic stimulation, excessive insulin, alkalemia, barium poisoning, poor potassium intake (e.g., alcoholics, anorexia nervosa), excessive potassium excretion (e.g., diarrhea, laxative abuse, profuse sweating during athletic training), and renal loss of potassium (e.g., renal tubular acidosis, osmotic diuresis, and medication use, such as large doses of penicillin antibiotics).

Treatment Acute attacks may respond to oral potassium chloride. Monitoring of ECGs, serum potassium levels, and muscle strength helps determine the frequency of these doses. Milder attacks resolve spontaneously, and mild exercise of the weakened muscles speeds recovery. If a patient has a severe attack and is unable to swallow or is vomiting, very cautious intravenous infusion of potassium may be necessary. Treating physicians should keep in mind that a patient’s serum potassium levels do not represent a total body deficit of potassium but rather a temporary intracellular shift. Therefore potassium replacement formulas tend to overestimate the replacement needs and result in potentially dangerous hyperkalemia. Preventive therapy for attacks of hypokalemic weakness is usually needed. A low-sodium (2–3 g/day) and low-carbohydrate (60–80 g/ day) diet, avoidance of exposure to cold and overexertion, and supplemental doses of potassium chloride taken two to four times daily are preventive measures that may help. However, no convincing data are available to indicate that oral potassium chloride prevents attacks. Acetazolamide in divided doses usually abolishes attacks of weakness in most patients when taken daily. Dichlorphenamide is another carbonic anhydrase inhibitor that is useful as preventive treatment if acetazolamide proves ineffective. Carbonic anhydrase inhibitors produce a metabolic acidosis, and despite their kaluretic action and their tendency to lower serum potassium levels, they appear to act on skeletal muscle to stabilize potassium flux, especially during insulin stimulation. There are rare familial cases of hypokalemic periodic paralysis in which acetazolamide exacerbates attacks of weakness. This weakness appears to be a consistent but not universal feature of hypokalemic periodic paralysis families carrying sodium channel mutations. In these families, triamterene or spironolactone may control the attacks.

Periodic Paralysis With Cardiac Arrhythmia: Andersen–Tawil Syndrome Clinical Features Andersen syndrome (Jurkat-Rott et al., 2015; Statland and Barohn, 2013) or, as recently recognized, Andersen–Tawil

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syndrome, is a rare inherited disorder with an estimated prevalence of 0.08/100,000 that is characterized by periodic paralysis, long QT syndrome, ventricular dysrhythmias, and skeletal developmental abnormalities. Skeletal abnormalities include low-set ears, widely spaced eyes, scoliosis, short stature, small mandibles, and fifth-digit clinodactyly (Statland and Barohn, 2013). The early reports of this disorder raised the possibility of hyperkalemia during attacks of weakness, but as more specific identification of kindreds with Andersen– Tawil syndrome has occurred, it is apparent that the disorder occurs with both hyper- and hypokalemia. One form is a variant of hypokalemic periodic paralysis. Patients with this type of hypokalemic weakness have short stature, clinodactyly, and microcephaly, and ventricular dysrhythmias (Figure 151-7). Attacks of weakness develop during the first or second decade. The attacks of limb weakness can vary from mild, resembling those in the sodium channel form of hyperkalemic periodic paralysis, to severe, resembling the typical calcium channel form of hypokalemic periodic paralysis. The major difference is that occasionally the episodes of weakness are associated with syncopal attacks and rarely sudden death. The cardiac arrhythmias and extrasystoles improve with an elevation in extracellular potassium, whereas hypokalemia tends to aggravate the cardiac dysrhythmias. Cardiac symptoms can be provoked by digitalis; are refractory to disopyramide phosphate, propranolol, and phenytoin; and may respond to imipramine. Weakness and cardiac symptoms in some patients occur following corticosteroid treatment. Patients with Andersen–Tawil syndrome have a neurocognitive phenotype, with individuals having deficits in executive function and abstract reasoning compared with their siblings. Isolated reports have also identified patients with afebrile seizures, dilated cardiomyopathies, and renal tubular defects (Statland and Barohn, 2013).

Genetics One of the responsible mutations involves the KCNJ2 gene encoding the inward-rectifying potassium channel Kir2.1. Autosomal-dominant inheritance occurs with variable severity within families. See the online version of chapter for more information.

Pathophysiology See the online chapter for commentary on pathophysiology.

Clinical Laboratory Tests Periodic monitoring of the ECG (or Holter monitoring) is important to identify covert dysrhythmias. ECG can reveal premature ventricular contractions, QT interval prolongation, large U-waves, and bidirectional ventricular tachycardia. DNA testing is helpful in confirming the diagnosis. Secondary forms of periodic paralysis must be ruled out with assessments of thyroid, renal, and adrenal functions. Muscle biopsy may help to distinguish patients with Andersen–Tawil syndrome from those with other myopathic disorders, especially various congenital myopathies. Electrophysiologic cold studies are helpful in confirming the presence of skeletal muscle membrane and excitability using the exercise nerve conduction study, which can in many patients distinguish those with known sodium, chloride, and calcium channel mutations from individuals with Andersen–Tawil syndrome.

Treatment Acetazolamide in doses used to treat sodium channel forms of hyperkalemic periodic paralysis is sometimes effective in preventing attacks of weakness. Dichlorphenamide or

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flecainide may provide an effective alternative if acetazolamide fails. Oral potassium repletement with ECG monitoring can be used during episodic weakness if a patient’s serum potassium concentration is low (Statland and Barohn, 2013). If serum levels of potassium are high, exercise or carbohydrates may shorten an attack. Cardiac dysrhythmias are less frequent if serum potassium is permitted to range from 4 to 4.4 mEq/L. However, this elevation in potassium may be difficult to achieve because it is typically not feasible with the use of carbonic anhydrase inhibitors. In general, agents that create drug-induced hypokalemia or prolong QT intervals should be avoided. Management of the cardiac dysrhythmia is best handled by a cardiologist. Cardiac dysrhythmia in this condition is typically difficult to control and can result in sudden cardiac death.

Thyrotoxic Periodic Paralysis Clinical Features Attacks of thyrotoxic periodic paralysis tend to develop in the late teens and during the 20s. Thyrotoxic periodic paralysis is much more frequent in Asians and males; 95% of cases are sporadic. Precipitating factors include sleep, hot weather, and excessive physical activity. Recurrent attacks of weakness may occur in over 60% of patients who have not returned to the euthyroid state. Cardiac problems, including sinus tachycardia, atrial fibrillation, supraventricular tachycardia, and ventricular fibrillation, can occur.

Pathophysiology See the online chapter for commentary on pathophysiology.

Genetics The gene defect responsible for thyrotoxic hypokalemic periodic paralysis remains unclear. See the online chapter for more information.

Clinical Laboratory Tests Measurement of thyroid function tests and the ECG are essential in establishing the diagnosis and in directing treatment. Other aspects of clinical laboratory evaluation are as described for familial hypokalemic periodic paralysis.

Treatment Treatment consists of antithyroid therapy until the patient achieves the euthyroid state. Preventive measures should be undertaken after treatment of the acute attack as described for primary familial hypokalemic periodic paralysis. Propranolol is often effective in preventing attacks in thyrotoxic periodic paralysis. Recent studies emphasize the importance of propranolol as an initial treatment and suggest caution about the use of potassium replacement. Acetazolamide is ineffective and may worsen or precipitate symptoms in thyrotoxic hypokalemic periodic paralysis and should be avoided. In general, beta-blocking drugs are helpful to use throughout the early stages of management until the patient becomes euthyroid. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details.

SELECTED REFERENCES Cannon, S.C., 2002. An expanding view for the molecular basis of familial periodic paralysis. Neuromuscul. Disord. 12 (6), 533–543. Heatwole, C.R., Moxley, R.T. III, 2007. The nondystrophic myotonias. Neurother. 4 (2), 238–251. Heatwole, C.R., Statland, J.M., Logigian, E.L., 2013. The diagnosis and treatment of myotonic disorders. Muscle Nerve 47 (5), 632–648. Jurkat-Rott, K., Rudel, R., Lehmann-Horn, F., 2015. Muscle Channelopathies: Myotonias and Periodic Paralyses. In: Darras, B.T., Roydon Jones, H., Ryan, M.M., et al. (Eds.), Neuromuscular Disorders of Infancy, Childhood and Adolescence. Elsevier, London, pp. 719–734. Kamsteeg, E.J., Kress, W., Catalli, C., et al., 2012. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2. Eur. J. Hum. Genet. 20 (12), 1203–1208. Matthews, E., Fialho, D., Tan, S.V., et al., 2010. The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment. Brain 133 (Pt 1), 9–22. Moxley, R.T., Ciafaloni, E., Guntrum, D., 2015. Myotonic Dystrophy. In: Darras, B.T., Jones, R., Ryan, M.M., et al. (Eds.), Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Elsevier, London, pp. 697–718. Statland, J.M., Barohn, R.J., 2013. Muscle channelopathies: the nondystrophic myotonias and periodic paralyses. Continuum (Minneap Minn) 19 (6 Muscle Disease), 1598–1614. Suetterlin, K., Mannikko, R., Hanna, M.G., 2014. Muscle channelopathies: recent advances in genetics, pathophysiology and therapy. Curr. Opin. Neurol. 27 (5), 583–590. Udd, B., Krahe, R., 2012. The myotonic dystrophies: molecular, clinical, and therapeutic challenges. Lancet Neurol. 11 (10), 891–905.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig 151-1 Mother and her son affected by myotonic dystrophy type 1 child with DM1 riding his tricycle, and a mother with her two daughters affected by myotonic dystrophy type 1. Fig 151-2 Postulated pathologic mechanisms underlying myotonic dystrophy types 1 and 2. Fig 151-3 Evaluation of infant with decreased facial movement and one or more of these other findings: suspect congenital myotonic dystrophy. Fig 151-4 Evaluation of child with developmental and/or cognitive delay: suspect childhood myotonic dystrophy type 1. Fig 151-5 Comparison of up and down gaze and eye closure. Fig 151-6 A patient with acetazolamide-responsive sodium channel myotonia. Fig 151-7 Andersen syndrome Table 151-2 Summary of Clinical Problems of Congenital Myotonic Dystrophy in Infants and Childhood Onset (1–10 years old) Myotonic Dystrophy Type 1 (DM1) and Their Management

152  Management of Children with Neuromuscular Disorders Dennis J. Matthews, Joyce Oleszek, Julie A. Parsons, and Oren Kupfer

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

The management of pediatric neuromuscular disorders is complex and challenging. Developing an effective management plan requires an understanding of the underlying pathophysiology, genetics, and natural history, as well as the interactions of normal maturation, treatment modalities, and the environment. Optimum management requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder (Bushby et al., 2009). Implementing comprehensive management strategies can favorably alter the natural history of the disorder and improve function, quality of life, and longevity (Fig. 152-1). This chapter will discuss general recommendations for management of pediatric neuromuscular disorders along with specific recommendation for individual diseases. Appropriate management of patients with neuromuscular disorders requires an accurate diagnosis, including the relevant patient and family history, and focused general, musculoskeletal, neurologic, and functional physical examinations. All diagnostic information should be interpreted, not in isolation, but within the context of relevant historical information, family history, examination findings, laboratory data, molecular diagnostic studies, electrophysiologic findings, and pathologic information, if obtained (McDonald, 2010). Therapeutic treatment includes early intervention, ageappropriate functional training, therapy programs, play, therapeutic exercise, adjustment to disability support and transition planning. Engaging in play activities and working on developing activities of daily living are the primary mechanisms by which children with neuromuscular disorders can maintain muscle strength. The available evidence suggests that in patients with neuromuscular diseases, both strength training and aerobic exercise programs appear to be safe, without any notable deleterious effects. Gentle, low impact aerobic exercise (swimming, stationary bicycling) improves cardiovascular performance, increases muscle efficiency, and lessens fatigue (Narayanaswami et al., 2014). Muscles can be strengthened by prescribing progressive resistance exercises, stretching and aerobic exercise. A minimum of once-a-day muscle contraction at 30% to 50% of maximal strength for 3 to 5 minutes, 3 times per week, for a single muscle group has been shown to be effective. High resistance strengthening has not demonstrated additional benefit. Patients who are participating in an exercise program need to be aware of the warning signs of overwork weakness, which includes feeling weaker rather than stronger within 30 minutes post exercise or excessive muscle soreness 24 to 48 hours after exercise, severe muscle cramping, heaviness in the extremities, and prolonged shortness of breath. Significant muscle pain or myoglobinuria in the 24-hour period after specific activity is a sign of overexertion and indicates that activity should be modified. The management of limb contractures in patients with progressive neuromuscular disease and the role of stretching, orthotics, and surgery have been comprehensively reviewed.

Principle therapies include: 1) regularly prescribed periods of daily standing and walking if the patient is functionally capable of being upright; 2) passive stretching of muscles and joints with a daily home program; 3) positioning of the legs to promote extension and oppose joint flexion when the patient is nonweight-bearing; and 4) splinting, which can be useful measure for the prevention or delay of ankle contracture (Bushby et al., 2009). Stretching to maintain optimal muscle resting length as well as viscoelastic properties is important for maintaining muscle function. Muscles that cross two joints, such as the gastrocnemius, hamstrings, hip flexors, biceps, and the long back extensors, are particularly prone to develop contractures. Once a contracture has developed, the treatment is active and passive range of motion exercises combined with a sustained terminal stretch on a daily basis. The intensity of stretch should be of a mild degree without discomfort. Static stretches are held 15 to 60 seconds. Sustained stretching can be obtained by splinting orthotics. Resting ankle foot orthoses (AFOs) can help to prevent or minimize progressive equinus contractures. Knee-ankle-foot orthoses (KAFOs) can be of value in late ambulatory and early nonambulatory stages to allow standing and limited ambulation for therapeutic purposes (see Fig. 152-2). A passive standing device can be used with either no or mild hip, knee, or ankle contractures. Dynamic splinting provides tension in the desired direction with the use of springs or elastic bands. This type of splinting is often used in the hand and arm because it allows a measure of function while providing stretching. To achieve optimal joint position, it is sometimes necessary to surgically lengthen the contracted tendon. In the upper extremity, elbow flexion contractures in dystrophic myopathies may occur soon after wheelchair transition secondary to static positioning of the arms and elbow flexion on the armrests of the wheelchair. Other associated deformities include forearm pronator tightness and wrist flexion-ulnar deviation in the later stages of the disease. Mild elbow flexion contractures of 15° or less are of no functional consequence. Severe elbow flexion contractures of greater than 60° are associated with decreased distal upper extremity function and produce difficulty when dressing. Nighttime resting splints, which promote wrist extension, metacarpophalangeal extension, and proximal interphalangeal flexion, are recommended. Daytime positioning should emphasize wrist and finger extension, but splinting should not compromise sensation or function. Weakness is the major cause of loss of ambulation in Duchenne muscular dystrophy (DMD), not contracture formation. The primary indication for orthopedic surgical tenotomies is the provision of optimal alignment. Little evidence supports the efficacy of early prophylactic lower extremity surgery in DMD for prolonging ambulation. The release of contractures at both the heel cord and iliotibial band may be necessary to obtain optimal alignment. Hip and knee flexion contractures generally are not severe enough

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Neuromuscular and skeletal management Tools Creatine kinase Genetic testing Muscle biopsy

coordin l care ati ica o in Family

Corticosteroid management

Interventions Diet control and supplementation Gastrostomy Pharmacological management of gastric reflux and constipation

GI, speech/ swallowing, nutrition management

Psychosocial management

Pulmonary management Tools Spirometry Pulse oximetry Capnography PCF, MIP/MEP, ABG

Orthopaedic management

Interventions Tools Assessment of ROM Tendon surgery Posterior spinal fusion Spinal assessment Spinal radiograph Bone age (left wrist and hand radiograph) Bone densitometry

Patient with DMD

Management of other complications

Tools Upper and lower GI investigations Anthropometry

Rehabilitation management

Diagnostics

Interventions Stretching Positioning Splinting Orthoses Submaximum exercise/activity Seating Standing devices Adaptive equipment Assistive technology Strollers/scooters Manual/motorised wheelchairs

n

Considerations Age of patient Stage of disease Risk factors for side-effects Available GCs Choice of regimen Side-effect monitoring and prophylaxis Dose alteration

Interventions Genetic counselling Family support

Cl

Assessments Clinical evaluation Strength Function ROM

Assessments ROM Strength Posture Function Alignment Gait

Interventions Volume recruitment Ventilators/interfaces Tracheostomy tubes Mechanical insufflator/ exsufflator

Assessments Coping Neurocognitive Speech and language Autism Social work

Cardiac management Tools ECG Echo Holter

Interventions Psychotherapy Pharmacological Social Educational Supportive care

Interventions ACE inhibitors  blockers Other heart failure medication

Figure 152-1.  Interdisciplinary management of DMD. (With permission from Bushby, K., Finkel, R., Birnkrant, D.J., et al., 2010.Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9(1), 77–79.)

to require surgery. The ankle deformity may be corrected by either a tendo-Achilles lengthening (TAL) or a TAL combined with a surgical transfer of the posterior tibialis muscle tendon to the dorsum of the foot. Those still ambulating independently without orthotics use their ankle equinus posturing from the gastrocnemius-soleus group to create a knee extension moment at foot contact, thus stabilizing the knee when the quadriceps muscle is weak. Several authors have cautioned against isolated heel cord tenotomies. Overcorrection of the heel cord contracture may result in immediate loss of the ability to walk without bracing unless the quadriceps are grade 4 strength or better. Adaptive devices are frequently used to maintain function. During the early ambulatory phase, a lightweight wheelchair can be used for distances. As the weakness progresses in the late ambulatory phase, use of manual wheelchair, scooter, or power chair can be considered. As functional community ambulation declines, a power wheelchair is advocated. Generally, children can be taught to safely operate a power wheelchair at the developmental age of approximately 2 years. The initial power wheelchair prescription needs to consider the natural history of the neuromuscular disease disorder over the following 5 years, as some children will develop the need for a power recline system. In more severely disabled, the power wheelchair electronics should be sufficiently sophisticated to incorporate alternative drive control systems, environmental control adaptations, and possibly augmentative communication

systems in patients who are unable to vocalize. The power wheelchair should include: a solid custom seat and back, lateral trunk supports, hip guides, headrest, power tilt/recline, elevating or swing away leg rests, and a pressure-relieving cushion. Upper extremity weakness can be augmented with a lap tray, extended straws, balance forearm orthoses, and environmental controls. Bathing equipment, hospital bed, and transfer devices are frequently used in nonambulatory patients. Severe spinal deformity in progressive neuromuscular disorders leads to multiple problems, including poor sitting balance, difficulty with upright seating and positioning, pain, difficulty in parental or attendant care, and potential exacerbation of underlying restrictive respiratory compromise. Fixed pelvic obliquity (pelvic tilt) may increase the risk of developing pressure ulcers due to imbalanced seating. Increased spinal deformity may require the patient to utilize the upper extremities to support an upright position, thereby leaving the hands unable to be used for other activities. Populations at risk for scoliosis include DMD, autosomal recessive LGMD, congenital muscular dystrophy, FSH muscular dystrophy, congenital myotonic muscular dystrophy, spinal muscular atrophy II and III, and Friedreich ataxia (Wang et al., 2007). Close clinical monitoring is essential for children at risk for scoliosis. Baseline spinal radiography is indicated near time of wheelchair dependency and then annually for curves less than



20 degrees. Curves may progress rapidly during the adolescent growth spurt, and children will then need to be monitored every 6 months with clinical assessments and spine radiographs. Patients who are likely to require surgical arthrodesis at some point should be monitored with pulmonary function tests every 6 months. Scoliosis progression in the thoracic spine can lead to the development of restrictive lung disease and increased need for noninvasive positive pressure ventilation, especially during sleep. Patients with DMD are expected to lose 4% of their forced vital capacity per year with an additional 4% decline for each 10 degree increase of their scoliosis. Similar reductions in pulmonary function with an increase in scoliosis have also been demonstrated in children with spinal muscular atrophy (SMA). The management of spinal deformity with orthotics is relatively ineffective in DMD. Spinal orthoses are often reported to be uncomfortable and poorly tolerated in this population. Furthermore, vital capacity potentially can be lowered with constrictive orthoses. On the other hand, in neuromuscular diseases with spinal deformity beginning in the first decade of life such as SMA, congenital muscular dystrophy, congenital myotonic muscular dystrophy, some congenital myopathies, and congenital myasthenic syndromes, spinal orthoses are generally used to improve sitting balance. Recent data have demonstrated markedly decreased incidence of scoliosis and progression to surgery for scoliosis in children with DMD treated with glucocorticoids. In a nonrandomized comparative cohort of 54 children, 6 of 30 (20%) of children in the glucocorticoid group developed scoliosis and had surgery, compared with 22 of 24 (92%) in the group not treated with glucocorticoids. Surgical correction of scoliosis should be considered based upon the patient’s curve progression, pulmonary function, and bone maturity. Evidence suggests that earlier surgery results in better outcomes. The beneficial effects on pulmonary function remains controversial, but the rate of decline may be slowed. The extent of the fusion depends on the degree of spinal curvature, pelvic obliquity, and mobility. Generally, posterior spinal fusion is appropriate for curves greater than 30 degrees. If there is pelvic obliquity greater than 15 degrees, it is necessary to perform correction and stabilization from the upper thoracic region to the sacrum (Fig. 152-4). Multidisciplinary preoperative evaluation is recommended before considering treatment for scoliosis in DMD and SMA. These evaluations are useful to prepare the patient and optimize the treatment plan to minimize surgical complications. These assessments also can prove critical for families who are trying to decide whether or not to pursue surgery. In some cases, patients are so severely compromised medically that surgery no longer is a practical option due to unacceptably high risks of postoperative complications. At minimum, the preoperative evaluation should include pulmonary, anesthesia, cardiology, and nutritional assessments. Sleep studies are often recommended to assess for hypoxia and obstructive sleep apnea. Pulmonary evaluation helps prepare the patient and surgeon for the potential need for postoperative respiratory support that can range from supplemental oxygen to mechanical ventilation with tracheostomy. A plan should also be in place for changes in seating equipment that will be needed after the major alteration in body contour after scoliosis surgery. Most children will no longer comfortably fit in their old custom seating systems after scoliosis correction. Resuming upright posture as soon as possible after surgery is important to help with expansion of the lungs and prevention of atelectasis and pneumonia.

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Figure 152-4.  Posterior spinal fusion.

Figure 152-5.  VEPTR (vertical expandable prosthetic titanium rib) implants.

For children who develop severe scoliosis at a young age (younger than 10 years), however, spinal fusion has been discouraged due to the concern that it will lead to restrictive lung disease as the child grows. Various “growth friendly” surgical options have been studied in neuromuscular patients. Growing rod treatment involves short fusions of the spine at the upper and lower ends with connecting rods that are periodically distracted (every 6 months) to maintain growth. VEPTR (vertical expandable prosthetic titanium rib) implants function in a similar manner, with fixation proximally on the ribs instead of the spine (see Fig. 152-5). Although these advances can be beneficial for some patients, they have high complication rates. A rod that can be expanded via a magnet

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external to the patient has recently been approved for use in the United States and may prove beneficial for young patients with neuromuscular scoliosis. Complications occur at a high rate in neuromuscular scoliosis surgery. Surgical site infection has been reported in 5% to 15% of patients. Infection typically requires return to the operating room for debridement and prolonged antibiotic treatment. Pulmonary and gastrointestinal complications in neuromuscular scoliosis are also frequent, and seen in up to 50% of patients. Postoperative respiratory support is frequently needed as is enteral or parenteral nutritional support. Complications are also frequent in growing rod and VEPTR surgery for neuromuscular scoliosis. These include failure of rib/spine anchors and infection. Together, these complications affect about 1 in 3 patients undergoing growing rod or VEPTR treatment. Complications appear to be less frequent in patients with SMA compared with idiopathic diagnoses, perhaps due to decreased functional demand on the nonfusion constructs. Quality of life data after surgery for neuromuscular scoliosis is sparse. Scoliosis surgery in patients with SMA and DMD is generally thought to provide good functional results with improvements in sitting balance, caregiver burden, and patient/parent perception of self-image after surgery. Respiratory involvement in neuromuscular disorders is variable depending on the diagnosis. It may be progressive or static. In some disorders such as Duchenne muscular dystrophy, the progression of respiratory involvement is predictable. The pathophysiology depends on the pattern of muscle weakness. Weakness of the diaphragm, accessory respiratory muscles, and pharynx can lead to impaired cough strength, recurrent pneumonia, aspiration, persistent atelectasis, restrictive lung disease, hypoventilation, obstructive sleep apnea, and chronic respiratory failure. Scoliosis can further complicate respiratory function by contributing to chest wall restriction by impairing normal chest and diaphragm mechanics. Neonatal respiratory distress or failure is seen in many of the congenital myopathies, spinal muscular atrophy type I, and myotonic dystrophy type I. These infants often require assisted ventilation, provided either invasively or noninvasively. They may also require airway clearance with chest physiotherapy or mechanical insufflation-exsufflation (commonly referred to as cough assist). Examination findings include feeding difficulty, tachypnea, nasal flaring, accessory muscle use, thoracoabdominal asynchrony (“see-saw breathing”), weak cough, decreased air entry, crackles, and dullness to percussion. In toddlers and children, respiratory muscle dysfunction may or may not be commensurate with other skeletal muscle function (e.g., age-appropriate developmental milestones such as sitting, crawling, and walking). Therefore a high index of suspicion for respiratory disease is needed. In toddlers or patients in whom voluntary pulmonary function testing is not possible due to cognitive or other barriers, detailed history is needed. Questions should focus on daily respiratory symptoms of cough, dyspnea, exercise tolerance (if applicable), swallowing difficulty, history of pneumonia, and difficulty with anesthesia. As diaphragm function is often more affected in the supine position and during sleep, detailed inquiries searching for sleep-disordered breathing are vital. These findings may be subtle and questions should include the presence or absence of snoring, overt apnea or gasping, abnormal respiratory patterns, restless sleep, nocturnal diaphoresis, frequent awakenings, enuresis, morning headaches, mood on awakening, and need for daytime sleep. Children whose sleep is disrupted may also experience attention deficits and hyperactivity rather than daytime somnolence. Should any concerns for impaired sleep-disordered breathing arise, referral for a

formal polysomnogram (not overnight home pulse oximetry) is recommended. In children who can complete voluntary pulmonary function tests, findings include decreased vital capacity (restrictive defect), decreased inspiratory and/or expiratory pressures, and decreased peak cough flows. Vital capacity may be further reduced in the supine position. A 20% decrease in vital capacity from prone to supine position is consistent with diaphragm dysfunction and increases the risk for sleep-disordered breathing. Every patient with a neuromuscular disorder and known or suspected respiratory manifestations should be referred to a pulmonologist with expertise in neuromuscular disease. Frequency and nature of monitoring is determined by the underlying diagnosis, interval history, pulmonary function, and polysomnography where relevant. Published guidelines are available for Duchenne muscular dystrophy, spinal muscular atrophy, congenital myopathies as a whole, and congenital muscular dystrophies as a whole (Finder et al., 2004; Manzur et al., 2003; Wang et al., 2012). All infants and children should receive standard immunizations. Influenza immunization should only be given using inactivated virus vaccine given by intramuscular injection and not with a live attenuated vaccine given by nasal inhalation. Infection with respiratory syncytial virus (RSV) leads to more severe RSV-related disease in infants and children with neuromuscular impairment than in those without neuromuscular impairment. Therefore passive RSV immunization with palivizumab has been recommended by some providers. Immunization with pneumococcal polysaccharide vaccine (PPSV) is recommended for those patients with respiratory disease over the age of 5 years. Treatment of respiratory weakness is supportive and focuses on improving cough clearance, optimizing sleepdisordered breathing, and maximizing oxygenation and ventilation, all while improving quality of life. Supplemental oxygen may correct hypoxemia but may lead to worsened hypercapnia by eliminating the hypoxemic drive to breathe. Mechanical airway clearance, similar to mechanical insufflationexsufflation, is used when peak cough flow is impaired. Daily mechanical insufflation may also play a role in maintaining chest compliance. Breath stacking, glossopharyngeal breathing, and abdominal thrusts (also called “quad cough”) have been used to varying degrees of success. Other modalities of airway clearance such as inhaled bronchodilators, inhaled or oral mucolytics, and mechanical vibration (e.g., pneumatic vest or intrapulmonary percussive ventilation) have not been well-studied in neuromuscular disorders. These are often used as adjunctive therapies, especially in the setting of acute respiratory illness. Continuous positive airway pressure (CPAP) is not recommended as it does not provide inspiratory support for normal tidal breathing. Bilevel positive airway pressure provides continuous airway pressure to maintain functional residual capacity as well as inspiratory tidal support. Settings for nocturnal use are best determined in the sleep laboratory during sleep. Progression to daytime hypercapnia and chronic respiratory failure occurs in many neuromuscular disorders. This can be managed noninvasively (with nasal or oronasal interfaces or mouthpiece ventilators) or invasively with tracheostomy. Clinical monitoring with pulse oximetry and noninvasive measurements of CO2 can also direct mechanical ventilation strategies. Many patients are not able to tolerate noninvasive ventilation initially and may benefit from sleep psychology services for desensitization therapy. Discussions about goals of care, end-of-life decisions, and code status should be conducted well in advance of any surgery or the development of chronic respiratory disease. This



should be undertaken on a recurrent basis with providers with whom the patient and family are familiar. Enlisting the assistance of palliative care services is a vital but often neglected part of the patient’s care. Cardiac involvement is not uniform in neuromuscular diseases. Yet in some disorders such as Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), some of the limb-girdle muscular dystrophies, and myotonic dystrophy, cardiac disease is a major cause of morbidity and mortality. Early diagnosis and detection of cardiac involvement provides opportunity for early therapy and intervention, which will hopefully affect positive outcomes. In DMD, cardiac manifestations include cardiomyopathy and cardiac arrhythmia. Dystrophin is present both in the myocardium as well as in the cardiac Purkinje cells that affect conduction. Cardiomyopathy is progressive and a major source of morbidity and mortality in DMD and BMD. Myocardial disease is present before symptoms becoming apparent. By age 10, cardiomyopathy is clinically evident and virtually all boys by age 18 are affected. ECG abnormalities are present in almost all boys with DMD age 13 years and over. Most boys will have a resting tachycardia. This is possibly due to autonomic disturbance or direct involvement of the sinus node. As cardiomyopathy progresses, decreased stroke volumes can also result in tachycardia. Fibrosis localized to the posterior wall of the left ventricle has been noted in DMD but not in other muscular dystrophies. Close cardiac monitoring is essential. Current care guidelines recommend that patients have a baseline cardiac assessment at the time of diagnosis or at least by 6 years old. Baseline assessments include electrocardiogram and a noninvasive cardiac imaging study such as echocardiogram. Subsequently, patients should have a cardiac evaluation every 2 years until the age of 10, then annually thereafter. If symptoms occur earlier than age 10, they should be evaluated more urgently. Increased frequency of evaluations should occur if ventricular dysfunction is diagnosed. Early pharmacologic therapy is indicated. Angiotensinconverting-enzyme inhibitors such as lisinopril or enalapril to reduce afterload are typically used as first-line therapy. Alternatively, angiotensin II receptor blockers such as losartan may be used. Diuretics and beta-blockers are also appropriate as recommended by published heart failure guidelines. Patients with DMD commonly have a sinus tachycardia but should be assessed including use of event monitoring if necessary. There are a variety of opinions on routine use of cardiac MRI devices, steroid use, and appropriateness of transplant in these patients. Although in general the BMD phenotype is milder and weakness develops more slowly, cardiac failure may progress rapidly, independent of progression of skeletal myopathy. In fact, some patients may present with cardiomyopathy and no discernable skeletal involvement. Seventy-five percent or more of BMD patients have ECG abnormalities, but resting sinus tachycardia is not typical as it is in DMD. Cardiac transplant should be considered in cases of BMD when rapid cardiac failure is diagnosed in the face of slowly progressive functional impairment. Selected types of limb-girdle muscular dystrophy have associated cardiomyopathy and warrant referral to a cardiologist and close follow-up. Laminopathies (LMNA mutations) carry a high risk of cardiac disease including primary dilated cardiomyopathy conduction defects and both supraventricular and ventricular arrhythmias. Cardiac involvement is early, and sudden death has been reported. Patients with dystroglycanopathies frequently have myo­ cardial dysfunction. Patients with the fukutin-related protein (FKRP) gene develop an early dilated cardiomyopathy whereas those with the Fukuyama-type present in the second decade.

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Thirty to fifty percent of patients with FKRP have cardiomyopathy. Arrhythmias have not been reported. No increased risk of cardiac involvement is seen in COL6 or SEPN1 diseases. LAMA 2 (merosin deficiency) patients develop severe heart failure, noted in about one-third of patients whether or not they are symptomatic. Care guideline recommendations suggest that all patients undergo cardiac evaluation at the time of diagnosis. If diagnosed with dystroglycanopathy or laminopathy, annual cardiac examinations are recommended. If symptomatic, examinations every 6 months are suggested. Standard evaluations consist of ECG and echocardiogram in most patients, but because of the risk of arrhythmias and paroxysmal conductive defects in LMNA, 24-hour Holter monitoring is useful. Tachyarrhythmia and conduction abnormalities are commonly observed in myotonic dystrophy type 1. Cardiomyopathy is not typical. Cardiac complications as a cause of death include sudden unexpected death possibly due to arrhythmias, ischemic heart disease, and progressive left ventricular dysfunction. The mean age of death is 53 years, with a third due to cardiovascular disease or sudden death. Prolonged PR and or QRS interval, second- or third-degree heart block, nonsinus rhythm noted on ECG, or an atrial tachyarrhythmia predicted sudden death in one study. Conduction defects progress and severe bradycardia or asystole may occur secondary to atrioventricular heart block. Patients with myotonic dystrophy should be monitored with yearly ECGs and referred to cardiology if prolongation of PR or QRS complex is noted or if the patient has any cardiac symptoms. Early placement of a pacemaker or defibrillator should be considered. Primary cardiomyopathies are rare in congenital myopathies. Some cases of nemaline myopathy have had transient cardiac failure and ECG abnormalities. Guidelines suggest that screening evaluations occur every 2 years in asymptomatic congenital myopathy patients if their genetic diagnosis is uncertain. Kearns-Sayre syndrome is a mitochondrial myopathy featuring a triad of progressive external ophthalmoplegia, pigmentary retinopathy, and heart block. Patients may have ptosis, proximal weakness, short stature, hearing loss, and endocrine disorders. Cardiac pacemakers may be placed in patients with conduction blocks. For any patient with neuromuscular weakness, decreased mobility, or weak abdominal muscles, constipation and reflux are chronic medical concerns. Standard treatments for constipation include dietary management, hydration, use of stool softeners, laxatives, and agents to stimulate GI motility (Ducolax, Sennakot). For acute constipation, in addition to the agents mentioned, enemas may be needed. A routine bowel management program should be introduced soon after diagnosis. Chronic constipation may require daily use of agents such as lactulose or polyethylene glycol in addition to increased fluid intake and diet modification. H2 receptor antagonists (ranitidine, cimetidine), protonpump inhibitors (omeprazole, lansoprazole), or antacids (magnesium or calcium carbonate) are typically used for medical management of gastroesophageal reflux. Sucralfate may be used in addition. Prokinetic agents such as metoclopramide or erythromycin may be considered if delayed gastric emptying or decreased gastric motility is diagnosed. For children on chronic corticosteroids for DMD, myasthenia gravis, or inflammatory myopathies, antacids, ranitidine or protonpump inhibitors should be considered for GI prophylaxis. Patients with myotonic dystrophy commonly have gastrointestinal issues. Bowel dysmotility may result in constipation and diarrhea. They have esophageal issues and are at higher risk for cholelithiasis. Liver function studies may be

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mildly elevated but typically not progressive Triglycerides and cholesterol may be elevated as well. DMD patients are at risk for intestinal pseudoobstruction, gastric dilatation, and dysphagia. Delayed gastric emptying in disorders such as SMA may lead to decreased oral intake. Many neuromuscular disorders have dysphagia as another prominent feature. Palatal and pharyngeal muscles are affected in myasthenia gravis, congenital myasthenic syndromes, SMA, and congenital myopathies such as myotubular myopathy. Choking, aspiration, pocketing food, or pooling of secretions may all result from pharyngeal muscle dysfunction. Fatiguing during meals and prolonged meal times (longer than 30 min) may occur. Patients with myotonic dystrophy or facioscapulohumeral dystrophy may have severe facial weakness leading to difficulty chewing effectively. Swallowing problems may present with coughing, aspiration pneumonia, and unintentional or unexplained weight loss. When swallowing concerns are raised, patients should be evaluated promptly. Speech therapists, nutritionists, dentists, and gastroenterologists are all members of the multidisciplinary team who can address these issues. A swallowing study is typically indicated when there are concerns about swallow safety. As weakness progresses, recurrent pneumonias or continued weight loss may necessitate discussion regarding placement of a gastrostomy tube for feeding. Patients with severe SMA have bulbar dysfunction. With less severe involvement, the degree of dysfunction is variable. Patients may have difficulty getting food to their mouths, limited mouth opening, fatigue with chewing, poor oral manipulation of food, and poor coordination of swallow. As patients lose head control, they are unable to use compensatory postures for swallowing. Reflux can be a life-limiting event in patients with SMA, which necessitates consideration for a Nissen procedure in addition to G-tube placement. Careful monitoring of weight and nutritional status for neuromuscular patients is an integral part of medical management. With decreased movement and decreased calorie expenditure, patients are at risk for gaining excess weight. On the contrary, decreased oral intake due to fatigue and dysphagia can lead to weight loss. Nutrition and dietician consults are helpful in management of these issues. Common to all neuromuscular diseases is concern for bone health. Muscle strength has a significant effect on bone density. Nonambulatory neuromuscular patients and children with chronic steroid exposure (DMD, myasthenia gravis, inflammatory myopathies) are at heightened risk for osteoporosis or osteopenia. As a result of these conditions, patients develop fractures, compression fractures, and kidney stones. According to the International Society for Clinical Densitometry guidelines (2014), if a child with risk factors for osteoporosis in the absence of trauma develops a vertebral fracture, the diagnosis of osteoporosis is confirmed. The society suggests monitoring of the spine with a lateral spine radiograph. Although there is no true consensus in terms of monitoring or prevention of osteoporosis, treatment with calcium and vitamin D is recommended. Prophylactic use of bisphosphonates has been tried without evidence that fracture rates are diminished (Quinlivan et al., 2010). Boys with Duchenne or Becker muscular dystrophy are even at increased risk for osteopenia/osteoporosis and fractures secondary to decreased mobility and muscle weakness. The addition of steroids compounds the combined risk, resulting in significant scoliosis, osteopenia, osteoporosis, and fractures (Henricson et al, 2013). Growth is also affected by chronic steroid use, although there are some regimens (high-dose weekend) that reportedly do not induce short stature. It is important to monitor side effects of chronic steroid use such as weight gain, Cushingoid

features, hirsutism, acne, delayed growth, delayed puberty, hypertension, glucose intolerance, gastroesophageal reflux and ulcers, cataracts, disordered sleep, and behavioral changes. Vitamin D levels should also be monitored and supplemented if low. Patients with myotonic dystrophy have multiple endocrine abnormalities, including hypothyroidism and insulin resistant diabetes. Men have hypogonadism, erectile dysfunction, decreased sperm counts, and decreased fertility. An increase in miscarriages and menstrual irregularities are common in women. Insulin-like growth factor 1 levels may be decreased as well as decreased growth hormone release. Monitoring with thyroid stimulating hormone, fasting glucose, or hemoglobin A1C should be a part of routine healthcare in these patients. As a part of comprehensive care for neuromuscular disorders of any kind, monitoring emotional and psychosocial well-being is of upmost importance. Patients and their families face many kinds of stress—financial, social, and emotional, as well as physical. These issues should be acknowledged from very early on in the relationship so that trust and good communication are established from the outset. If the resources are available, a social worker or other qualified professional who is knowledgeable about neuromuscular disease should be introduced at the first appointment. Assessment of family and patient stressors and resources, coping skills, and emotional adjustment to the diagnosis is an ongoing, dynamic process that will continue to change over time. Continuity of care is a priority. A clinic coordinator can be very helpful to serve as a point person for a patient or family. The coordinator can provide education to the patient and family as well as the school or daycare, communicate with the medical team, offer a wide variety of resources, and ongoing support. Depending on the diagnosis and clinical presentation, palliative care may be another excellent resource to be involved early in the clinical course. Help with family and sibling support, partnering in difficult decision making, offering spiritual guidance, and dealing with loss and bereavement are a few of the palliative care services that may improve quality of life for a patient and their family. Many neuromuscular patients will need an IEP (individual education plan) developed in conjunction with their school. An IEP is formulated to guide therapies, insure accessibility and safety, modify physical activity (if indicated), and address learning issues that may accompany such diagnoses as DMD or myotonic dystrophy. Boys with DMD are likely to have intellectual disabilities, specifically learning disorders, and behavioral problems such as attention deficit disorder, obsessive compulsive disorder, and autism spectrum diagnoses. Depression and anxiety may be evident both in the boys as well as their families. Congenital myotonic dystrophy patients have significant cognitive impairment, and in the noncongenital form, intelligence is generally lower (86 to 92 full-scale IQ), although IQ values vary and seem to correlate with size of the CTG repeat expansion at the DM1 gene. Other behavioral issues such as apathy, executive dysfunction, memory difficulty, and avoidant behavior are common. Children with complex medical and genetic conditions are living longer than was predicted in the past due to better treatments and overall care. Often, the success of excellent pediatric medicine results in young adults who require ongoing, sometimes intensive, medical supervision throughout their lives. Children with DMD are living longer into adulthood due to a variety of improvements in healthcare interventions. These include multidisciplinary care, regular cardiac and respiratory monitoring, corticosteroid initiation, and assisted ventilation. Patients with neuromuscular disease present many complex transition issues and medical problems. Transitioning from a



nurturing pediatric care system to a more self-directed adult care model can be very difficult for patients and their families. Adult healthcare providers may lack expertise and interest in childhood-onset disabling conditions and services can be fragmented. Preserving wellness, function, independence, activity, participation in society, and quality of life needs to be the ultimate focus, not necessarily episodic or acute care management. A consensus policy statement, issued by the American Academy of Pediatrics, the American Academy of Family Physicians, and the American College of Physicians American Society of Internal Medicine, states that the transition of care should “maximize lifelong functioning and potential through the provision of high-quality, developmentally appropriate healthcare services that continues uninterrupted as the individual moves from adolescence to adulthood” (AAFP et al., 2002). An effective transition includes having a primary care provider with responsibility for transition planning, incorporating the necessary knowledge and skills to provide developmentally appropriate healthcare transition services, maintaining an up-to-date portable medical summary, creating a written healthcare transition plan by age 14, implementing recommended preventive service guidelines, and ensuring continuous health insurance coverage (AAFP et al., 2002). According to the 2005–2006 National Survey of Children With Special Healthcare Needs, only 41.2% of youth aged 12 to 17 years have ever talked with healthcare providers about their changing health-related needs, decreasing dependence on parents for health management, or their eventual transition to adult care. Healthcare professionals should be aware of both positive feelings (sense of achievement) and negative feelings (anxiety about the future) about transition. It is important to provide support to address negative feelings and the progressive effects of neuromuscular disorders such as DMD. There are many barriers that challenge families, patients, and physicians alike, which greatly complicate the process. For example, the age of typical transition can be a time when cardiac and/or pulmonary status is most vulnerable in boys with DMD, thus emphasizing the importance of transition to an adult multidisciplinary clinic or providers well versed in DMD. As young adults with disabilities transition to more independence, physicians need to educate patients and their families about potential age-related changes and medical issues. Prevention strategies require anticipation of potential secondary conditions, recognition of changes that alter function and require intervention, and an understanding of interventions that have an influence on function. This requires that adults with childhood-onset disabling chronic diseases have access to knowledgeable healthcare providers and the medical systems necessary to implement a medical home approach to management of chronic illness and disease. Environmental, communication, attitudinal, and systems barriers must be overcome. Pain is a significant problem for most patients with neuromuscular disease, although it is not typically a direct consequence of the disease. Most commonly, the pain is caused by immobility. A significant correlation has been shown between increased pain and lower levels of general health, vitality, social function, and physical role. Pain assessment needs to be a standard aspect of care. In a study of adults with DMD, symptoms of fatigue (40.5%), pain (73.4%), anxiety (24%), and depression (19%) were reported, and individuals often had multiple conditions. End-of-life directives are a critical part of anticipatory care. The role of palliative care to maximize quality of life in

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patients with progressive neuromuscular disease cannot be overlooked. Respiratory failure can occur suddenly or in association with a prolonged process. Many families are hesitant to discuss end-of-life issues during periods of medical stability, but it is important that education about ventilatory and palliative options be discussed before ventilatory failure. There is evidence that healthcare professionals underestimate the quality of life of ventilator-dependent patients with DMD. Those choosing to forgo long-term ventilation must receive palliative care and guidance. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES American Academy of Pediatrics, AAFP, American College of Physicians-American Society of Internal Medicine, 2002. A consensus statement on healthcare transitions for young adults with special healthcare needs. Pediatrics 110 (6), 1304–1306. Bushby, K., Finkel, R., et al., 2009. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 9 (2), 177–189. Finder, J.D., Birnkrant, D., Carl, J., et al., 2004. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am. J. Respir. Crit. Care Med. 170 (4), 456–465. Henricson, E.K., Abresch, T., Cnaan, A., et al., 2013. The cooperative international neuromuscular research group Duchenne natural history study: glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures. Muscle Nerve 48 (1), 55–67. Manzur, A.Y., Muntoni, F., Simonds, A., 2003. Muscular dystrophy campaign sponsored workshop: recommendation for respiratory care of children with spinal muscular atrophy type II and III. 13th February 2002, London, UK. Neuromuscul. Disord. 13 (2), 184–189. McDonald, C., 2010. Neuromuscular Diseases. In: Alexander, M., Matthews, D.J. (Eds.), Pediatric Rehabilitation. Demos, New York, pp. 277–333. Narayanaswami, P., Weiss, M., et al., 2014. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology 83 (16), 1453–1463. Quinlivan, R., Shaw, N., Bushby, K., 2010. 170th ENMC International Workshop: bone protection for corticosteroid treated Duchenne muscular dystrophy. 27–29 November 2009, Naarden, The Netherlands. Neuromuscul. Disord. 20 (11), 761–769. Wang, C.H., Dowling, J.J., North, K., et al., 2012. Consensus statement on standard of care for congenital myopathies. J. Child Neurol. 27 (3), 363–382. Wang, C.H., Finkel, R.S., Bertini, E.S., et al., 2007. Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J. Child Neurol. 22 (8), 1027–1049.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 152-2 Resting ankle foot orthoses (AFOs). Fig. 152-3 Neuromuscular scoliosis.

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Systemic and Autonomic Nervous System Diseases

Endocrine Disorders of the Hypothalamus and Pituitary in Childhood and Adolescence Roger K. Long and Stephen M. Rosenthal

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Through integrated neural and hormonal signaling, the hypothalamus and pituitary regulate a broad range of physiologic processes, including statural growth, sexual maturation, lactation, metabolic actions ascribed to adrenal (glucocorticoid) and thyroid hormones, appetite, and water balance. Each of these physiologic processes involves hypothalamic/pituitary regulation of a variety of target tissues, which, in turn, regulate hypothalamic/pituitary function through feedback loops. A comprehensive endocrine approach to abnormalities of any of these physiologic loops or axes requires consideration of disorders intrinsic to the hypothalamus/pituitary or to the target tissues. This chapter will focus on those endocrine disorders specifically caused by abnormalities of the hypothalamus and pituitary.

ANATOMIC AND PHYSIOLOGIC ASPECTS The hypothalamus is an evolutionarily conserved region of the mammalian brain. The hypothalamus is separated by the third ventricle and functions as the primary control center for a variety of physiologic processes, integrating neural and hormonal signaling. Hypothalamic nuclei are not welldemarcated regions; however, these cell groups in the walls of the third ventricle possess specific physiologic functions. The supraoptic and paraventricular nuclei produce arginine vasopressin (AVP, also known as antidiuretic hormone [ADH]) and oxytocin. Paraventricular nuclei and arcuate nuclei release thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), somatostatin (SST), growth-hormonereleasing hormone (GHRH), gonadotropin-releasing hormone (GnRH), and dopamine into the hypophysial portal circulation to regulate the synthesis and release of anterior pituitary hormones. In addition, hypothalamic neurons that regulate appetite and energy balance are also located in the paraventricular and arcuate nuclei of the hypothalamus, such as proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti-related protein (AgRP)–expressing neurons. The pituitary (hypophysis) is housed in the sella turcica and is attached to the hypothalamus by the hypophysial stalk, which serves as an anatomic and functional link between the hypothalamus and the pituitary. The optic chiasm is situated directly anterior to the pituitary stalk (Fig. 153-1). The pituitary is small, weighing about half a gram, and is divided into the anterior lobe (adenohypophysis), which is embryonically derived from oral ectoderm (Rathke’s pouch); the posterior lobe (neurohypophysis), which is a downward extension of the diencephalon; and a vestigial intermediate lobe. Six hormones,

growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), are synthesized, stored, and secreted from welldifferentiated distinct cell types (somatotrophs, thyrotrophs, corticotrophs, gonadotrophs, and lactotrophs) within the adenohypophysis. The neurohypophysis synthesizes, stores, and secretes AVP and oxytocin. The blood supply in the hypothalamic–pituitary–portal system allows bidirectional hypothalamic–pituitary hormonal interaction. The superior hypophysial arteries from the internal carotid arteries form a primary plexus that travel down to the anterior pituitary as the major blood supply. The hypothalamic–pituitary–portal circulation carries the hypothalamic releasing and inhibiting hormones to the adenohypophysis. Retrograde blood flow within the internal capillary plexus (gomitoli), derived from the stalk branches of the superior hypophysial arteries, provides local hormonal feedback to the hypothalamus. Normal development of the hypothalamus and the pituitary relies on expression of multiple homeodomain transcriptions factors, morphogenic proteins, and growth factors. Differentiation of anterior pituitary cell types requires a spatiotemporally regulated cascade of homeodomain transcription factors. Several pituitary-specific transcription factors, such as Lhx3/Lhx4 (LIM-homeobox-3 and 4), Rpx (Rathke’s pouch homeobox, also known as Hesx1), Pitx (pituitary homeobox), Prop-1, Pit-1, POU1F1, Sox2, and Sox3, are important determinants of pituitary cell lineages. Mutations in these and other transcription factors can lead to either isolated or combined pituitary hormone deficiencies, with or without detectable anatomic abnormalities (Dauber et al., 2014).

HYPOTHALAMIC/PITUITARY DISORDERS OF PUBERTAL DEVELOPMENT Normal Physiology of Puberty and Adrenarche Puberty is the transitional period between the juvenile state and adulthood, characterized by attainment of secondary sex characteristics and reproductive capability. The control center of puberty is comprised of hypothalamic GnRH neurosecretory neurons (pulse generator). The GnRH pulse generator becomes pulsatile by midgestation, and remains active until about 6 months of age in boys and 12 to 24 months in girls. Between late infancy and the onset of puberty, the GnRH pulse generator becomes relatively quiescent as a consequence of a poorly defined central nervous system (CNS) inhibitory mechanism. After a quiescent period of approximately 10 years, the

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GnRH pulse generator is disinhibited, leading to increased amplitude and frequency of LH and FSH secretion, and resulting in increased sex steroid production (estradiol and testosterone) and attainment of physical puberty. Kisspeptin and the kisspeptin receptor, also known as GPR54, have emerged as key regulators of the hypothalamic–pituitary–gonadal (HPG) axis, triggering and guiding the tempo of sexual maturation at puberty (Oakley et al., 2009). In addition, the tachykinin neurokinin B and its receptor NK3R also serve as central regulators for normal gonadatropin secretion and pubertal development, and MKRN3 appears to have an inhibitory function in pubertal regulation (Abreu et al., 2013; Bulcao et al., 2014). The normal age of onset of secondary sexual characteristics is 8 to 13 years in girls and 9 to 14 years in boys. The appearance of secondary sexual characteristics, acceleration of growth, and the capacity of reproduction are hallmarks of puberty. In females, secondary sexual characteristics include breast development, the appearance of pubic and axillary hair, maturation of the labia, and estrogenization of the vaginal mucosa. The development of pubic and axillary hair is influenced by androgens produced in both the adrenal cortex and the ovary. Menarche usually occurs 2 to 3 years after initiation of breast development. The pubertal growth spurt, which normally occurs in the early stages of puberty for girls, can result in a gain in height of 25 cm or more. In males, puberty begins with testicular enlargement (≥2.5 cm in the longest dimension) followed by the appearance of sexual hair and phallic enlargement. The growth spurt occurs during midpuberty, which results in an average 28-cm gain in height. Abnormalities of puberty include sexual precocity and delayed or arrested puberty, each with a broad differential diagnosis.

Sexual Precocity Sexual precocity is usually defined as the development of secondary sexual characteristics before 6 to 7 years of age in girls, and before 9 years of age in boys. Precocious puberty is defined as early puberty specifically resulting from premature reactivation of the GnRH pulse generator. Precocious puberty most commonly is idiopathic, but can result from a broad range of abnormalities, including CNS tumors, hamartoma of the tuber cinereum, congenital malformations, subarachnoid cysts, CNS infection, irradiation, and trauma. The incidence of precocious puberty is significantly higher in females. In studies of girls with precocious puberty, idiopathic precocious puberty ranges from 63% to 74%. In contrast, only 6% of boys with precocious puberty are idiopathic. Idiopathic precocious puberty is a diagnosis of exclusion and it is, thus, essential to search for underlying neurologic causes. Tumors involving the posterior hypothalamus, such as glioma, germinoma, and teratoma, can cause precocious puberty. Most of these tumors are thought to trigger early puberty by interfering with mechanisms that normally inhibit the GnRH pulse generator. Few LH/FSH-secreting adenomas have been reported. Hamartoma of the tuber cinereum, a congenital malformation, can cause central precocious puberty. Hamartomas are small lesions (4 to 25 mm), may be sessile or pedunculated, and usually do not enlarge with time (Fig. 153-2). Histologically, they appear to be composed of normal brain tissue and contain GnRH secretory neurons, which may serve as an “ectopic pulse generator.” Human chorionic gonadotropin (hCG)–secreting tumors can cause sexual precocity in boys. Such patients do not have central precocious puberty, in that they do not have premature reactivation of the hypothalamic GnRH pulse generator. Rather, the ectopic hCG interacts with the LH/hCG receptor on testicular Leydig cells, resulting in increased testosterone secretion and virilization. In girls, ovarian estrogen secretion

requires both LH and FSH. Thus ectopic secretion of hCG alone causes sexual precocity only in boys. The accurate diagnosis of precocious puberty and its cause requires a detailed history, physical examination, hormonal testing, and imaging studies of the CNS. Precocious puberty may be familial, rare gain-of-function mutations in KISS1 and GPR54 (KISS1R) have been found, and loss-of-function mutations in MKRN3 represent the most frequent known cause of familial central precocious puberty. The occurrence of early breast and pubic hair development is often seen in girls with precocious puberty, whereas testicular enlargement and other signs of virilization are seen in boys. Hormonal analysis demonstrates increased amplitude and frequency of LH and FSH pulsatile secretion, resulting from increased pulsatile secretion of GnRH. This finding can be demonstrated either by serial sampling of LH and FSH or by single LH/FSH measurements using highly sensitive assays. Dynamic testing using GnRH or a GnRH agonist is also used routinely to diagnose precocious puberty. Magnetic resonance imaging (MRI), with particular attention to the hypothalamic–pituitary area, should be carried out in any child diagnosed with precocious puberty.

Management If a CNS lesion that causes precocious puberty is identified, an appropriate treatment plan for that lesion should be developed. Surgical treatment of hamartomas of the tuber cinereum carries a significant risk of morbidity and mortality, whereas medical management with GnRH agonist demonstrates excellent long-term response. Rarely, the rapid progression of pubertal development is reversed or arrested after treatment of CNS disorders causing precocious puberty. More commonly, once puberty has been initiated, it will continue, despite treatment of the primary CNS disorder. Such patients require hormonal treatment with a GnRH agonist, which desensitizes pituitary GnRH receptors, leading to suppression of the HPG axis. This treatment is commonly given by regular depot intramuscular injection or implant placement. Longterm studies demonstrate resumption of normal puberty after discontinuation of a GnRH agonist.

Delayed or Arrested Puberty Delayed puberty may be defined, in boys, by the absence of testicular enlargement by 14 years of age, and in girls, by the absence of breast development by 13 years of age. The differential diagnosis of delayed puberty can be divided into three major categories: constitutional delay in growth, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism. Constitutional delay in growth, the most common cause of delayed puberty, is a normal variant, and is thought to result from a prolonged quiescent period of the GnRH pulse generator. Such patients often have a family history of delayed puberty and have delayed skeletal maturation without evidence of endocrinopathy or other organic diseases. Hypergonadotropic hypogonadism indicates a defect at the level of the gonads. Hypogonadotropic hypogonadism indicates a defect at the level of the hypothalamus or pituitary, and can be congenital or acquired, can occur alone or in association with multiple hypothalamic and pituitary hormone deficiencies, and may be organic or functional in etiology.

Isolated Congenital Hypogonadotropic Hypogonadism Isolated hypogonadotropic hypogonadism (IHH) caused by congenital GnRH deficiency may or may not be associated with olfactory abnormalities. IHH associated with anosmia or



Endocrine Disorders of the Hypothalamus and Pituitary in Childhood and Adolescence

hyposmia is referred to as Kallmann syndrome, and is thought to be a consequence of defective embryonic migration of GnRH neurons from the olfactory placode to the hypothalamus. Kallmann syndrome is the most common form of IHH. Considerable genetic heterogeneity exists for hypogonadotropic hypogonadism with or without anosmia; it is transmitted in an X-linked, autosomal-dominant, autosomalrecessive, or oligogenic fashion with variable penetrance. Mutations in the KAL1 gene account for half of males with X-linked hypogonadotropic hypogonadism and only 5% of sporadic IHH cases. The clinical phenotype of KAL1 mutation includes microphallus, cryptorchidism, and anosmia. Some patients may also have unilateral renal agenesis, synkinesia (mirror movements), high-arched palate, cerebellar ataxia, and pes cavus. IHH without olfactory abnormalities (normosmic IHH) and Kallman syndrome are associated with autosomal loss-of-function mutations of the fibroblast growth factor receptor 1 (FGFR1) (also known as KAL2), and with mutations in a variety of other genes, including FGF8 (ligand for FGFR1), prokineticin-2 (PROK2), and prokineticin receptor-2 (PROKR2). Individuals with CHARGE syndrome often manifest hypogonadotropic hypogonadism and olfactory bulb aplasia, features of Kallmann syndrome. Mutations of CHD7 (CHARGE syndrome gene) have been identified in patients with Kallmann syndrome, suggesting that IHH caused by CHD7 mutations is a mild variant of CHARGE syndrome. Lack of correlation between genotype and phenotype has been described in Kallmann syndrome. Normosmic IHH is associated with mutations in a variety of genes, including the GnRH receptor, the GNRH1 gene, GPR54, TAC3, and TACR3. Another form of X-linked hypogonadotropic hypogonadism is associated with adrenal hypoplasia congenita caused by defects of DAX1. DAX1 encodes a transcription factor that appears to play key developmental roles in the hypothalamus, pituitary, gonad, and adrenal cortex. In addition, mutations in the beta subunits of FSH and LH have been reported in association with primary amenorrhea and hypogonadism.

Hypogonadotropic Hypogonadism Associated with Multiple Hypothalamic/Pituitary Hormone Deficiencies Hypogonadotropic hypogonadism can also present in combination with other hypothalamic/pituitary hormone deficiencies. Mutations of pituitary transcription factors known to cause delayed puberty include Prop-1 and Lhx3. Combined pituitary hormone deficiencies caused by mutations in Prop-1 occur with an incidence of about 1 in 8000 births. Patients with mutations in Prop-1 have combined pituitary hormone deficiencies, which may include deficiencies of GH, PRL, TSH, and gonadotropins. Such patients have hypogonadotropic hypogonadism in association with short stature and hypothyroidism. Mutations in Lhx3 have been associated with anterior pituitary hypoplasia and complete deficits of GH, PRL, TSH, and gonadotropins. Lhx3 mutations are also associated with decreased range of motion in the cervical spine. Other genetic factors that lead to delayed puberty include mutations of prohormone convertase (PC1), leptin, and leptin receptor genes. A defect in PC1 has been shown to disrupt GnRH processing, and results in hypogonadotropic hypogonadism and obesity associated with impaired processing of insulin and POMC. Mutations in leptin and the leptin receptor are associated with a similar clinical picture of hypogonadotropic hypogonadism, hyperinsulinemia, and obesity. Congenital midline defects of the CNS, such as septo-optic dysplasia (SOD), empty sella syndrome, and Rathke’s cyst, are often associated with hypothalamic/pituitary dysfunction, which may include hypogonadotropic hypogonadism.

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Numerous CNS lesions can lead to hypogonadotropic hypogonadism, including CNS tumors, CNS infection, invasive diseases, cranial irradiation, and trauma. These CNS disorders often present with combined anterior and posterior pituitary hormone deficiencies. CNS tumors of the sella and parasellar region associated with multiple hypothalamic/ pituitary hormone deficiencies include craniopharyngioma, pituitary adenomas, optic and hypothalamic gliomas, and germ-cell tumors. Delayed or arrested puberty is the second most common presenting symptom of CNS tumors after headache. Craniopharyngiomas, the most common tumor of the sella and parasellar region in children, are slow-growing, space-occupying tumors (Fig. 153-3). Most patients present before their teenage years with headache, visual loss, and multiple hypothalamic/pituitary hormone deficits. Pituitary adenomas in children with pituitary hormone hypersecretion usually present as microadenomas (1 cm in diameter) are rare, but can also cause delayed puberty, at least in part, through elevation of prolactin as a consequence of stalk compression.

Functional Hypogonadotropic Hypogonadism Reproductive capability is intimately linked to nutritional and metabolic homeostasis. Chronic systemic disease, malnutrition, hypothyroidism, hypercortisolism, poorly controlled diabetes mellitus, and anorexia nervosa are known to cause delayed or arrested pubertal development as a consequence of hypogonadotropic hypogonadism. Functional gonadotropin deficiency may be associated with marijuana use and may occur in some female athletes and ballet dancers. In general, weight loss to less than 80% of ideal weight may result in functional gonadotropin deficiency.

Evaluation of Delayed or Arrested Puberty As part of an initial evaluation, basal gonadotropin levels (LH, FSH) should be measured. Elevated gonadotropins indicate primary ovarian or testicular failure, whereas low or normal gonadotropins indicate either constitutional delay or hypogonadotropic hypogonadism. A GnRH stimulation test is often useful in distinguishing patients with constitutional delay from those with hypogonadotropic hypogonadism. If hypogonadotropic hypogonadism is strongly suspected, further evaluation to identify a specific etiology should be undertaken. An important aspect of the physical examination is evaluation of the sense of smell. Any patient with proven hypogonadotropic hypogonadism should have a thorough evaluation of all hypothalamic/pituitary hormones and should undergo an MRI with particular focus on the third ventricular area.

Management Once the etiology of delayed or arrested puberty has been established, an appropriate treatment plan can be designed. For constitutionally delayed pubertal development, short-term (3 to 6 months) low-dose sex steroid replacement may be useful to induce maturation of the GnRH pulse generator. Permanent hypogonadotropic hypogonadism requires longterm sex hormone replacement. Testosterone for boys can be administrated either by intramuscular or subcutaneous injection or topically. Long-term hormonal therapy for girls

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includes the use of oral, intramuscular, or transdermal estrogen and progestin cycling.

production of CRH/ACTH will cause adrenal glucocorticoid insufficiency.

DISORDERS OF PROLACTIN SECRETION Normal Biochemistry and Physiology   of Prolactin

Adrenocorticotropic Excess

Regulation of prolactin secretion is distinct from that of other anterior pituitary hormones. PRL is the only pituitary hormone that is regulated predominantly by the hypothalamus through an inhibitory mechanism mediated by dopamine via the hypothalamic–pituitary–portal circulation. The principal physiologic functions of PRL are enhanced mammary gland development during pregnancy and lactation. PRL may be increased through physiologic and pathologic mechanisms. Physiologic stimuli include pregnancy, lactation, stress, sleep, and exercise. Pathologic causes of hyperprolactinemia include prolactinomas; injury to the hypothalamic–pituitary stalk; a variety of systemic disorders, including chronic renal failure and cirrhosis; and a variety of drugs.

Clinical Features and Management of Hyperprolactinemia In postpubertal females the principal clinical feature of hyperprolactinemia, regardless of the cause, is galactorrhea, which may be unilateral or bilateral. Other clinical features may include delayed or arrested puberty and hypogonadism; menstrual irregularities, including amenorrhea in females; and gynecomastia in males secondary to hypogonadism. Prolactinoma is the most common tumor of the pituitary, comprising about 50% of anterior pituitary adenomas. Most prolactinomas are microprolactinomas, and normally do not cause significant mass effects. Macroprolactinomas are predominately found in males because of poor appreciation of hypogonadal symptoms and inability to manifest menstrual irregularities or galactorrhea, early indicators of hyperprolactinemia. If a prolactinoma is diagnosed, therapeutic options include medical management with dopamine agonists, surgery, and adjunctive radiotherapy. Medical management is considered the principal intervention; however, microprolactinomas can be removed surgically, though with variable recurrence rates. Macroprolactinomas are less likely to be cured surgically and often require chronic dopamine agonist treatment. Dopamine agonists are effective and safe pharmacologic interventions for both micro- and macroprolactinoma. Withdrawal of medication after long-term therapy has been safe, although careful monitoring of tumor progression is necessary. Adjunctive radiotherapy has been considered beneficial in some patients with macroprolactinoma. The skill and experience of the surgeon clearly play a role in determining the optimal treatment and outcome.

HYPOTHALAMIC/PITUITARY DISORDERS OF GLUCOCORTICOID PRODUCTION ACTH is produced in response to stimulation, principally by hypothalamic CRH, and increases adrenal production of cortisol, the principal glucocorticoid. Cortisol, in turn, regulates the production of both CRH and ACTH through negative-feedback loops. An intact hypothalamic–pituitary– adrenal (HPA) axis is essential for general homeostasis, including regulation of blood pressure and glucose, and for response to stress. Increased levels of circulating glucocorticoids lead to Cushing’s syndrome, whereas hypersecretion of pituitary ACTH leads to Cushing’s disease. Inadequate

Excessive production of ACTH from the pituitary arises either from CRH overproduction or from a primary ACTH-producing adenoma. The first sign of Cushing’s disease in a growing child is often impaired linear growth. Other classic signs and symptoms of Cushing’s disease include central obesity, buffalo hump, plethora, “moon facies,” acne, striae, hypertension, hirsutism, fatigue, pubertal delay or arrest, bruising, and headache. Usually, at the time of diagnosis, ACTH-producing adenomas are significantly smaller than other pituitary adenomas (Fig. 153-4). Determination of the cause of Cushing’s syndrome can pose significant challenges. Patients with hypercortisolism will demonstrate elevated urinary cortisol excretion and loss of normal diurnal variation in plasma cortisol and ACTH. Endogenous hypercortisolism is either ACTH dependent or ACTH independent. Of the ACTH-dependent causes, Cushing’s disease is most common. A rare ACTH-dependent cause is ectopic ACTH production associated with a variety of extrapituitary neoplasms. In general, patients with Cushing’s disease show suppression of cortisol and ACTH only with high-dose dexamethasone administration. An MRI of the hypothalamic/ pituitary area should be obtained if Cushing’s disease is suspected, though small adenomas may not be visualized. Bilateral inferior petrosal sinus sampling before and after ovine CRH stimulation may be utilized to determine a pituitary source of ACTH production. Transsphenoidal resection of pituitary adenomas has emerged as the treatment of choice for Cushing’s disease (Lonser et al., 2013). Because of small size, some of these tumors are difficult to identify intraoperatively. The recurrence rate after surgery is about approximately 8%, even in the hands of skilled neurosurgeons (Lonser et al., 2013). Radiotherapy has been shown to be effective for unsuccessful transsphenoidal surgery. Other therapeutic options for recurrent Cushing’s disease include repeated pituitary exploration, bilateral adrenalectomy, and the use of pharmacologic agents that directly impair cortisol synthesis and secretion.

Adrenocorticotropic Hormone Deficiency Secondary adrenal insufficiency is defined as hypocortisolism as a consequence of ACTH deficiency. Secondary adrenal insufficiency can be isolated or occur as part of multiple hypothalamic/pituitary deficiencies. Chronic suppression of CRH and ACTH by long-term glucocorticoid therapy also can result in secondary adrenal insufficiency. Isolated ACTH deficiency is a rare cause of secondary adrenal insufficiency, caused by either CRH deficiency or a primary decrease in ACTH production by corticotrophs. Clinical presentation is highly variable. Neonatal onset of isolated ACTH deficiency usually presents with sudden, severe episodes of hypoglycemia, sometimes with seizure and coma. Neonates may also present with prolonged cholestatic jaundice. Death may occur if treatment is not initiated promptly. Over 70% of these patients have a loss-of-function mutation in the TPIT gene, which encodes a transcription factor that is expressed specifically in corticotrophs and is required for expression of POMC, the precursor of ACTH. ACTH deficiency can be associated with multiple hypothalamic/pituitary hormone deficiencies as described previously. Secondary adrenal insufficiency is characterized by an inappropriately low serum cortisol level and a nonelevated ACTH



Endocrine Disorders of the Hypothalamus and Pituitary in Childhood and Adolescence

level suggestive of inadequacy of the HPA axis. Assessment of the HPA axis adequacy is challenging. A peak cortisol level after an injection of synthetic ACTH may be used to assess adrenal gland responsiveness to ACTH. However, a false normal response will occur in the setting of acute pituitary dysfunction. HPA axis integrity can be confirmed by dynamic testing protocols that measure the adrenal glucocorticoid production response to acute hypoglycemia induced by insulin injection or an overnight cortisol insufficiency caused by metyrapone treatment, an inhibitor of the last enzymatic step in cortisol production. Cortisol (hydrocortisone) replacement is based on studies of the cortisol secretory rate in the pediatric population, which is 7 to 9 mg/m2/day. During periods of significant stress, such as febrile illness and surgery, such patients are managed routinely with a temporary increase in glucocorticoids (given orally or parenterally) at doses up to 50 mg/m2/day of hydrocortisone.

HYPOTHALAMIC/PITUITARY DISORDERS OF STATURAL GROWTH Statural growth is a complex process influenced by multiple factors. Endocrine regulation of postnatal growth stems from hormones produced in the hypothalamus and the pituitary, including GHRH, SST, GH, TRH, TSH, CRH, and ACTH. Abnormal statural growth related to either GH deficiency or GH excess is discussed in this section. Pulsatile GH secretion is regulated principally by two hypothalamic regulatory peptides, GHRH and SST. Acute glucocorticoid administration stimulates GH secretion, whereas chronically elevated glucocorticoids inhibit GH, as seen in Cushing’s disease and during chronic administration of glucocorticoids. Sex steroids (estradiol and testosterone) stimulate GH secretion, contributing to a pubertal rise in GH. In addition, GH levels are decreased in hypothyroidism. The growth-promoting effects of GH are mediated principally through endocrine, autocrine, and paracrine production of insulin-like growth factors (IGFs).

Growth Hormone Deficiency Children with congenital GH deficiency are of normal size at birth. However, after approximately 6 months of life, growth failure becomes apparent when linear growth becomes GH dependent. Usually, children with GH deficiency are short and cherubic, with a doll-like appearance. Approximately 10% to 20% of GH-deficient patients present with severe hypoglycemia in addition to short stature. In the neonatal period, hypoglycemia and microphallus strongly suggest GH deficiency. Although abnormalities can occur at any level of the GHRH-GH-IGF-I axis, the majority of these abnormalities occur at the hypothalamic/pituitary level. In fact, most patients with GH deficiency (80% to 90%) are GHRH deficient. As with gonadotropins or ACTH, a deficiency of GH may be isolated or associated with other hypothalamic/pituitary hormone abnormalities. Isolated GH deficiency has been reported to be familial in 3% to 30% of cases. Mutations have been found in only a minority of such patients, primarily involving the GH1 and GHRHR genes. Mutations in the gene Rpx/Hesx1 are associated with septo-optic dysplasia, a common midline malformation characterized by the classical triad of optic nerve hypoplasia, midline malformations (such as agenesis of the corpus callosum and absence of the septum pellucidum), and pituitary hypoplasia with consequent panhypopituitarism. The phenotypes of mutations in the Rpx/

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Hesx1 gene are highly variable, ranging from isolated GH deficiency without any midline defects, to the complete spectrum of the disease with panhypopituitarism. Evaluation of a child with suspected GH deficiency includes a thorough history, physical examination, and careful review of growth charts and laboratory studies. Severe neonatal hypoglycemia is suggestive of GH deficiency. Most children with GH deficiency will have not only short stature, but also a subnormal height velocity with relative preservation of weight and head circumference. The diagnosis of GH deficiency is often difficult to make with a single blood test, in light of the pulsatile nature of GH secretion. GH-dependent IGF-I and IGF binding protein 3 (IGF-BP3) levels, and provocative tests of GH secretion have been used widely to evaluate GH status. If a diagnosis of GH deficiency is made, it is essential to evaluate all pituitary hormones, and to obtain an MRI with particular attention to the third ventricular area. The principal treatment of children with GH deficiency is recombinant GH administered as a daily subcutaneous injection. Some children with GH deficiency on the basis of GHRH deficiency have been treated successfully with GHRH. Adequacy of treatment is determined by assessment of growth velocity and serum IGF-I and IGF-BP3 levels. Recent studies demonstrate beneficial effects of continued GH treatment (at lower doses) after final height is reached in adolescents with permanent GH deficiency. GH treatment occasionally is associated with side effects, such as increased intracranial pressure, hyperglycemia, and slipped capital femoral epiphysis.

Growth Hormone Excess Gigantism is a rare condition caused by GH excess in children who have open epiphyses, primarily caused by increased GH production from the pituitary. GH-producing adenomas constitute up to 10% of pituitary adenomas. Ectopic GHRH overproduction is a rare cause of GH excess. In addition, McCune–Albright syndrome (MAS) can present with gigantism because of constitutively active G proteins in somatotrophs that result in increased GH secretion. Accelerated longitudinal growth and acromegalic features (enlarged head, large hands and feet, big tongue, and broad nose) are the most prominent signs of GH excess. In girls, menstrual irregularity is common. Mass effect of the tumor can cause impaired vision and headache caused by increased intracranial pressure. Some patients also may have hyperprolactinemia as a result of cosecretion. A diagnosis of pituitary gigantism is made by demonstrating nonsuppressible GH in response to glucose loading, in association with elevated IGF-I and IGF-BP3 levels. Usually, sellar MRI will reveal a pituitary mass. The goal of treatment in GH-secreting adenomas is normalization of GH and IGF-I levels. Transsphenoidal surgery has resulted in a greater than 80% cure rate, and thus remains the first choice of treatment. If surgery is unsuccessful, somatostatin analogs, GH receptor antagonists, and dopamine agonists can be used. Somatostatin analogs may be used as first-line treatment should the patient prefer medication over surgery (Colao et al., 2009). Radiotherapy may be beneficial to treat an adenoma that increases in size despite medical therapy.

HYPOTHALAMIC/PITUITARY DISORDERS OF THYROID FUNCTION Normal Thyroid Physiology Under regulation by the hypothalamus and pituitary, the thyroid gland produces thyroid hormones, which have broad effects on metabolism, growth, and CNS development. TSH is

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a heterodimeric glycoprotein consisting of alpha and beta subunits. The alpha subunit is common to TSH, LH, FSH, and hCG, whereas the beta subunit confers specificity. TSH acts on the thyroid gland to stimulate thyroid hormone synthesis and secretion. TSH is negatively regulated by thyroid hormones and positively regulated by TRH.

Arcuate nucleus POMC α-MSH AgRP NPY

Paraventricular nucleus lateral hypothalamic area Anorexigenic Orexigenic

MC4R YIR

Central Hypothyroidism Central (hypothalamic/pituitary) hypothyroidism is rare in comparison to primary hypothyroidism, and may be congenital or acquired. Signs and symptoms associated with hypothyroidism may arise insidiously and are often nonspecific. In the neonatal period, newborns may have lethargy, hypotonia, hypothermia, or prolonged jaundice. Untreated hypothyroidism during infancy and early childhood can result in developmental delay, mental retardation, and poor statural growth. Presenting symptoms in older children include weight gain, subnormal height velocity, constipation, cold intolerance, hoarse voice, dry skin, and lethargy. Congenital TSH deficiency occurs in 1 : 50,000 to 150,000 newborns. Underlying etiologies include isolated TSH deficiency, developmental defects of the hypothalamus and pituitary, and familial panhypopituitarism. Isolated TSH deficiency is caused by usually autosomal-recessive mutations in the TSH beta subunit. TSH deficiency, in combination with other pituitary hormone deficiencies, is seen frequently in patients with HESX1, PIT-1, and PROP-1 mutations or CNS insults. In addition, isolated central hypothyroidism can result from a lossof-function mutation in the TRH receptor. Patients with congenital TSH deficiency are usually not detected by neonatal screening for hypothyroidism, as most programs are designed to screen for the hyperthyrotropinemia that accompanies primary hypothyroidism. With respect to laboratory assessment of thyroid function, it is critical to recognize that normal ranges vary significantly with age. In particular, TSH and free T4 are relatively high in newborns in comparison to older infants, children, and adolescents. The principal goals of treating central hypothyroidism are normalization of thyroxine levels and prevention of mental retardation and growth impairment. Thus thyroxine replacement should be instituted promptly after diagnosis of hypothyroidism, regardless of etiology.

Central Hyperthyroidism Most cases of hyperthyroidism in the pediatric population are autoimmune and TSH-independent. Central hyperthyroidism as a consequence of a pituitary TSH-secreting adenoma is exceedingly rare. Such patients may have a prominent local mass effect of the tumor. Signs and symptoms of hyperthyroidism, such as agitation, tall stature, goiter, tremor, and palpitation, are manifested in central hyperthyroidism. Biochemically, patients with central hyperthyroidism have elevated concentrations of TSH in the context of elevated T4 and T3. If a pituitary adenoma is not identifiable on imaging studies, rare selective pituitary T3 resistance attributable to inactivating mutation of thyroid hormone receptor beta should be considered. Surgical removal of the tumor is the treatment of choice for TSH-secreting pituitary adenoma. The treatment of selective pituitary T3 resistance remains a therapeutic challenge.

HYPOTHALAMIC DISORDERS OF APPETITE REGULATION AND ENERGY BALANCE Appetite and energy balance are regulated by a complex network, in which the hypothalamus serves as the central

Leptin

Insulin

PYY

Adipocytes

Pancreas

Small intestine and the colon

Long-term signals

Ghrelin

Food intake Energy balance

Stomach

Short-term signals

Figure 153-5.  Hormonal regulation of food intake and energy balance in the hypothalamus. The dashed lines indicate inhibitory effects and the solid lines with arrows indicate stimulatory effects. Long-term signals affecting body fat mass include leptin and insulin, whereas short-term signals determining meal initiation and termination include peptide YY3–36 and ghrelin. AgRP, agouti-related protein; αMSH, α-melanocyte-stimulating protein; MC4R, melanocortin 4 receptor; POMC, proopiomelanocortin; PYY, peptide YY3–36; Y1R, Y1 subtype of neuropeptide Y (NPY) receptor.

processing unit for hormonal, nutritional, and neuronal input from both peripheral tissue and higher brain centers. In humans, it is well known that hypothalamic damage can lead to excessive weight gain, hypothalamic obesity. These patients present with excessive weight gain without response to caloric restriction or exercise. Traditionally, the ventromedial hypothalamus has been viewed as the “satiety” center, because damage to the ventromedial hypothalamus can cause hyperphagic obesity. In contrast, the lateral hypothalamus has been viewed as the “feeding” center, because its disruption leads to hypophagia and weight loss. Insights into mechanisms of hypothalamic obesity derive from advances in our understanding of hypothalamic control of appetite regulation and energy balance (Fig. 153-5). Energy storage and appetite are regulated at the hypothalamus through signaling by leptin and insulin. Both leptin and insulin affect anorexigenic and orexigenic pathways in the hypothalamus. The effects of leptin are quantitatively much greater than that of insulin, and there are complex responses of various neuron subsets within hypothalamic nuclei (Sohn et al., 2013; Morton et al., 2014). In the anorexigenic pathway, leptin maintains expression of POMC in the arcuate nuclei, and POMC-derived α-melanocyte-stimulating hormone (αMSH) activates the melanocortin-4 receptor (MC4R) in the paraventricular nuclei and the lateral hypothalamic area. This melanocortin signal is appetite suppressing. In addition, leptin and insulin inhibit NPY and AgRP within the arcuate nuclei, both of which are appetite-stimulating peptides. NPY decreases POMC expression through the neuropeptide Y1 receptor (Y1R). AgRP is an antagonist for MC4R, competing with α-MSH for binding to the MC4R and leading to increased food intake. Hypothalamic obesity frequently is seen in children with hypothalamic insults, such as brain tumor, surgery, irradiation, or trauma. Approximately 50% of children with craniopharyngioma develop hypothalamic obesity. Other tumors, such as germinoma, optic glioma, prolactinoma, and hypothalamic astrocytoma, also are associated with hypothalamic obesity. These patients usually have unrelenting weight gain



Endocrine Disorders of the Hypothalamus and Pituitary in Childhood and Adolescence

after tumor removal or radiotherapy, without documented excessive food intake. Reduced physical activity, rather than increased energy intake, was shown to be primarily responsible for obesity in patients with craniopharyngioma. Decreased resting energy expenditure also may be present in children after brain tumor therapy, including hypothalamic irradiation (greater than 51 Gy). Numerous examples of monogenic obesity have been described at many levels of hypothalamic control of energy balance, including leptin, leptin receptor, POMC, prohormone convertase 1/3 (PC1/3), and MC4R (Ranadive and Vaisse, 2008). Mutations in leptin and leptin receptor are extremely rare monogenic forms of morbid obesity. The children reported with leptin deficiency had normal birth weight, but became hyperphagic in infancy and developed severe obesity with undetectable levels of leptin. Exogenous administration of leptin induced sustained weight loss because of loss of fat mass. Similar results were observed in adults with congenital leptin deficiency. Mutations of the leptin receptor also are associated with severe childhood obesity associated with absent pubertal development, reduced levels of both TSH and GH, and impaired immune function. Loss-of-function mutations in POMC result in severe hyperphagia and obesity as a consequence of lack of MC4R activation by α-MSH, and adrenal insufficiency as a consequence of defective synthesis of ACTH. Patients may also have red hair from lack of MC1R activation by α-MSH in melanocytes. Mutations in PC1/3, thought to result in defective processing of POMC to α-MSH, as well as defective ACTH synthesis, lead to hyperphagia, early onset obesity, and partial ACTH deficiency. MC4R mutations have been found in 2.5% of obese children, representing the most common genetic defects in human obesity.

HYPOTHALAMIC/PITUITARY DISORDERS OF WATER BALANCE Under normal circumstances, plasma osmolality is maintained within a relatively narrow range by adequate water intake, regulated by thirst, and appropriate free water excretion by the kidneys, mediated by appropriate secretion of vasopressin (AVP). AVP is produced in the magnocellular neurons, which originate in the paraventricular and supraoptic nuclei of the hypothalamus and terminate in the posterior pituitary gland. AVP exerts its antidiuretic action by binding to the X chromosome–encoded V2 vasopressin receptor (V2R) on the basolateral membrane of renal collecting duct epithelial cells. After V2R activation, the water channel aquaporin 2 (AQP-2) is shuttled to the apical membrane of collecting duct epithelial cells, resulting in increased water permeability and antidiuresis. AVP secretion is regulated principally by changes in plasma osmolality and in effective circulating volume. AVP levels are normally low and do not increase until plasma osmolality exceeds 280 mOsm/kg, but responds to as little as 1% increases in plasma osmolality. AVP secretion also is regulated by changes in blood volume. Baroreceptors in the venous and arterial circulation become activated when stretched by increases in intravascular volume, leading to inhibition of AVP secretion. In addition, a variety of other factors affect AVP secretion. It is stimulated by pain, stress, and a variety of drugs, and is inhibited by surgery, trauma, and infiltrative processes of the hypothalamus. Clinical disorders of water balance are common, and abnormalities in many steps involving AVP secretion and responsiveness have been described (Ranadive and Rosenthal, 2009). The focus of this section is on the principal hypothalamic/pituitary disorders of water balance, diabetes

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insipidus (DI), and the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Diabetes Insipidus DI may result from a deficiency of AVP or from nephrogenic causes that manifest resistance to AVP. Central DI is rarely congenital and more frequently acquired. Congenital central DI may be associated with congenital conditions, including congenital hypopituitarism, Wolfram syndrome, and SOD, and through both autosomal-dominant and autosomalrecessive mutations in the AVP/NPII gene. Of the latter, the autosomal-dominant causes are more common, and are thought to be a consequence of heterozygous mutations in the AVP/NPII gene that lead to misfolding of the precursor AVP/ NPII protein. The dominant negative effect is thought to occur as a consequence of the misfolded precursor protein, which accumulates in the endoplasmic reticulum of vasopressinergic neurons, ultimately resulting in death of these neurons. In such patients, clinical DI usually develops several months to years after birth. A rare autosomal-recessive form of central DI has been reported, resulting in a biologically inactive AVP. Acquired forms of DI occur in association with a variety of disorders in which there is destruction or degeneration of vasopressinergic neurons. Etiologies include primary tumors (e.g., craniopharyngioma, germinoma) or metastases, infection (meningitis, encephalitis), histiocytosis, granuloma, vascular disorders, and autoimmune disorders (lymphocytic infundibuloneurohypophysitis). Acquired DI may occur in association with trauma and surgery. Idiopathic DI is a diagnosis of exclusion, and one that is made with decreasing frequency concurrent with improved sensitivity of CNS MRI and of cerebrospinal fluid and serum tumor markers. The principal presenting sign of DI is polyuria, which, in addition to deficiency or impaired responsiveness to AVP, may result from an osmotic agent (e.g., hyperglycemia in diabetes mellitus) or from excessive water intake (primary polydipsia). Hypernatremia usually does not occur if patients have an intact thirst mechanism, adequate access to fluids, and no additional ongoing fluid losses (e.g., diarrhea). Infants with DI, in addition to polyuria and polydipsia, may be irritable and have fever of unknown origin, growth failure secondary to inadequate caloric intake, and hydronephrosis. Older children may have nocturia and enuresis. DI may not be apparent in patients with coexisting untreated anterior pituitarymediated adrenal glucocorticoid insufficiency, as cortisol is required to generate a normal free water loss. A diagnosis of DI can be made if screening laboratory studies reveal serum hyperosmolality concurrent with inappropriately dilute urine. However, as most patients with DI do not have hyperosmolality and hypernatremia, a standardized water deprivation test is useful to distinguish DI. If DI is indicated during the water deprivation test, then an AVP level should be obtained and AVP or a synthetic analog (desmopressin) should then be administered to distinguish AVP deficiency from AVP unresponsiveness. Once a diagnosis of central DI is made, a brain MRI of the third ventricular area should be obtained. An absent posterior pituitary “bright spot” is seen in virtually all patients with central DI. Under normal circumstances, a posterior pituitary bright spot is seen on T1-weighted images because of stored AVP in neurosecretory granules (see Fig. 153-1). In central DI patients with an absent posterior pituitary bright spot, an otherwise-normal MRI warrants close follow up with cerebrospinal fluid tumor markers and cytology, serum tumor markers, and serial contrast-enhanced brain MRIs for early detection of an evolving occult hypothalamic-stalk lesion.

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In addition to treatment of a primary disease causing central DI, the drug of choice for most patients with AVP deficiency is desmopressin. This AVP analog has markedly reduced vasopressor activity in comparison to native AVP, has a prolonged half-life, and can be administered orally, intranasally, or by subcutaneous injection.

pontine myelinolysis. Generally, it is recommended that plasma sodium be corrected to a “safe” level of approximately 120 to 125 mEq/L, at a rate of no greater than 0.5 mEq/L per hour, with an overall correction that does not exceed 12 mEq/L in the initial 24 hours and 18 mEq/L in the initial 48 hours of treatment.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details.

SIADH is characterized by the inability to excrete a free water load, with inappropriately concentrated urine, and resultant hyponatremia, hypo-osmolality, and natriuresis in the absence of renal dysfunction, hypothyroidism, and adrenal insufficiency. Although most patients with SIADH have inappropriately measurable or elevated levels of plasma AVP relative to plasma osmolality, 10% to 20% of patients with SIADH do not have measurable AVP levels. This may reflect issues of assay sensitivity or may indicate a syndrome resembling SIADH, nephrogenic syndrome of inappropriate antidiuresis (NSIAD), which is associated with an activating mutation in the X-linked V2R and unmeasurable circulating levels of AVP. Euvolemia in chronic SIADH is an important distinguishing factor in the evaluation of a patient with serum hypoosmolality and has a bearing on treatment issues. Euvolemia in chronic SIADH is thought to represent an adaptation to water overload. Natriuresis, thought to be mediated in part through secretion of atrial natriuretic peptide, also contributes to volume regulation in chronic SIADH. Cerebral salt wasting, associated with some intracranial diseases (e.g., subarachnoid hemorrhage), is often considered in the differential diagnosis of SIADH. However, the hypo-osmolality, hyponatremia, and natriuresis in cerebral salt wasting are associated with volume contraction, which distinguishes this disorder from the euvolemic condition of SIADH. A large number of disorders and conditions are associated with SIADH. These include disorders of the CNS (e.g., infection, trauma, cerebrovascular accident, tumors), surgery, ectopic AVP production from non-CNS tumors, medications, and pulmonary disorders. Therapy for SIADH includes treatment of the underlying disorder (or discontinuation of an offending drug) and fluid restriction. Replacement of lost body sodium also may be necessary but usually can be achieved through normal dietary salt intake. Severe hyponatremia may be associated with CNS abnormalities, including seizures, and may require treatment with hypertonic intravenous sodium chloride solution. Concurrent use of a diuretic, such as furosemide, may be indicated. Urea has been used as an osmotic diuretic in pediatric SIADH and NSIAD. A variety of nonpeptide V2R antagonists have been approved by the Food and Drug Administration for use in adults. If SIADH and hyponatremia are acute (48 hours), overzealous treatment can result in CNS damage, including central

SELECTED REFERENCES Abreu, A.P., Dauber, A., Macedo, D.B., et al., 2013. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med. 368, 2467–2475. Bulcao, M.D., Nahime, B.V., Latronico, A.C., 2014. New causes of central precocious puberty: The role of genetic factors. Neuroendocrinology 100, 1–8. Colao, A., Auriemma, R.S., Galdiero, M., et al., 2009. Effects of initial therapy for five years with somatostatin analogs for acromegaly on growth hormone and insulin-like growth factor-I levels, tumor shrinkage, and cardiovascular disease: A prospective study. J. Clin. Endocrinol. Metab. 94, 3746. Dauber, A., Rosenfeld, R.G., Hirschhorn, J.N., 2014. Genetic evaluation of short stature. J. Clin. Endocrinol. Metab. 99, 3080–3092. Lonser, R.R., Wind, J.J., Nieman, L.K., et al., 2013. Outcome of surgical treatment of 200 children with Cushing’s disease. J. Clin. Endocrinol. Metab. 98, 892–901. Morton, G.J., Meek, T.H., Schwartz, M.W., 2014. Neurobiology of food intake in health and disease. Nat. Rev. Neurosci. 15, 367– 378. Oakley, A.E., Clifton, D.K., Steiner, R.A., 2009. Kisspeptin signaling in the brain. Endocr. Rev. 30, 713. Ranadive, S.A., Rosenthal, S.M., 2009. Pediatric disorders of water balance. Endocrinol. Metab. Clin. North Am. 38, 663–672. Ranadive, S.A., Vaisse, C., 2008. Lessons from extreme human obesity: Monogenic disorders. Endocrinol. Metab. Clin. North Am. 37, 733–751. Sohn, J.W., Elmquist, J.K., Williams, K.W., 2013. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 36, 504–512.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 153-1 T1-weighted magnetic resonance images of the normal hypothalamus/pituitary in an 8-year-old girl. Fig. 153-2 Hamartoma of the tuber cinereum in a 3-year-old girl by magnetic resonance imaging. Fig. 153-3 Craniopharyngioma in a child by magnetic resonance imaging. Fig. 153-4 Adrenocorticotropic hormone-secreting pituitary adenoma in a 15-year-old girl by magnetic resonance imaging.

of the Autonomic Nervous System: Autonomic 154  Disorders Dysfunction in Pediatric Practice Jose-Alberto Palma, Lucy Norcliffe-Kaufmann, Cristina Fuente-Mora, Leila Percival, Christy L. Spalink, and Horacio Kaufmann An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Dysfunction of the autonomic nervous system (ANS) is an increasingly recognized health problem in the pediatric population. Patients with ANS dysfunction may present with a number of seemingly unrelated symptoms, including lightheadedness on standing, syncope, labile blood pressure, problems with sweating or thermoregulation, gastrointestinal dysmotility, bladder urgency or incontinence, and sleep abnormalities. The vast majority of complaints in children referred to an autonomic disorders clinic correspond to physiologic responses to emotional states. Neuronal pathways connect the limbic system to the autonomic system, and as a consequence, emotions have a profound effect on autonomic outflow to the organs. In these cases, rather than a primary autonomic disorder, the symptoms result from activation of the classic “flightor-fight” autonomic response to a perceived (but not always obvious) threat. Autonomic dysfunction in children can be secondary to metabolic disorders, including obesity, anorexia, and diabetes. Severe, sometimes life-threatening derangements of autonomic function occur in a number of rare genetic and autoimmune disorders. Autonomic dysreflexia as a result of spinal cord lesions and afferent baroreflex failure as a result of neck tumors or as sequelae of surgery or radiotherapy can occur in children and adolescents and presents with dramatic blood pressure volatility.

ANATOMY AND PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM Anatomy of the Autonomic Nervous System The ANS innervates most of the organs in the body and controls involuntary functions to maintain homeostasis. In 1898, physiologist John Langley divided the ANS into three branches: sympathetic, parasympathetic, and enteric. The sympathetic and the parasympathetic nervous system have opposing actions.

Efferent Autonomic Pathways The autonomic outflow from the central nervous system (CNS) to the effector organs consists of a two-neuron pathway with one synapse in the peripheral autonomic ganglia (Fig. 154-1). Sympathetic Efferent Pathways.  The cell bodies of preganglionic sympathetic neurons are in the intermediolateral cell column (IML) of the thoracic and lumbar spinal cord (levels T1 through L3). Preganglionic sympathetic axons leave the spinal cord as small myelinated fibers to synapse with (post)ganglionic neurons in sympathetic ganglia close to the spinal cord. Unmyelinated axons from postganglionic neurons

emerge from sympathetic ganglia to synapse with target organs. Preganglionic sympathetic neurons in the IML cell column receive direct descending excitatory inputs from hypothalamic nuclei and from the ventromedial and rostral ventrolateral medulla (RVLM). Preganglionic sympathetic axons exit the spinal cord through the ventral roots toward paravertebral or prevertebral ganglia. Parasympathetic Efferent Pathways.  The cell bodies of preganglionic parasympathetic neurons are located in the brainstem and at the sacral (S2-S4) level of the spinal cord. Axons of preganglionic parasympathetic neurons are myelinated and leave the brainstem or spinal cord to synapse with cell bodies of postganglionic parasympathetic neurons in autonomic ganglia close to (or within) the effector organs. Short unmyelinated postganglionic parasympathetic fibers synapse with target tissues. Efferent Neurotransmission.  Acetylcholine is the neurotransmitter of preganglionic neurons, both sympathetic and parasympathetic. Acetylcholine, via activation of nicotinic receptors, produces excitation of postganglionic neurons. The main neurotransmitter of postganglionic sympathetic neurons is norepinephrine, which activates alpha- and beta-adrenergic receptors. The sympathetic neurons innervating sweat glands release acetylcholine, which activates muscarinic receptors. The main neurotransmitter of postganglionic parasympathetic neurons is also acetylcholine, which acts on different types of muscarinic receptors (Fig. 154-1).

Afferent Autonomic Pathways The classic descriptions of the ANS were of a purely efferent motor system. The ANS, however, has afferent pathways that run parallel to the efferent pathways and can also be divided into sympathetic and parasympathetic. Parasympathetic afferents are small-diameter fibers that transmit information to the CNS via the vagus (X) and glossopharyngeal (IX) nerves and have their cell bodies in the nodose and petrosal ganglia, respectively. Vagal afferents relay information from aortic, cardiac, pulmonary, and gastrointestinal receptors. Glossopharyngeal afferents carry signals from baroreceptors and chemoreceptors in the carotid sinus. Parasympathetic afferents synapse with neurons in the NTS in the brainstem. Sympathetic afferents relay information about an array of physiologic variables, including the mechanical, thermal, chemical, metabolic, and hormonal status of the skin, muscle, joints, teeth, and viscera. They are responsible for muscular and visceral sensations, vasomotor activity, hunger, thirst, and “air hunger.” These neurons synapse with neurons in lamina I of the dorsal horn of the spinal cord. Lamina I neurons in turn project densely to the IML cell column synapsing with preganglionic sympathetic neurons, forming a spino-spinal loop for autonomic reflexes.

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Muscarinic receptor

Nicotinic receptor

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Preganglionic neuron

Cardiac muscle Smooth muscle

NE

Muscarinic receptor Postganglionic neuron

Sweat glands

ACh

Nicotinic receptor Preganglionic neuron

ACh

Adrenal medulla

Figure 154-1.  Elements of the parasympathetic and sympathetic nervous systems. Most organs receive both sympathetic and parasympathetic innervation, except for the blood vessels (only sympathetic adrenergic), the sweat glands (only sympathetic cholinergic), and the adrenal medulla (receives direct sympathetic innervation from the intermediolateral cell column in the spinal cord).

Central Nervous System Integration Spinal, brainstem, and rostral cortical areas modulate signals from the afferent pathways, resulting in precise reflex activation or inhibition of autonomic efferent nerves. A well-studied example of an autonomic reflex pathway is the arterial baroreflex (Fig. 154-2). As with other polysynaptic autonomic reflexes, baroreflex information is integrated with other sensory information and with input from more rostral cortical areas.

CLINICAL APPROACH TO THE DIAGNOSIS OF PEDIATRIC AUTONOMIC DISORDERS Clinical History Taking Children with autonomic dysfunction can present with a variety of symptoms involving different organs. Detailed history taking is of paramount importance to establish a diagnosis. A structured clinical interview can provide valuable diagnostic clues. Careful review of current medications can rule out drug-induced causes. A thorough family history is key to the diagnosis of genetic disorders.

Orthostatic Intolerance Because the sympathetic nervous system plays a crucial role maintaining blood pressure and cerebral blood flow when standing, orthostatic intolerance with symptoms of tissue hypoperfusion is the most characteristic presentation of sympathetic failure (see following discussion). The clinical interview should be framed with the goal of carefully reconstructing the events, signs, symptoms, and outcome of the syncopal/ presyncopal episode. Syncope.  Most children are referred to an autonomic clinic after experiencing brief episodes of transient loss of consciousness. Although seizures are frequently suspected, syncope is much more frequent. Syncope is defined as a transient loss

of consciousness and postural tone resulting from global cerebral hypoperfusion; it is short-lived, with spontaneous recovery and no neurologic sequelae. Urinary incontinence and myoclonic jerks can occur in children with both reflex syncope and seizures, but a clear-cut aura and postictal confusion are signs of a seizure. Tongue biting is rare in syncope but common in seizures. Syncope most commonly occurs when standing, whereas seizures have no postural predilection. Questions should aim to differentiate reflex (vasovagal) syncope—a reversible physiologic condition with a benign prognosis—from cardiac syncope or chronic impairment of sympathetic outflow. Although the latter is very infrequent in children, it does occur in genetic and immune-mediated autonomic disorders. Orthostatic Intolerance with Orthostatic Tachycardia.  The second most commonly encountered problem in an autonomic clinic is the so-called postural tachycardia syndrome (PoTS), a heterogenous syndrome common in young females. It is associated with a myriad of symptoms, including lightheadedness, palpitations, tremulousness, weakness, fatigue, exercise intolerance, hyperventilation, paresthesiae, shortness of breath, anxiety, chest pain, nausea, acral coldness or pain, and difficulty concentrating. Syncope is not common in PoTS. The overlap with anxiety/panic disorders is often readily apparent. Abnormal Gastrointestinal Motility.  Constipation and diarrhea are common in children with functional autonomic disorders and are also a side effect of some medications or diets. Reduced salivation and dry mouth (xerostomia) can occur in autoimmune autonomic disorders and may result in dysphagia when eating. Autonomic diseases affecting the esophagus (e.g., achalasia) may cause dysphagia and heartburn. Abdominal distension, nausea, vomiting, and early satiety as a consequence of gastroparesis can be seen in metabolic disorders (e.g., diabetes, anorexia nervosa).



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SON PVN Afferent pathways A1 IX

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CVL

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Sympathetic ganglion Arterioles or venules Figure 154-2.  The arterial baroreflex. The arterial baroreceptors are mechanoreceptors located in the carotid sinus (innervated by the glossopharyngeal nerve, IX) and aortic arch (innervated by the vagus nerve, X) that respond to stretch elicited by increase in arterial pressure. Baroreceptor afferents provide monosynaptic excitatory inputs to the nucleus of the solitary tract (NTS) in the brainstem. Barosensitive NTS neurons initiate a sympathoinhibitory pathway that involves projections from the NTS to the caudal ventrolateral medulla (CVL) that send inhibitory projections to sympathoexcitatory neurons in the rostral ventrolateral medulla (RVLM). There is also direct input from the NTS to the vagal preganglionic neurons of the nucleus ambiguus (NAmb). These neurons project to the cardiac ganglion neurons that promote bradycardia. The baroreflex, via the NTS, also inhibits secretion of vasopressin by neurons of the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus, by inhibiting cells of the A1 noradrenergic group.

Neonatal severe constipation is a feature of Hirschsprung disease. Nausea and vomiting in response to emotional or physical stimuli occur in the rare genetic condition familial dysautonomia, although such occurrences are more frequently a result of functional disorders (e.g., cyclic vomiting syndrome). Genitourinary Symptoms.  Urinary symptoms are frequent in children, and in most cases they are not indicative of an underlying autonomic disorder. Interpretation in young children should take into account that 10% of those younger than 8 years old suffer from daytime or nocturnal enuresis. In rare cases, daytime enuresis is attributable to detrusor overactivity. Urinary retention can be seen in autoimmune autonomic disorders and in spinal cord injury (Neveus and Sillen, 2013). In adolescents and young men, erectile dysfunction and failure to ejaculate can be a consequence of autonomic dysfunction. Milky-colored urine may represent retrograde ejaculation. Thermoregulatory Abnormalities.  Anhidrosis and hypohidrosis are manifestations of sympathetic cholinergic failure, and lesions causing these abnormalities can occur anywhere from the level of the cerebral cortex to the eccrine sweat glands. Anhidrosis can lead to hyperthermia, heat stroke, and death. In spinal cord injury there often is a band of hyperhidrosis above the lesion with anhidrosis below. Hypothermia may occur in hypothalamic disorders and spinal cord injury.

Hyperhidrosis (excessive sweating beyond that required for thermal homeostasis) can be generalized or focal. It should be distinguished from normal night sweats, which can occur in up to 12% of healthy children. In the vast majority of cases, hyperhidrosis is linked to anxiety. Hyperhidrosis may accompany episodes of paroxysmal sympathetic activation in familial dysautonomia or pheochromocytoma. Ocular Symptoms.  Blurry vision and photophobia can be symptoms of abnormal autonomic innervation of the pupil. Impaired lacrimation may be a sign of autonomic impairment of the lacrimal glands. Respiratory Symptoms.  Hyperventilation is common and can be found in up to 15% of children and adolescents. Hyperventilation is frequently a feature in patients with functional autonomic symptoms, including PoTS and reflex syncope. Daytime symptoms of hypoventilation and central sleep apnea in children include decreased attention span, poor performance in school, and behavioral changes.

PEDIATRIC AUTONOMIC DISORDERS Pediatric autonomic disorders can be classified in several ways. Table 154-1 depicts proposed schemes based on the pathophysiological features of autonomic dysfunction in children. In clinical practice, the main goal is to distinguish functional disorders, which are very common, from the more severe, but rare disorders.

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TABLE 154-1  Classifications of Pediatric Autonomic Disorders Etiology

Topography

Frequency

Neurotransmission

Functional Reflex (vasovagal) syncope Postural tachycardia syndrome Orthostatic intolerance without tachycardia

Generalized Reflex (vasovagal) syncope Postural tachycardia syndrome Orthostatic intolerance without tachycardia Hereditary sensory autonomic neuropathies Other rare genetic disorders Reflex (vasovagal) syncope Postural tachycardia syndrome Orthostatic intolerance without tachycardia Immune-mediated

Common Reflex (vasovagal) syncope Postural tachycardia syndrome Orthostatic intolerance without tachycardia Obesity Diabetes Anorexia nervosa Other metabolic disorders

Pandysautonomia (adrenergic and cholinergic failure) Autoimmune autonomic ganglionopathy Acute autonomic and sensory neuropathy Guillain-Barré syndrome Paraneoplastic neuropathies Porphyria

Inherited Hereditary sensory autonomic neuropathies Other rare genetic disorders

Pupil Argyll Robertson pupil Adie pupil Horner syndrome Pourfour du Petit syndrome

Rare Immune-mediated Traumatic Hereditary sensory autonomic neuropathies Other rare genetic disorders

Pure adrenergic failure Dopamine-beta hydroxylase deficiency Pure adrenergic neuropathy

Metabolic Obesity Diabetes Anorexia Other metabolic disorders

Face Cluster headache Harlequin syndrome Gustatory sweating

Immune-mediated Autoimmune autonomic ganglionopathy Guillain-Barre syndrome Anti-NMDA receptor encephalitis Paraneoplastic autonomic neuropathy Sjögren disease

Limbs Raynaud phenomenon Acrocyanosis Primary idiopathic hyperhidrosis

Pure cholinergic failure Botulism Lambert-Eaton syndrome Adie pupil Chagas disease Acute cholinergic neuropathy

Infectious Chagas disease HIV Tetanus Neoplasia Catecholamine-secreting tumors Brainstem and posterior fossa tumors Trauma and malformations Spinal cord injury Traumatic brain injury Syringomyelia Arnold-Chiari Drugs Postsurgical or postradiotherapy Acquired baroreflex failure

Functional Disorders of Unknown Origin Reflex (Vasovagal) Syncope Reflex syncope (i.e., the common faint, also known as vasovagal, neurally mediated, or neurocardiogenic syncope) refers to a sudden fall in blood pressure and slowing of the heart rate causing impaired cerebral perfusion that leads to a brief episode of loss of consciousness and muscle tone. Patients with reflex syncope usually describe classical prodromal signs and symptoms (pallor, diaphoresis, nausea, abdominal discomfort, yawning, sighing), and many children begin to hyperventilate in the time leading up to the faint. If blood pressure continues to fall, cerebral and retinal hypoperfusion (visual disturbances, concentration difficulties, and lightheadedness) develop just before the loss of consciousness. Scenarios likely to provoke reflex syncope are motionless standing,

elevated ambient temperatures, and dehydration. Known emotional triggers are fear, anger, blood sampling, pain, and TV programs about medical matters (Wieling et al., 2009). The prevalence of reflex syncope in the pediatric population is high. A survey of young adults averaging 20 years of age showed that about 20% of males and 50% of females reported having experienced at least one syncopal episode in their lifetime. The median age at the first episode of reflex syncope is approximately 15 years. In most cases, reflex syncope can be diagnosed by eyewitness accounts and careful reconstruction of the event. In cases when the diagnosis is not straightforward, prolonged tilt testing can be helpful by replicating symptoms while recording the typical acute drop in blood pressure and slowing of the heart rate (Fig. 154-4). Key aspects of the management of young patients with reflex syncope include reassurance, advice, and patient



Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice Neurogenic orthostatic hypotension 150

CO2 Blood pressure Heart rate (mmHg) (mmHg) (bpm)

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Figure 154-4.  Changes in heart rate (HR), blood pressure (BP), and ventilation pattern during head-up tilt test. A, In a normal subject, no major changes are observed in BP, HR, or end-tidal CO2 during the tilt test. B, Neurogenic orthostatic hypotension features a dramatic decrease in blood pressure and absence of compensatory increase in heart rate. Hyperventilation does not occur. C, Reflex (vasovagal) syncope. During the episode, a dramatic decrease in blood pressure occurred, accompanied by a decrease in HR; CO2 levels also decreased right before and during the syncope. D, In postural tachycardia syndrome (PoTS), heart rate increases during tilt and CO2 levels decrease, with no significant changes in BP. The bar above the graphs denotes the period during the 60-degree-angle head-up tilt.

education. Time should be taken to identify triggers that exaggerate venous pooling and provoke syncope. Children should be taught nonpharmacologic measures that can prevent or abort the episode, including slow breathing and muscletensing maneuvers to increase venous return. Increasing salt and water intake and sleeping with the head of the bed raised are helpful nonpharmacologic means to expand intravascular volume. In cases of refractory reflex syncope, the shortacting pressor agent midodrine can be used “on demand” to improve orthostatic intolerance before situations known to trigger syncope. Pacemakers are ineffective (Kaufmann and Hainsworth, 2001).

Postural Tachycardia Syndrome Postural tachycardia syndrome (PoTS) is a complex disorder that is not well understood. It is characterized by chronic symptoms of orthostatic intolerance accompanied by a heartrate increment within 10 minutes of standing or head-up tilt with no orthostatic hypotension. Current consensus criteria of PoTS require, at least, a heart rate increment of 40 beats/min in children aged 12 to 19 years (Fig. 154-4).

Symptoms may develop gradually or acutely, range from mild to severe, and resolve spontaneously or continue intermittently for years. Syncope is not a typical feature of PoTS. Many children with PoTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. The pathophysiology of PoTS is unclear but likely involves a combination of factors, including cardiovascular deconditioning, hyperventilation, and volume depletion. Emotional comorbidities, including somatic hypervigilance, anxiety, and depression, are common and contribute to symptom chronicity. The severity of the symptoms is often linked to the degree of hyperventilation-induced hypocapnia, which exacerbates venous pooling and tachycardia. Many patients with PoTS go on to develop additional symptoms, including constipation, bloating, bladder sensitivity disorders, and chronic headache, and despite comprehensive workup, usually no structural cause can be identified. Management of PoTS should begin by removing any medications that produce tachycardia, including norepinephrine reuptake inhibitors and stimulants. Surreptitious use of

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diuretics should be ruled out in any adolescent or young adult with elevated renin levels. Exercise training and cognitive behavioral therapy are the most appropriate inventions. Correcting the standing heart rate with beta blockers or cholinesterase inhibitors may not be effective to improve symptoms (Benarroch, 2012).

Metabolic Disorders Obesity The prevalence of pediatric obesity (defined as a body mass index [BMI] ≥ 95th percentile for age and sex) has more than tripled during the past decades in the United States, and around 20% of children and adolescents are now overweight. Epidemiologic studies have evaluated the effect of obesity in cardiac autonomic modulation in children. Most studies show an increase in sympathetic and a decrease in parasympathetic function with abnormal cardiac circadian patterns. The pathophysiology of autonomic abnormalities in obesity is not well understood but is likely mediated by comorbidities such as sleep apnea, metabolic abnormalities, and arterial hypertension. Children with obesity as a result of genetic disorders, such as Prader-Willi syndrome, appear to have diminished parasympathetic nervous system activity.

Eating Disorders Anorexia nervosa is a potentially life-threatening eating disorder characterized by an intense fear of gaining weight, distorted body image, and amenorrhea. It affects 0.5% to 4% of adolescent girls in the United States, and its incidence has increased over the past few decades. Children with anorexia are predisposed to arrhythmias and sudden cardiac death. Bradycardia, hypotension, and cardiac atrophy are all features of the disease. Patients have significantly lower heart rates at night and increased heart rate variability. These abnormalities are reversible after weight recovery. Bulimia nervosa affects 1% to 2% of adolescent girls in the United States and has similar cardiovascular autonomic findings.

Diabetes Mellitus Although diabetes mellitus is one of the most common causes of autonomic dysfunction in adults, signs and symptoms of autonomic dysfunction are infrequent in pediatric patients. However, autonomic neuropathy should be considered in adolescents and young adults with long duration of type 1 diabetes mellitus, who may have early evidence of cardiovascular autonomic dysfunction.

Other Metabolic Disorders Hypothyroidism (with symptoms of fatigue, dry skin, sleep disturbances, and constipation) and hyperthyroidism (with symptoms of fever, tachycardia, hypertension, and gastrointestinal abnormalities) can present with symptoms of autonomic dysfunction. Symptoms of Addison disease include hypotension, hyperpigmentation, and adrenal crises.

Autonomic Dysfunction Secondary to   Focal Disease Areas distributed throughout the neuraxis, including the anterior insula, anterior cingulate cortex, amygdala, hypothalamus, periaqueductal gray matter, parabrachial nucleus, and several regions of the medulla, are involved in autonomic control, particularly in cardiovascular regulation. Therefore lesions of various etiologies (e.g., trauma, hydrocephalus,

demyelination, stroke, malformations, tumors) can potentially cause autonomic dysfunction. Spinal cord injury in the pediatric population is relatively rare. More than half of pediatric spinal cord injuries occur in the cervical area. Signs and symptoms depend on the level of the lesion and whether the section is complete or incomplete. Destruction of the descending cardiovascular autonomic pathways results in (a) blunted release of norepinephrine when upright, leading to neurogenic orthostatic hypotension, and (b) loss of inhibitory and excitatory supraspinal input to the sympathetic preganglionic neurons, leading to unrestrained sympathetic activity of fibers arising below the level of the lesion (referred to as “autonomic dysreflexia”), particularly in subjects with an injury at the T6 level or above.

ACQUIRED AFFERENT BAROREFLEX FAILURE Bilateral destruction of baroreceptor afferent neurons in the glossopharyngeal and vagus nerves that relay information to the NTS can result in afferent baroreflex failure. Patients with baroreflex failure have extremely labile blood pressure and heart rates. Many alternate between orthostatic hypotension and paroxysmal hypertension. Hyperadrenergic signs and symptoms usually dominate the clinical picture and can resemble those of a pheochromocytoma. Causes of afferent baroreflex failure include nerve injury secondary to neck surgery or delayed effect of radiotherapy to the neck for cancer, or trauma; brainstem strokes that damage the nucleus of the solitary tract and other areas of the brainstem; and rare hereditary conditions that affect the development of afferent baroreceptor pathways, including familial dysautonomia and Moebius syndrome. Treatment involves techniques to manage stress and medications to control blood pressure. Preliminary data suggest that carbidopa, a DOPA decarboxylase inhibitor that does not cross the blood–brain barrier, may reduce norepinephrine surges and lessen blood pressure peaks.

Catecholamine-Secreting Tumors Paragangliomas are rare neuroendocrine tumors derived from neural crest cells that arise in the peripheral ANS. Pheochromocytomas are paragangliomas that arise from chromaffin cells of the adrenal medulla. These are characterized by unpredictable paroxysmal episodes of excessive catecholamine secretion, resulting in hypertension, tachycardia, and headaches. Approximately 50% are malignant. Treatment requires surgery.

Autoimmune Autonomic Disorders Guillain-Barré Syndrome Guillain-Barré syndrome (GBS) is less common in children than in adults, with an incidence of 0.4 to 1.3 cases per 100,000 per year in children in the United States; it is rarely seen in children younger than 2 years old. GBS (also known as acute inflammatory demyelinating polyneuropathy) is responsible for most cases of acute and subacute flaccid paralysis in infants and children. Approximately two thirds of patients diagnosed with GBS had a respiratory or gastrointestinal infection prior the start of the symptoms. Autonomic instability with episodes of hypertension and hypotension and cardiac arrhythmia can occur. This can be life threatening, so close monitoring is required. Other autonomic symptoms such as gastrointestinal and bladder dysfunction can also be present. Treatment includes intravenous immunoglobulin (IVIG) or plasma exchange.



Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice

Autoimmune Autonomic Ganglionopathy Autoimmune autonomic ganglionopathy is characterized by an acute-onset widespread sympathetic and parasympathetic failure. Cholinergic deficits are pronounced and include severe impairment of gastrointestinal motility, with gastroparesis and constipation, bladder retention, dry eyes, and dry mouth. Abnormal pupillary responses are common. Orthostatic hypotension can be severe. There is no motor or sensory impairment. In 30% to 50% of patients, high titers of antibodies against the neuronal ganglionic nicotinic acetylcholine receptor (AChR) are identified. In the remaining cases, other autoantibodies not yet identified are the likely cause. Patients may respond to IVIG, plasma exchange, or rituximab. Some cases in children and adolescents have been reported, although its incidence in children is unknown.

Acute Autonomic and Sensory Neuropathy Acute autonomic and sensory neuropathy is a rare disorder in which patients develop acute-onset fine-touch and proprioceptive sensory deficits leading to severe ataxia. Autonomic involvement includes neurogenic orthostatic hypotension, lack of sweating, and urinary and fecal incontinence. Plasma norepinephrine levels are low or undetectable. In most cases a gastrointestinal or respiratory infection precedes the neuropathy, suggesting an immune-mediated process, in some cases associated with antigalactocerebrosidase or antisulfatide antibodies. IVIg and plasma exchange have been used, with varied success (Koike et al., 2010).

Anti-NMDA Receptor Encephalitis Anti-NMDA receptor encephalitis results from antibodies against the NR1 and NR2 subunits of the NMDA receptor. Symptoms in children include behavioral and personality changes. As the diseases progresses, patients develop sleep disorders, seizures, movement disorders, and autonomic in­­ stability (tachycardia, hypertension, hypoventilation, urinary incontinence, and hypothermia or hyperthermia). It has been linked to ovarian neoplasms, although it has been described in patients without cancer (Florance et al., 2009).

Lambert-Eaton Myasthenic Syndrome In addition to weakness and reduced or absent deep tendon reflexes, autonomic dysfunction is a recognized feature of Lambert-Eaton myasthenic syndrome (LES). Dry mouth is the most frequent autonomic symptom, followed by sweating abnormalities and impaired cardiac parasympathetic reflexes. The majority of patients have antibodies against PQ-type voltage-gated calcium channels (VGCC), and approximately 30% of patients have N-type VGCC autoantibodies. This syndrome is frequently found in association with small-cell carcinoma of the lung, but it has also been found in patients without neoplasms. Lambert-Eaton syndrome is very rare in children.

Dipeptidyl-Peptidase-Like Protein-6 (DPPX) Potassium Channel Antibody Encephalitis Dipeptidyl-peptidase-like protein-6 (DPPX) potassium channel antibody encephalitis, a recently described autoimmune encephalitis, affects adults and young teenagers and is characterized by the presence of antibodies against DPPX, a subunit of Kv4.2 potassium channels. Main features are insidious and subacute cognitive impairment, abnormal eye movements, dysphagia, insomnia, and autonomic abnormalities, most prominently gastrointestinal symptoms (diarrhea, gastroparesis, constipation), followed by urinary symptoms,

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fluctuating hyperthermia/hypothermia, and asymptomatic ventricular tachycardia.

Genetic Autonomic Disorders There are a number of rare, early-onset genetic disorders that affect the ANS. Although the extent of autonomic involvement varies, certain genetic conditions are associated with widespread autonomic dysfunction.

Hereditary Sensory and Autonomic Neuropathies Hereditary sensory and autonomic neuropathies (HSANs) are a group of rare disorders caused by different mutations that affect different aspects of the development, function, or survival of sensory and autonomic neurons. Classification is evolving as a result of the discovery of increasing numbers of mutations and the availability of whole-exome sequencing (Table 154-2). For each HSAN type, penetrance is complete, but phenotypic expression varies markedly. Impaired pain and temperature perception are common traits. HSAN Type 1.  HSAN type 1 is the most common HSAN, but it is an adult-onset disorder. Patients have varying degrees of sensorineural hearing loss, distal anhidrosis, and episodes of lancinating pain in the limbs. There are several subtypes (Table 154-2). HSAN Type 2.  HSAN type 2 is an autosomal-recessive disorder characterized by impaired temperature, pain, and finetouch sensation. Onset varies from birth up until the beginning of the teens. There are at least four causative gene mutations, resulting in subsequent subtype designations (A through D). Autonomic involvement varies markedly (Table 154-2). HSAN Type 3 (Familial Dysautonomia).  HSAN type 3 (familial dysautonomia, Online Mendelian Inheritance in Man database (OMIM) #223900) is an autosomal-recessive disease almost exclusively affecting children with Eastern European Jewish ancestry. Over 99% of affected patients are homozygous for the founder point mutation (6T>C change) in the gene encoding for the elongator-1 protein (ELP-1), known also as I-k B kinase-associated protein (IKAP). IKAP (ELP-1) is expressed in most cells throughout the body. The deficiency of IKAP (ELP-1) during embryogenesis affects the development of primary sensory (i.e., afferent) neurons that carry information to the CNS with cell bodies in the dorsal root and cranial nerve ganglia. Efferent (motor) neurons are mostly spared. In contrast to other HSANs, in HSAN type 3, autonomic dysfunction dominates the clinical picture. The main autonomic defect in patients with HSAN type 3 is in the afferent (sensory) neurons that convey incoming information from the arterial baroreceptors, resulting in the unusual combination of orthostatic hypotension and paroxysmal hypertension. Although reduced in number, the efferent sympathetic nerves are functionally active. Supine plasma norepinephrine levels are normal. Stimuli that activate efferent sympathetic neurons, independently of baroreceptor afferent pathways, such as cognitive tasks and emotional arousal, dramatically increase blood pressure, heart rate, and circulating norepinephrine levels (Norcliffe-Kaufmann, Axelrod, and Kaufmann, 2010). Episodic retching and vomiting attacks accompanied by skin blotching, diaphoresis, hypertension, and tachycardia (“dysautonomic crises”) are common. These are the result of sudden increases in circulating catecholamines that are unrestrained by baroreceptor feedback. End-organ target damage (e.g., chronic kidney disease) occurs as a long-term consequence of hypertension and excessive blood pressure variability.

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TABLE 154-2  Hereditary Sensory and Autonomic Neuropathies Type

Gene

Inheritance

Onset

Autonomic Features

Sensory Features

Other Features

HSAN 1A

SPTLC1

AD

Adult

Varying degrees of distal anhidrosis

HSAN 1B HSAN 1C

3p24-p22 locus SPTLC2

HSAN 1D HSAN 1E HSAN 1F

ALT1 DMNT1 ATL3

Progressive loss of pain, temperature, and fine-touch sensation; Varying degrees of sensorineural hearing loss Episodes of lancinating limb pain

One case with congenital presentation reported with severe growth and mental retardation, microcephaly, hypotonia, and respiratory insufficiency Cough and gastroesophageal reflux Varying degrees of distal muscle weakness — Early-onset dementia —

HSAN 2A HSAN 2B

WNK1 FAM134B

HSAN 2C HSAN 2D

KIF1A SCN9A

HSAN 3

IKAP (ELP-1)

AR

HSAN 4

NTRK (TRKA)

HSAN 5

None None None AR

Childhood or adolescence

None Varying degrees of hyperhidrosis, urinary incontinence, and pupillary abnormalities None Urinary and fecal incontinence, reduced sweating

Varying degrees of progressive loss of pain, temperature, and fine-touch sensation

Newborn

Impaired lacrimation Orthostatic hypotension Paroxysmal hypertension and vomiting episodes with skin blotching Normal or increased sweating

Impaired pain and temperature sensation with preserved fine-touch sensation

Described in Ashkenazi Jewish ancestry; Neonatal hypotonia; Respiratory and feeding difficulties; Neuropathic joints Optic neuropathy Chronic lung disease Scoliosis; Rhabdomyolysis Renal failure Varying degrees of cognitive and behavioral problems

AR

Newborn

Anhidrosis; Episodic hyperthermia Undetectable plasma norepinephrine

Loss of pain and temperature sensation Preserved fine-touch and vibration sensation

Frequent fractures Neuropathic joints Slow-healing wounds Varying degrees of cognitive and behavioral problems

NGFβ

AR

Newborn

Variable degree of anhidrosis

Loss of pain and temperature sensation. Preserved fine touch and vibration sensation

Frequent fractures Neuropathic joints Tooth loss from gingival disease

HSAN 6

DST

AR

Newborn

Impaired lacrimation Labile blood pressure and heart rate Hyperthermia and skin-blotching episodes

Loss of pain and temperature sensation

Described in Ashkenazi Jewish ancestry; Neonatal hypotonia Respiratory and feeding difficulties, delayed psychomotor development, neuropathic joints All described patients died before age 3

HSAN 7

SCN11A

AD (only a heterozygous de novo mutation described)

Newborn

Hyperhidrosis and gastrointestinal dysfunction

Loss of pain and temperature sensation

Frequent fractures Neuropathic joints Slow-healing wounds

—

— Lack of fungiform lingual papillae, hyposmia, hearing loss, hypogeusia, and bone dysplasia



Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice

Superficial pain perception is severely decreased, but patients complain of abdominal discomfort and/or bone pain following fractures or surgical procedures, suggesting that some visceral pain perception is preserved. Corneal analgesia often results in abrasions and ulcerations complicated by alacrima. Patients with HSAN type 3 have been shown to have a specific type of optic neuropathy that resembles mitochondrial neuropathies. Gait ataxia and incoordination, resulting from a lack of muscle spindle afferents, affect patients from birth and progressively worsen over time. Other features include feeding problems as a result of neurogenic dysphagia, failure to thrive, and increased frequency of rhabdomyolysis. Cognitive and behavioral issues, such as anxiety, reduced IQ, emotional overreaction, and emotional rigidity, prevent many patients from living independently. Abnormal spinal curvature, corrective spinal surgery, depressed ventilatory drive, sleep-disordered breathing, and frequent aspirations compromise respiratory function. The incidence of sudden death, particularly during sleep, is increased. Therapeutic focus in HSAN type 3 is on reducing the catecholamine surges caused by blunted baroreceptor feedback (i.e., afferent baroreflex failure). Carbidopa is frequently used to block dopamine production outside the CNS and prevent dopamine-induced vomiting. Additional therapeutic measures include management of neurogenic dysphagia, early treatment of aspiration pneumonias, and noninvasive ventilation during sleep. Clinical trials of compounds that increase levels of IKAP (ELP-1) are under way (Palma et al., 2014). HSAN Type 4 (Congenital Insensitivity to Pain with Anhidrosis).  HSAN type 4 (OMIM #256800) is an autosomalrecessive disorder first described in children with mental retardation, insensitivity to pain, self-mutilating behavior, and unexplained fevers. A cardinal feature of the disease is complete anhidrosis in response to thermal, emotional, or direct stimulation of the skin. Self-mutilation is extremely common. Pinprick sensation is also diminished. Skin wounds and bone injuries heal poorly. Joints are susceptible to repeated trauma, resulting in neuropathic joints and osteomyelitis. Avoidance of harmful stimuli is crucial to prevent recurrent injuries but is frequently difficult to accomplish because patients usually have intellectual disability with impulsivity and reckless behaviors. HSAN type 4 is associated with missense, nonsense, and frame-shift mutations in the gene that encodes for the neurotrophic tyrosine kinase-1 receptor (NTRK, previously known as TRK or TRKA). Skin biopsies of patients with HSAN type 4 reveal that sweat glands are preserved, but they lack sympathetic cholinergic innervation, thus the anhidrosis, which can lead to hyperthermia and death. Patients with HSAN type 4 have very low or undetectable levels of circulating norepinephrine but normal epinephrine levels, suggesting that lack of NTRK-NGF signaling affects the development of sympathetic adrenergic neurons but spares chromaffin cells in the adrenal medulla. Interestingly, despite the very low norepinephrine levels indicating impaired or absent sympathetic activity, patients with HSAN type 4 have normal cardiovascular responses to orthostatic stress (NorcliffeKaufmann et al., 2015). HSAN Type 5.  Patients with HSAN type 5 (OMIM # 608654) have a selective loss of temperature and pain sensation, leading to painless fractures, bone necrosis, and neuropathic joints. The have variable degrees of sweating impairment. The disorder is caused by homozygous mutations in the nerve growth factor β (NGFB) gene. Heterozygous carriers can present in adulthood with a mild phenotype.

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HSAN Type 6.  Reported in a large consanguineous Ashkenazi Jewish family, HSAN type 6 is a severe autosomal-recessive disorder resulting from homozygous truncating mutations in the dystonin gene (OMIM #614653). The disorder is characterized by neonatal hypotonia, areflexia, respiratory and feeding difficulties, delayed psychomotor development, neuropathic joints, labile blood pressure and heart rate, and lack of corneal reflexes. All patients died before age 3. HSAN Type 7.  Reported in two unrelated patients (OMIM # 615548), HSAN type 7 includes the clinical features of congenital insensitivity to pain resulting in self-mutilations, slow-healing wounds, painless fractures, hyperhidrosis, and gastrointestinal dysfunction requiring parenteral nutrition. The disorder results from de novo heterozygous missense mutations in the SCN11A gene. Other Syndromes with Sensory and Autonomic Involvement.  Navajo familial neurogenic arthropathy was initially described in Native American (Navajo) children. It is characterized by diminished or absent sweating with variable sensory deficits, ranging from insensitivity to pain (leading to fractures, corneal injuries, and neuropathic joints) to normal sensation. Stuve-Wiedemann syndrome (OMIM #601559), also known as neonatal Schwartz-Jampel syndrome type 2 (SJS2), is an autosomal-recessive disorder caused by mutations in the LIFR gene. It is characterized by bowing of the lower limbs, wide metaphyses with abnormal trabecular pattern, and camptodactyly (one or more fingers permanently bent as a result of fixed-flexion deformity of the proximal interphalangeal joints). Additional features include feeding and swallowing difficulties, respiratory distress, and episodes of hyperthermia, which can be fatal in the first months of life. Sensory abnormalities, including decreased sensitivity to pain and temperature, lead to corneal injury and absent deep tendon reflexes. Cognition and behavior appear to be normal. Hypertrichosis is common.

Inborn Errors of Metabolism Dopamine Beta-Hydroxylase Deficiency.  Dopamine betahydroxylase deficiency, a rare disorder, is caused by mutations in the gene encoding the enzyme dopamine beta-hydroxylase (DBH), which converts dopamine to norepinephrine (OMIM # 223360). Affected patients have undetectable levels of plasma norepinephrine and epinephrine, with increased dopamine levels. Newborns can show a delay in eye opening and palpebral ptosis. Hypotension, hypoglycemia, and hypothermia may occur early in life. The absence of norepinephrine leads to deficient vasoconstriction, resulting in hypotension, syncope, and reduced exercise capacity. Symptoms generally worsen in late adolescence and early adulthood. Treatment with droxidopa (Northera®), a synthetic norepinephrine precursor, replenishes norepinephrine, increases blood pressure, and improves symptoms of hypotension (Biaggioni and Robertson, 1987). Aromatic L-Amino Acid Decarboxylase Deficiency.  Aromatic L-amino acid decarboxylase deficiency, an extremely rare autosomal recessive disorder, is caused by mutations in the DDC gene. The enzyme aromatic L-amino acid decarboxylase (AADC) converts L-dopa and 5-hydroxytryptophan to dopamine and serotonin, respectively (OMIM #608643). Neonatal symptoms include poor feeding, lethargy, ptosis, hypothermia, hypotension, intermittent eye movement abnormalities (oculogyric crises), hypotonia, and motor symptoms such as rigidity and difficulty with movements. Diagnosis is based on measurement of AADC activity in plasma and DDC

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gene sequencing. Increased levels of urinary vanillactic acid (VLA) are diagnostic. Treatment is aimed at correcting the neurotransmitter abnormalities with different medications (e.g., dopamine agonists, monoaminoxidase inhibitors, selective serotonin reuptake inhibitors, pyridoxine, droxidopa, 5-hydroxytriptophan). Menkes Disease.  Also known as kinky-hair disease, Menkes disease is an X-linked neurodegenerative disease of impaired copper transport. It is caused by mutations in the ATP7A gene (OMIM #309400). Children usually present at 2 to 3 months of age with loss of developmental milestones, failure to thrive, truncal hypotonia, and epileptic and myoclonic seizures. Autonomic abnormalities are not well characterized, although orthostatic hypotension and chronic diarrhea have been reported. Decreased serum copper and serum ceruloplasmin levels can be useful in the differential diagnosis. Decreased norepinephrine levels have been found. An elevated hydroxyphenylalanine (DOPA) and dihydroxyphenylglycol (DHPG) ratio resulting from decreased activity of DBH may be observed, with higher values reflecting more severe disease. Treatment with droxidopa might be useful. Fabry Disease.  Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, is caused by mutations in the GLA gene, resulting in deficient or absent activity of the lysosomal enzyme alpha-galactosidase A (OMIM # 301500). This leads to systemic accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in plasma and organ cells throughout the body, including autonomic and dorsal root ganglia. Clinical manifestations begin in childhood or adolescence and include severe neuropathic or limb pain, telangiectasias and angiokeratomas, and renal manifestations. Symptoms of autonomic dysfunction include sweating abnormalities (hypohidrosis or hyperhidrosis), decreased lacrimation, decreased salivation, and gastrointestinal dysmotility. The degree of cardiovascular autonomic involvement is unclear. Porphyrias.  Porphyrias are inherited defects in the biosynthesis of heme. Acute intermittent porphyria (OMIM #176000) is the most common form of porphyria and is inherited in an autosomal-dominant manner. It is characterized by acute, recurrent episodes of abdominal pain, gastrointestinal dysfunction, and neurologic impairment. Patients are asymptomatic in between episodes. Autonomic abnormalities include tachycardia, hypotension, urinary retention, and gastrointestinal symptoms (nausea, vomiting, diarrhea, or constipation). Acute attacks rarely occur before puberty and can be pre­ cipitated by medications, alcohol, infection, starvation, and hormonal changes. Increased urinary excretion of deltaaminolevulinic acid (ALA) and porphobilinogen (PBG) during the attacks supports the diagnosis. Porphyria variegata (OMIM #176200) is also an autosomaldominant disorder and is caused by heterozygous mutations in the gene encoding for protoporphyrinogen oxidase (PPOX). The clinical features are similar to those of acute intermittent porphyria, but with an increased frequency of skin photosensitivity and hypertrichosis.

Hirschsprung Disease Also known as aganglionic megacolon, Hirschsprung disease is characterized by congenital absence of ganglionic cells in the myenteric and submucosal plexuses of the gastrointestinal tract. Affected patients have severe gastroparesis, leading to partial or complete bowel obstruction and dilatation of the colon. Cardiovascular autonomic dysfunction has been described. Mutations in the RET gene and several other identified loci increase susceptibility to the disorder.

Heterozygous mutations in the ECE1 gene (OMIM #613870) cause Hirschsprung disease with cardiac defects and autonomic dysfunction (episodes of severe agitation in association with tachycardia, hypertension, and hyperthermia).

Congenital Central Hypoventilation Syndrome and Related Ventilatory Disorders Congenital central hypoventilation syndrome (CCHS; OMIM #209880) is an autosomal-dominant disorder most commonly caused by mutations in the PHOX2B, RET, GDNF, EDN3, ASCL1, and BDNF genes. These patients typically present in the first hours of life with cyanosis and increased hypercapnia during sleep. They have an impairment of ventilatory and arousal responses to both hypercapnia and hypoxemia. Children with CCHS often have additional autonomic symptoms, including severe constipation, dysphagia, pupillary abnormalities, and decreased body temperature. Sympathetic activity can be exaggerated. Pitt-Hopkins syndrome (OMIM # 610954), caused by heterozygous (sometimes de novo) mutations of the TCF4 gene, is characterized by abnormal psychomotor development, distinctive facial features, microcephalia, clubbing, and intermittent hyperventilation followed by apnea during both wakefulness and sleep.

Allgrove Syndrome and Related Disorders Also known as achalasia-addisonianism-alacrima syndrome, and triple-A syndrome, Allgrove syndrome is caused by mutations in the gene encoding the protein aladin (AAAS; OMIM #231550). It is inherited in a recessive fashion. Children present with classic symptoms of primary adrenal insufficiency, including hypoglycemic seizures and shock. Less frequently, they present with recurrent vomiting, dysphagia, and failure to thrive, or ocular symptoms associated with alacrima. At presentation, review of systems may also be positive for hyperpigmentation, developmental delay, seizures, hypernasal speech, and symptoms related to orthostatic hypotension. Alacrima, achalasia, and mental retardation (AAMR) syndrome is an autosomal-recessive disorder caused by homozygous mutations in the GMPPA gene and characterized by onset of features at birth or in early infancy. Patients with AAMR do not have adrenal insufficiency.

Other Genetic Disorders with Autonomic Dysfunction Rett Syndrome.  Rett syndrome is a neurodevelopmental disorder that occurs almost exclusively in females. Autonomic dysfunction results in abnormal, irregular breathing during wakefulness and sleep, including hyperventilation, hypoventilation, and apnea; abnormal heart-rate variability; and labile blood pressure with episodic hypertension and tachycardia. Almost a third of all deaths from Rett syndrome are sudden and unexpected, which has been linked to autonomic dysregulation. Alexander Disease.  Alexander disease, an autosomaldominant disease, is caused by mutations (usually de novo) in the gene encoding glial fibrillary acidic protein (GFAP; OMIM # 203450). The disorder is subclassified as infantile, juvenile, or adult onset. Patients present with seizures, megalencephaly, developmental delay, and spasticity. They have early signs of autonomic dysfunction, including constipation, episodic hypothermia, and sleep-disordered breathing. Brain MRI typically shows cerebral white-matter abnormalities affecting the frontal region; brainstem and cerebellar atrophy also can be present.



Disorders of the Autonomic Nervous System: Autonomic Dysfunction in Pediatric Practice

Hyperbradykininism.  Hyperbradykininism is an autosomaldominant disorder characterized by orthostatic hypotension (leading to lightheadedness upon standing and syncope), facial erythema, and purple discoloration of the legs after standing. Plasma bradykinin is elevated. Panayiotopoulos Syndrome.  Panayiotopoulos syndrome is a form of idiopathic benign childhood focal epilepsy in which the seizures are associated with signs of increased autonomic activity. Recent reports document hypertension, tachycardia, and release of vasopressin during the seizures, suggestive of activation of the central autonomic network. In rare cases, respiratory and cardiac arrest have been reported. Mutations in the SCN1A gene increase susceptibility for this disorder. Congenital Alacrima.  Children with congenital alacrima have markedly deficient lacrimation from infancy, leading to corneal epithelial lesions, presumably as a result of hypoplasia of the lacrimal glands. Genetic mutations have not yet been identified. Cold-Induced Sweating Syndrome.  Cold-induced sweating syndrome, an autosomal recessive disorder, presents in the neonatal period with orofacial weakness and feeding difficulties related to impaired sucking and swallowing. During the first year, most infants have episodes of unexplained fever. From childhood onward, the most disabling symptoms stem from impaired thermoregulation. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. The disorder is caused by homozygous or compound heterozygous mutations in the CRLF1 gene or in the CLCF1 gene (OMIM #272430 and # 610313). REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Benarroch, E.E., 2012. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin. Proc. 87 (12), 1214–1225. Biaggioni, I., Robertson, D., 1987. Endogenous restoration of noradrenaline by precursor therapy in dopamine-beta-hydroxylase deficiency. Lancet 2 (8569), 1170–1172.

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Florance, N.R., Davis, R.L., Lam, C., et al., 2009. Anti–N-Methyl-DAspartate Receptor (NMDAR) Encephalitis in Children and Adolescents. Ann. Neurol. 66 (1), 11–18. Kaufmann, H., Hainsworth, R., 2001. Why do we faint? Muscle Nerve 24 (8), 981–983. Koike, H., Atsuta, N., Adachi, H., et al., 2010. Clinicopathological features of acute autonomic and sensory neuropathy. Brain 133 (10), 2881–2896. Neveus, T., Sillen, U., 2013. Lower urinary tract function in childhood; normal development and common functional disturbances. Acta Physiol (Oxf) 207 (1), 85–92. Norcliffe-Kaufmann, L., Axelrod, F., Kaufmann, H., 2010. Afferent baroreflex failure in familial dysautonomia. Neurology 75 (21), 1904–1911. Norcliffe-Kaufmann, L., Katz, S.D., Axelrod, F., et al., 2015. Norepinephrine deficiency with normal blood pressure control in congenital insensitivity to pain with anhidrosis. Ann. Neurol. 77 (5), 743–752. Palma, J.A., Norcliffe-Kaufmann, L., Fuente-Mora, C., et al., 2014. Current treatments in familial dysautonomia. Expert Opin. Pharmacother. 15 (18), 2653–2671. Wieling, W., Thijs, R.D., van Dijk, N., et al., 2009. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain 132 (Pt 10), 2630–2642.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 154-3 Diagnostic evaluation of pediatric patients with orthostatic intolerance and transient loss of consciousness. Fig. 154-5 Tracing of Valsalva maneuver in a healthy subject showing muscle sympathetic nerve activity (MSNA) recording from the peroneal nerve electrocardiogram (ECG) and beat-to-beat blood pressure measured with plethysmography in the finger (BP) showing the four characteristic phases of the maneuver. Fig. 154-6 Histogram showing the incidence of reflex (vasovagal) syncope in a population of young individuals up to the age of 24. Fig. 154-7 Catecholamine pathways. Droxidopa (L-DOPS) converts to norepinephrine as a result of the action of the enzyme dopa-decarboxylase (L-amino acid aromatic decarboxylase).

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155  Disorders of Micturition and Defecation Israel Franco and Cecile Ejerskov

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Our understanding of bowel and bladder control has changed dramatically in the last 20 years with the introduction of fMRI and PET scanning of the brain. In this period of time, it has become more apparent that micturition and defecation involve and interplay with numerous sites in the spinal cord, brainstem, midbrain and cortex. In this chapter, we will examine the control of storing and emptying of urine and stool from what will be a new perspective, integrating the frontal lobes into the process and moving beyond the pons on which most of the literature had focused in the past.

DISORDERS OF MICTURITION Attainment of bowel and bladder control is an important milestone in the lives of children and their parents. When this occurs varies from geographic region to geographic region and from ethnic group to ethnic group, but the maturational order is the same regardless, with bowel control preceding bladder control, and the sequence being: 1. Nocturnal bowel control 2. Daytime bowel control 3. Daytime bladder control 4. Nocturnal bladder control What is certain is that girls tend to achieve continence quicker than boys, irrespective of the society in which they live. Daytime control is achieved between 3 to 4 years and nighttime control between 3.5 and 4 years of age. It may be obvious that we have refrained from using the term “diurnal incontinence” and are using the term “daytime incontinence.” Throughout this chapter, we will use the terminology recommended by the International Children’s Continence Society to allow for the proper communication in future clinical studies and to thereby enhance reproducibility of studies and outcomes (Austin et al., 2014). We will only deal with daytime urinary incontinence in this chapter. Nocturnal enuresis is a completely different entity that is best seen as an arousal disorder in the majority of patients. In fact, some patients have an appropriate diurnal variation in antidiuretic hormone production. Many children with nocturnal enuresis have “nonmonosymptomatic nocturnal enuresis,” nocturnal enuresis with daytime lower urinary tract symptoms. These entities are well discussed in consensus papers put out by the International Children’s Continence Society (Neveus et al., 2010). Voiding in the infant is a reflexive action which lacks adequate volitional control, because the frontal lobes are not yet able to properly inhibit micturition. This concept is verified in previous studies in which frontal lobe arousal was recognized even in newborns, and some even awaken before urination. The human neonate initially voids hourly, and there is evidence that there is an interrupted voiding pattern that is the result of dyssynergia between the bladder and the sphincter. By 1 to 2 years of age, children can hold their urine, but it is difficult for them to willfully relax the external

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sphincter. There is a gradual expansion in bladder capacity, and by 2 to 3 years of age, the bladder capacity has reached appropriate size to withhold urination for extended periods of time.

EPIDEMIOLOGY The prevalence of daytime incontinence varies widely from study to study. For the most part nocturnal enuresis tends to be more prevalent than daytime incontinence. A meta-analysis of 3 studies was performed giving an overall prevalence of 6.4%. The English ALSPAC longitudinal study (Heron et al., 2008) found the following trajectories for daytime incontinence over the age range 4.5 to 9.5 years: 1. Normative (86.2%); dry by 4.5 years 2. Delayed (6.9%); steadily decreasing probability of daytime incontinence from 80% at 4.5 years of age to less than 10% at 9.5 years of age 3. Persistent (3.7%); probability of daytime incontinence greater than 80% until 7.5 years of age with steady reduction to 60% at 9.5 years of age 4. Relapsing (3.2%); probability of daytime incontinence less than 10% at 5.5years of age, increasing to 60% at 6.5 years with slow decline thereafter There was no gender difference in the delayed group, but girls outnumbered boys in the persistent and relapsing groups. In one study that looked at children with persistent urinary incontinence who had urodynamics and imaging of their spines revealed that, if extrapolated out to 18 years of age, up to 33% of the children that were wetting at 10 years of age were likely to persist with some form of urinary symptoms. From a pediatric urologist’s perspective, the child who has OAB has a very good chance of becoming an adult who continues to have problems with OAB. This correlation has been seen in two published reports in adult females.

NEUROPSYCHIATRIC COMORBIDITY Children with elimination disorders have an increased rate of comorbid behavioral or psychological disorders. About 20% to 40% of children with daytime urinary incontinence are affected by comorbid behavioral disorder. In a large epidemiologic study of a cohort of 8213 children aged 7.5 to 9 years, children with daytime wetting had significantly increased rates of psychological problems, especially separation anxiety (11.4%), attention deficit (24.8%), oppositional behavior (10.9%), and conduct problems (11.8%). In the same cohort, 10,000 children aged 4 to 9 years were analyzed. Delayed development, difficult temperament, and maternal depression/ anxiety were associated with daytime wetting and soiling. In another population-based study that included 2856 children, the incidence of incontinence was 16.9% within the previous 6 months. In a retrospective study of patients with ADHD, 20.9% wetted at night and 6.5% wetted during the day. The odds ratios were 2.7 and 4.5 times higher, respectively, which



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means that there is unspecific association of ADHD and both nighttime and daytime wetting. The association of urinary incontinence and lower psychological well-being in adults also has been noted in other studies. Further discussion of neuropsychiatric disorders and urinary incontinence can be found in the online version of this chapter (von Gontard and Neveus, 2006).

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ANATOMY OF THE LOWER URINARY   TRACT (LUT) The three main components of the bladder are the detrusor smooth muscle, connective tissue, and urothelium. The detrusor constitutes the bulk of the bladder, and is arranged into inner longitudinal, middle circular, and outer longitudinal layers. Elastin and collagen make up the connective tissue, which determines passive bladder compliance. The detrusor maintains a baseline tension, which is modulated by hormones, local neurotransmitters, and the autonomic nervous system. Although the urothelium was previously thought to be an inert barrier, we now know that urothelial cells participate in afferent signaling. Bladder nerves terminate close to as well as on urothelial cells. Urothelial cells have pain receptors and mechanoreceptors, which can be modulated by ATP to activate or inhibit sensory neurons. Abnormal activation of these channels by inflammation can lead to pain responses to normally nonnoxious stimuli. Urothelial cells release factors such as acetylcholine, ATP, prostaglandins, and nitric oxide that affect sensory nerves (Fig. 155-2). The internal and external urethral sphincters (EUS) are vital for urinary continence. The internal urethral sphincter functions as a unit with the bladder base and trigone to store urine. The smooth muscle of the female EUS has less sympathetic innervation than the male, and the male EUS is larger in size. The skeletal muscle of the EUS has both slow and fast twitch fibers, of which the slow twitch fibers are more important in maintaining tonic force in the urethra. The lower urinary tract is innervated by both the autonomic and somatic nervous systems. Sympathetic nervous system control of the lower urinary tract travels via the hypogastric nerve (T10–L2) (Fig. 155-1, sympathetic preganglionic nucleus in thoracolumbar spinal cord), whereas parasympathetic control travels via the pelvic nerve (S2–S4) (Fig. 155-1, Gert’s nucleus in sacral spinal cord). The somatic motor neurons control the skeletal muscle of the EUS via the pudendal nerve (S2–S4). Its motor neurons are found in Onuf’s nucleus (Fig. 155-1, sacral spinal cord) The sympathetic and somatic nervous systems promote storage of urine and stool and facilitates ejaculation (Sympathetic: Storage and Shoot), whereas the parasympathetic system promotes bladder and bowel emptying and erections (Parasympathetic: Pee, Poop, and Point).

AFFERENT MECHANISMS The sensation of bladder fullness is carried by two types of afferent fibers via the pelvic, hypogastric, and pudendal nerves. Normal bladder sensations are carried by Aδ fibers, whereas C fibers become more important in diseased bladders. In humans, C fibers transmit pain sensations and are found in the urothelial and suburothelial layers, whereas Aδ fibers are found in the smooth muscle (Fig. 155-2). These fibers terminate in the dorsal horn of the lumbar and sacral cord. Spinal connections in this area mediate segmental reflexes. Some of the spinal interneurons send ascending projections to two nuclei in the brainstem. The gracile

Figure 155-1.  Afferent pathways for the control of micturition. (With permission from Birder, L., de Groat, W., Mills, I., et al., 2010. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol Urodyn 29, 128–139.)

nucleus relays nociception to the thalamus and cortex. The parabrachial nucleus is a major relay center for visceral afferent information going to the amygdala and the insular cortex integrating nociceptive and autonomic inputs. A significant degree of convergence of inputs from pelvic viscera is seen at the level of the medullary reticular formation. During bladder storage, afferent signals from the hypogastric nerve and pelvic nerve travel to the thoracolumbar and sacral spinal cord, respectively (Fig. 155-1). The hypogastric nerve sends signals via the sympathetic nervous system to block bladder contraction and contact the internal urethral sphincter. Onuf’s nucleus maintains contraction of the EUS, which is coordinated with bladder storage by the pontine micturition center (PMC) in the medial pons (Fig. 155-1). Once the bladder pressure threshold is exceeded, afferent signals travel via the pelvic nerve to synapse on interneurons in Gert’s nucleus in the S1–S2 spinal cord (Fig 155-3). These interneurons send projections up to the periaqueductal gray (PAG) in the midbrain to initiate voiding, which occurs if the cerebral cortex determines that it is appropriate to void. The medial anterior frontal lobes connect to the pudendal neurons via the corticospinal tracts (pyramidal tracts). They send connections to the PAG that sends caudal projections to the PMC, which is the final efferent center of the lower urinary tract. The

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Figure 155-3.  Efferent pathways for the control of micturition. (With permission from Birder, L., de Groat, W., Mills, I., et al., 2010. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol Urodyn 29, 128–139.)

PMC sends projections caudally via the corticospinal tracts in the cord to the sacral parasympathetic nucleus, activating the neurons which cause bladder contraction and EUS relaxation (Fig. 155-3). Bilateral pathologic involvement of the pyramidal tract, usually in the spinal cord, results in impaired volitional control of the urethral sphincter; therefore the urethral sphincter may undergo inappropriate relaxation, or increased sphincter activity may occur during detrusor contraction. This imbalance is termed detrusor-urethral sphincter dyssynergia (Birder et al. 2010).

Disorders that affect the spinal cord and have effects on the micturition and sensation are described in the online version of this chapter.

Periaqueductal Gray (PAG) and Pontine Micturition Center (PMC) The PAG is involved in neurobiological functions that include the control and expression of pain, analgesia, fear, anxiety, vocalization, lordosis, cardiovascular function, and



reproductive behavior. Conceptually the structure may be involved in balancing or segueing information related to survival. Forebrain projections to the PAG arise mainly from the prefrontal cortex, the insular cortex, and the amygdala. Further, the PAG receives highly organized projections from the central nucleus of the amygdala and, in turn, has reciprocal connections with the central nucleus. The PAG also projects to the thalamus, hypothalamus, brainstem, and deep layers of the spinal cord with some somatotopic organization, but projections to cortical regions have not been identified. The central role of the PAG is evident, as it both receives sacral afferents and transmits efferent signals (via the PMC) to the sacral spinal cord. During storage, it is chronically suppressed by a net inhibition from the many other regions shown in Figure 155-4A. These include prefrontal cortex and hypothalamus, as well as insula and anterior cingulate cortex. The posterior hypothalamic region, which is involved in fight or flight (defense) responses, has direct connections to the PAG and may account for the urination reported in conscious animals during a defense response (Linnman et al., 2012). The PMC, however. is the ultimate arbiter of lower urinary tract function, acting as a switch between the storage and voiding phases. It is believed that, for voiding to occur, the PMC requires both an excitatory signal from the PAG and a “safe” signal from the hypothalamus as suggested by Figure 155-4B. Micturition problems with inability to empty well and urinary retention have been associated with posterior fossa tumors, discrete pontine lesions, brainstem gliomas, or vascular lesions that support the role of the dorsolateral pons (pontine reticular nucleus and the reticular formation, adjacent to the medial parabrachial nucleus, and locus coeruleus). Functional imaging shows activations near the postulated location of the PMC during voiding. PMC activity during bladder filling has also been seen, though this might be inhibitory rather than excitatory. The area thought responsible for off-switching at the end of urination is the pontine continence center (PCC) also known as the L region described by Bradley. This area is located in the dorsolateral tegmentum. Projections form the PCC appear limited to Onuf’s nucleus. Activation of this site can cause the detrusor to relax and the pelvic floor musculature and urethral sphincter to contract. A few functional imaging studies appear to localize this area ventral, lateral, or caudal to the PMC.

Insula The cardinal feature of enteroceptive system is that the afferent input is from small diameter fibers (Aδ and C). These afferents project via the spinothalamic tracts to subcortical homeostatic centers, including the hypothalamus and PAG. In humans they relay in the thalamus and converge on the nondominant anterior insula. The insula has come to be regarded as the homeostatic afferent cortex and has been shown to be activated by a range of modalities associated with visceral sensation. Insula activation has been extensively studied in the fMRI experiments carried out by other investigators and have shown a correlation between the degree of bladder filling and insula activation in healthy controls (Figure 155-5A and B). The conscious desire to void or urgency is lost in extensive frontal lobe lesions involving the insula (Griffiths and Tadic, 2008).

Anterior Cingulate Cortex (ACC) The anterior cingulate cortex (ACC) is the cortical region associated with motivation. Motivation plays a critical role in human homeostasis. Therefore if the insula is regarded as the limbic sensory cortex, the ACC can be considered as the limbic

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motor cortex, the two being frequently seen to be coactivated in functional brain imaging studies. A wide range of cerebral functions has been attributed to the ACC over the years as its activation is seen with many different executive tasks but the demonstration that output was correlated with sympathetic activation led to the hypothesis that the ACC “mediates context-driven modulation of bodily arousal states.” The ACC also is the site in which pain is processed. The proximity of the nociceptive, motor, and attentional regions of ACC suggests possible local interconnections that might allow the output of the ACC pain area to command immediate behavioral reactions. Similarly, the ACC pain area might participate in the substantial interconnections between the ACC and the “fight or flight” regions of the midbrain and the periaqueductal gray matter. The anatomic connections between ACC, IC (rostral insula), SI, and SII (primary and secondary somatosensory cortices) suggest that these regions do not function independently in encoding different aspects of pain but are highly interactive. Another key feature of the ACC is the role it plays in autonomic control. Previous fMRI studies and neuropsychological and physiologic observations have shown that a direct link exists between ACC activity and modulation of cardiac function via sympathetic output. These observations argue for control of the ACC in the production and control of behaviorally integrated patterns of autonomic activity (Critchley et al., 2003).

Prefrontal Cortex The ventral region of prefrontal cortex (PFC) is involved in aspects of cognition, and the inferior lateral parts are involved in emotions. The orbitofrontal or prefrontal lateral cortex (PFLC) has extensive interconnections with the limbic system—the hypothalamus, amygdala, insula, and ACC. The importance of the prefrontal cortex in bladder control was established from clinical studies both by previous studies that found that acts of micturition and defecation occur in a normal manner; however, what is disturbed by this frontal lesion is the higher control of these acts. The lesion causes frequency and extreme urgency of micturition when the patient is awake and incontinence when asleep. The sensation of gradual awareness of increasing fullness of the bladder and the sensation that micturition is imminent are impaired. In the most complete form of the syndrome, the patient cannot inhibit the detrusor contraction of the micturition reflex and is forced to empty the bladder as soon as the reflex occurs. When the syndrome is less pronounced, the patient can make a conscious effort to stop the act of micturition and may or may not succeed. The lowering of the micturition reflex threshold may account for the fact that the patient does not feel the normal gradual filling of the bladder that underlies the desire to micturate; however, it cannot account for the unawareness of the sensations arising from the activity of pelvic and perineal muscles or of the sensation that urine is passing. A further discussion on the effects of strokes is in the online chapter. Cortical areas such as the prefrontal cortex have the ability to inhibit limbic system activation and have been implicated in the therapeutic effects of distraction techniques such as hypnosis therapy and the use of placebo. In the PFC, cortisol modulates dopaminergic projections with a remarkable degree of lateralization. Dopaminergic projections to the right hemisphere display an enhanced sensitivity to stressors that are perceived as severe and uncontrollable such as those that arise from social conflict. Thus chronic psychological stress can disinhibit reflexive circuits through a cortisol-induced right PFC dysfunction that is caused by a prolonged activation of the hypothalamicpituitary-adrenal axis. This reduction in activity in the PFC can

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PART XVIII  Systemic and Autonomic Nervous System Diseases Circuit 1 insula

IPFC

Circuit 2 Desire to void SMA/dACC

th

Urgency

mPFC

PAG Urethra, pelvic floor

Parahippocampal

PMC

Parasympathetic

Sa

Sa

Voiding reflex

Circuit 3 ON Bladder

Urethra

Figure 155-6.  Proposed interconnections between the different areas of the cortex, midbrain, and brainstem structures that are involved in the control of micturition. Arrows show probable directions of connectivity but do not preclude movement in the opposite direction. Three circuits are described that are critical to the control of micturition. The green area is the critical transit point that includes the periaqueductal gray area (PAG) and pontine micturition center (PMC). They control contraction and relaxation of the bladder via the sacral parasympathetic regions (Sa) and Onuf’s nucleus (ON). These reflexes are controlled by three cerebral neural pathways. Circuit 1 involves the thalamus (th), insula, and lateral prefrontal cortex (LPFC) that maps for desire to void, although the mPFC (medial prefrontal cortex) makes the executive decision when and where to void. Circuit 2 involves the supplemental motor area (SMA) and the dorsal anterior cingulate cortex (dACC). Here, urgency is processed as an emotion, and lesions in this area lead to urge incontinence; pain is processed here as well. Circuit 3 goes the parahippocampal area. Areas in blue are typically deactivated with filling; orange and red areas are activated with bladder filling. (From Griffiths, D., Clarkson, B., Tadic, S.D., Resnick, N.M., 2015. Brain mechanisms underlying urge incontinence and its response to pelvic floor muscle training. J Urol 194, 708–715.)

lead to the inability to inhibit the urge to urinate and it may lead to urge incontinence as well as fecal incontinence. The information in Figure 155-6 has been proposed as a summary illustration of the current thinking about brain control of the bladder during filling and emptying (Griffiths et al., 2015). Efferent mechanisms—peripheral See online chapter for discussion. Efferent mechanisms—central See online chapter for discussion

DIAGNOSIS History and Physical Examination The evaluation of the child with bowel and bladder dysfunction should start with a good history and physical examination. Generally, it is best to try to get the history from the child if he or she is cooperative, but in other cases there may be no choice but to obtain it from the parents. Crossing the legs, running to the bathroom, grabbing the penis, rubbing the clitoris, squatting, and sitting on the heels are all signs of urgency. These maneuvers trigger reflexive suppression of the voiding reflex. Urinary frequency is also another manifestation of an overactive bladder and quantifying the number of times that the patient goes to the bathroom and the amount is useful in determining whether there is true frequency. Urinary urge incontinence is another classic hallmark of overactive bladder. The physician should also ask about a history of dysuria. Dysuria without evidence of infection is usually due to

dyssynergic voiding. One should ascertain the type of stream and the strength. Whether the patient strains to void or uses the Credé maneuver is critical to know. In infants, grunting with urination may be a sign of dyssynergic voiding. On entering the room, the physician should take close note of the interaction between the child and parent as well as the child and the physician. Excessive anxiety or inappropriate fear is something that should be noted. The parents should be questioned as to whether this type of behavior is commonly present at home or during other stressful situations. A careful history should be taken with regards to a family history of anxiety, phobias, ADD/ADHD, or depression within the firstline family members. A thorough history of the bowel habits of the patient should be obtained from the patient directly. Documentation of the size and nature of the bowel movements should be obtained. Use of a diagram is quite beneficial, and it facilitates communication with the child. Chronic constipation can be a clue of a cord lesion, especially if it is refractory. The presence of bladder fullness or urgency and frequency would indicate that the sensory pathways are intact. Urgency in a neurologically impaired patient is a sign of a partial suprasegmental injury whereas a complete lesion is usually associated with incontinence associated with no warning or sensation. On the other hand, the patient that does not void unless prompted may have inappropriate sensation. Those that void with Valsalva or Credé maneuver can have a myogenic failure of the detrusor or failure of the efferent pathways. Obstruction would need to be excluded as well.



Autonomic dysreflexia may occur and is discussed in the online chapter. Peripheral motor lesions involving the conus medullaris, which anatomically is located between T12 and L1, or the cauda equina will lead the majority of patients to complain of an “obstructive” symptom and will need to strain or use the Credé maneuver to urinate. Further discussion of cauda equina, conus, and epiconus lesions are in the online chapter.

Physical Examination Examination of the abdomen is critical in determining whether there is stool present in the colon. Examination of the back will typically reveal a normal-appearing back and anocutaneous folds. In rare instances, one will notice flattening of the buttocks or abnormal creasing at the SI joint indicative of some type of sacral anomaly. Low-lying sacral dimples are typically not of concern. Dimples that are associated with tufts of hair or if located higher up on the back are of concern and should be evaluated with an MRI of the lumbosacral spine. Examination of the genitalia should be performed on all children with bowel and bladder dysfunction. First and foremost, one should look at the underwear when it is pulled down to help gauge the gravity of the problem. Visual inspection of the anus is a very useful tool, which allows one to assess whether the patient has skin tags, fissures, and hemorrhoids that are indicators of chronic problems with constipation or large bowel movements. Laxity of the anal sphincter is another good sign that the child is passing massive bowel movements or has a neurologic problem. Evidence of an anal wink is a sign of an intact sacral reflex arch (S2–S4) and is commonly seen as soon as the buttocks are separated to inspect the anus. Pinprick testing for sensation of the perineum and anus is critical as well. A bulbocavernosus reflex test should be performed and should be present in 98% of all males and 81% of females. Absence indicates a complete lower motor neuron lesion of the sacral cord that correlates well with perineal floor denervation. Digital rectal examination is rarely necessary in these children. If it is going to be done, then the bulbocavernosus reflex should be tested at the same time. Rectal examination neither confirms nor denies the presence of constipation. Examination of the patients smile is another critical part of the examination in children that have evidence of a severely trabeculated bladder or evidence of severe voiding dysfunction without sacral dysraphism. Children who have Ochoa urofacial syndrome (OMIM 236730) when asked to smile will have an unusual inversion of facial expression when smiling is attempted. The face becomes contorted into a grimace that makes it appear as if the subject is sobbing and crying, thus, making it possible to recognize afflicted patients early in life (Fig. 155-8). Please see the online chapter for a more thorough discussion of this topic.

Clinical Testing In children suspected of having a disorder of micturition or storage, the first study should be a urinalysis and urine culture to rule out infection that can lead to such symptoms. The next study should be a postvoid residual ultrasound measurement. This determines whether the patient is adequately emptying the bladder and thereby frequently helps to differentiate disorders of emptying from storage disorders, even though some children, especially those with functional voiding problems, can simultaneously have both disorders. If at all possible, uroflowmetry utilizing EMG of the perineal muscles should be done initially. Perineal EMG allows for the identification of external sphincter dyssynergia and internal sphincter

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dyssynergia that can be identified utilizing the lag time, which is the delay before the initiation in urination. Internal sphincter dyssynergia has been associated with dizziness and autonomic dysfunction (hypotension on standing without concomitant increase in heart rate) with specificity rates in the high 90s for both males and females when patients are asked if they get dizzy on standing. Renal and bladder ultrasounds are next in order if there is evidence of large bladder capacities or urinary retention or an abnormal uroflowmetry. Patients that exhibit markedly abnormal uroflowmetry or ultrasonography should then have a voiding cystourethrogram if indicated or a KUB radiograph with an AP and lateral of the spine at a minimum. Blood tests evaluating renal function are indicated if the ultrasound or VCUG are abnormal. In refractory patients, it is necessary to obtain a VCUG to further delineate voiding dynamics and to make sure that anatomic problems are not missed. Urodynamics are not necessary in patients who have functional voiding problems in the vast majority of cases. In one study, urodynamics did not offer any information that was not noted on the MRI if it was positive. If there is suspicion of a spinal problem, it is best to initially obtain a spinal MRI, and later, if a spinal abnormality is identified, then urodynamics are indicated to define the problem and to provide a baseline for future reevaluations to assess whether there is progression of the disease or before when surgery is to be done. There are noninvasive means of testing the bulbocavernosus reflex latency, but these are not done routinely in children.

Disorders of Defecation Normal Defecation Patterns Defecation patterns in childhood differ with age and are determined by the change from breastfeeding to solid foods. In breastfed infants, defecation occurs from six to seven times a day to once every seventh day, and, on average, three times daily. At 6 to 12 months, the average defecation rate is just lower than two times per day; at 1 to 3 years, the average defecation rate is one and a half times per day. At 3 to 12 years, the defecation rate settles at once daily. There is no difference in gender until puberty. During puberty and adulthood, the defecation rate among females is less than among males. To appreciate colorectal motility of defecation, the neurophysiology, and the various pathologic changes related hereto, it is important to understand the functional anatomy and neurophysiology of colon, rectum, and anus.

FUNCTIONAL ANATOMY OF COLON,   RECTUM, AND ANUS The main functions of the large intestine are intraluminal bacterial fermentation of nutrients resistant to digestive enzymes (e.g., short-chain fatty acids), reabsorption of water and electrolytes, and transport and storage of feces until it can be discharged from the body. Histologically, the wall of the large intestine is made up of mucosa, submucosa, tunica muscularis, and serosa. The mucosa consists of an inner layer epithelium, underlying the lamina propria, and the muscularis mucosa. Distributed within the columnar epithelium are absorptive cells, goblet cells, and enteroendocrine cells. The lamina propria is a connective tissue rich in cells. It includes immunocompetent cells, nerve fibers, fibroblasts, lymphatic vessels, and capillaries. The muscularis mucosa is a thin layer of intestinal smooth muscle. The submucosa consists of loose connective tissue and substantial fatty tissue; here lies the submucosal plexus (Meissner’s

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plexus), one of the plexuses of the enteric nerve system (ENS), together with larger nerves, blood, and lymph vessels. The tunica muscularis consists of the inner complete circular layer that, during contraction, divides the colon into segments—the characteristic haustra and an outer incomplete longitudinal layer, which is made up by three flat longitudinal bands, taenia coli. In the rectum, the taenia disappears, and the longitudinal muscle layer becomes complete. The feces is transported as a result of contractions in the muscle layer containing the myenteric plexus (Auerbach’s plexus), the other plexus of the ENS located between the circular and the longitudinal layers. The serosa consists of a mesothelial lining resembling the visceral peritoneal surface. The rectum initially runs distally and posteriorly, then directly downward, and finally anteriorly and ends as the anus in the perineum. The rectum is closely related to the bladder. The rectum is divided into two segments: the rectal ampulla and the anal canal. As a reservoir for storage of feces, the function of the rectum is to maintain fecal continence and allow defecation at an appropriate time and place. The upper and the lower part of the anal canal are separated by a mucocutaneous zone. The lower squamous epithelium is rich in somatosensory fibers and is highly sensitive to temperature, touch, movement, and pain. The anal canal in children is estimated to be between 2.5 and 3 cm long. At the anorectal junction, the puborectalis muscle creates an angle of approximately 80 degrees, which is considered to contribute to anal continence. The continuation of the circular smooth muscle layer constitutes the internal anal sphincter (IAS), whereas the external sphincter (EAS) consists of striated muscle and hence is partly under voluntary control. With the support from the pelvic floor, the levator ani muscle and the internal and external anal sphincters maintain a higher pressure in the anal canal than in the rectal ampulla (Fig. 155-10A and B).

Colorectal Motility and Defecation There are at least three regulatory mechanisms in the gastrointestinal tract; endocrine, paracrine, and the enteric nervous system (ENS). The scope of this paragraph is the ENS, its modulators and colorectal motility. Overall, neural control of colorectal motility is provided by the ENS, the intrinsic nervous system, modulated through the extrinsic nervous system; the lumbar sympathetic nerves; sacral parasympathetic nerves; and extrinsic sensory innervations.

THE INTRINSIC NERVOUS SYSTEM The majority of the neural control of colorectal motility is meditated by the ENS. Auerbach’s plexus mainly controls the motility, and Meissner’s plexus mainly controls the secretion and blood flow. Generally, the ENS consists of sensory neurons, interneurons, and both excitatory and inhibitory motor neurons. Different neurotransmitters, neuropeptides, and other molecules either inhibit (e.g., noradrenalin, dopamine, somatostatin) or increase (e.g., acetylcholine, serotonin, histamine) motility.

THE EXTRINSIC NERVOUS SYSTEM Indirectly, by modulating the ENS via the interneurons, the sacral parasympathetic nerves increase digestion and motility whereas the lumbar sympathetic nerves decrease digestion and motility. This is caused by an increase/decrease of vasodilation, secretion, and peristaltic activity and relaxation/ constriction of the sphincters. The colorectal extrinsic sensory innervation is provided by spinal afferent neurons and a subpopulation of these, mechanosensitive afferents that are

highly sensitive to intestinal distension by feces, can consequently be an important factor of conscious awareness of rectal filling, of continence, and in initiating defecation. The somatic innervation of the extrinsic anal sphincter is via a perineal branch of the S4 nerve and the pudendal nerve.

MUSCLE CONTRACTIONS AND   COLORECTAL MOTILITY Control of muscle contractions are discussed in the online version of this chapter. Defecation, to void feces from the distal colon and rectum, is a complex process involving the previously described ENS, autonomic nervous system, and smooth and striated muscles. It is initiated when a colonic mass movement continues to rectum generating a slow distension of the rectal wall. As the distension proceeds, the filling of the rectum stimulates the rectoanal inhibitory reflex (RAIR), mediated by the ENS, and causes relaxation of the IAS. Additionally, the rectum now serves as a conduit, and the RAIR stimulates the filling of the upper anal canal. The upper anal canal’s sensory innervations make it possible to detect consistency and thereby distinguish between air, solid or liquid. The filling creates the urge to defecate. Defecation will proceed with the voluntary relaxation of the puborectal muscle, straightening of the anorectal angle, and relaxation of the EAS. Defecation is normally improved by the Valsalva maneuver. As wall tension relaxes, the defecation reflex subsides and rectal compliance increases, which leads to a resting pressure of the anal canal higher than in rectum and thereby reaching continence.

CNS AND THE GUT More than 90% of the body’s serotonin (5-HT) is found in the enterochromaffin cells in the gastrointestinal canal, and plasma 5-HT has been found increased in diarrheal diseases and decreased in constipation. The 5-HT4 agonist, prucalopride, is used to treat chronic constipation if laxatives prove insufficient. It has shown promising results, but research among children is lacking (Brookes et al., 2009). Higher brain centers that influence and control defecation are the ACC, PFC, insula, the amygdala, the stria terminalis, and the hypothalamus. In humans, response to external stressors is mediated through the coordinated action of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic branch of the autonomic nervous system. With this in mind, research in treatment with 5-HT3-antagonist in irritable bowel syndrome among adults found a decrease in brain activity in the emotional motor systems with correlates to a decrease in gastrointestinal symptoms. One model for irritable bowel syndrome proposes that altered central stress circuits have been introduced. It is hypothesized that triggering of these circuits by external stressors results in the development of gut and extraintestinal symptoms in predisposed individuals. Central control of defecation and gastrointestinal function are in the same sites as that for urination (Mayer et al., 2006). Further discussion of this topic is in the online version of the chapter.

PATIENT EVALUATION History Fecal incontinence, constipation and abdominal pain are the most common complaints in children seeking help. In some patients, fecal incontinence and abdominal pain may be due



to constipation. But in other individuals, these symptoms may be isolated problems. Questioning should precede the same as for disorders of micturition. As with disorders of micturition, the same questioning process should be used except that specific questions assessing alterations in bowel habits, stool mass, stool color, and stool consistency should be done. The age at onset, frequency, related circumstances (e.g., time of day, association with sleep, behavioral aspects), and alterations in bowel habits, stool mass, stool color, and stool consistency should be established. It should be determined whether the child feels stool in the rectum, has the urge to defecate, whether soiling occurs without notice, or whether the child have some sensation when he/she has an accident. It is helpful to ascertain whether the child can differentiate between passage of flatus and feces. Similarly, efferent function can be evaluated by asking questions related to volitional inhibition of defecation. Fecal incontinence is unlikely to be due to spinal cord disease in the absence of urinary symptoms or neurologic abnormalities involving the lower limbs.

Neurologic Examination As the neural pathways are similar, neurologic evaluation of bowel incontinence parallels that described for disorders of micturition. Further insight to the examination is discussed in the online version of the chapter.

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Lumbosacral defects may be associated with reduced or absent external sphincter function, which is demonstrated by sphincter electromyography. Denervation potentials or reduced large-amplitude potentials may be observed. In Hirschsprung disease, manometric studies demonstrate an absence of the rectoanal inhibitory reflex; that is, the internal sphincter fails to relax in response to a transient rectal distention. The relaxation wave is absent.

Management Assessment of contributing factors, including psychosocial milieu, anorectal examination, and appropriate neurologic evaluation, is necessary for adequate management. Therapeutic approaches include dietary, behavioral, pharmacologic, and surgical methods. For fecal incontinence, the management of the concomitant constipation is paramount and a thorough bowel cleansing is in order. Education is important in achieving good outcome. Further discussion of management techniques is included in the online version. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES

Clinical Studies A simple flat plate of the abdomen is necessary to evaluate for constipation. An AP and lateral film should be done to look at the sacrum. In children with a history of imperforate anus, a sacral ratio less than 0.52 correlates well with spinal cord anomalies and with unfavorable prognosis in children with anorectal malformations. We also know that children with high imperforate anus have a 70% to 80% rate of neurogenic bladder dysfunction. Current promising pediatric anorectal investigations are manometry, measuring contractility in the anus and rectum, and impedance planimetry, studies of rectal compliance. Proctoscopy and fiber optic studies of the lower bowel are efficient methods of excluding the presence of structural abnormalities. Barium enema studies sometimes are necessary, as are defecography studies, which monitor the functional events visually during defecation.

Differential Diagnosis The most common cause of fecal incontinence is encopresis, which is not associated with neurologic dysfunction. Encopresis is fecal incontinence without organic cause for more than a month in children 4 years of age or older. Males outnumber females by 3.5 to 1. Children with fecal incontinence (or encopresis) have the highest rates of coexistent behavioral disorders: 30% to 50% of all children have clinically relevant behavioral disturbances. Many will exhibit withholding of stools that will lead to stool smearing of the underwear and, at times, outright full defecation. In some, the urge to control defecation many not be processed appropriately in executive areas, leading to inability to suppress the reflexive event. Neurogenic and other organic conditions causing bowel dysfunction must be excluded. Other causes of functional bowel problems such as irritable bowel syndrome and abdominal migraines may have their origins in the frontal lobes as well.

Austin, P.F., Bauer, S.B., Bower, W., et al., 2014. The standardization of terminology of lower urinary tract function in children and adolescents: update report from the Standardization Committee of the International Children’s Continence Society. J. Urol. 191, 1863– 1865 e13. Blankstein, U., Chen, J., Diamant, N.E., et al., 2010. Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors. Gastroenterology 138, 1783–1789. Birder, L., de Groat, W., Mills, I., et al., 2010. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol. Urodyn. 29, 128–139. Brookes, S.J., Dinning, P.G., Gladman, M.A., 2009. Neuroanatomy and physiology of colorectal function and defecation: from basic science to human clinical studies. Neurogastroenterol. Motil. 21 (Suppl. 2), 9–19. Critchley, H.D., Mathias, C.J., Josephs, O., et al., 2003. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 126, 2139–2152. Critchley, H.D., Mathias, C.J., Josephs, O., et al., 2006. Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain 126, 2139–2152. Griffiths, D., Clarkson, B., Tadic, S.D., et al., 2015. Brain mechanisms underlying urge incontinence and its response to pelvic floor muscle training. J. Urol. 194, 708–715. Griffiths, D., Tadic, S.D., 2008. Bladder control, urgency, and urge incontinence: evidence from functional brain imaging. Neurourol. Urodyn. 27, 466–474. Heron, J., Joinson, C., Croudace, T., et al., 2008. Trajectories of daytime wetting and soiling in a United Kingdom 4- to 9-year-old population birth cohort study. J. Urol. 179, 1970–1975. Linnman, C., Moulton, E.A., Barmettler, G., et al., 2012. Neuroimaging of the periaqueductal gray: state of the field. Neuroimage 60, 505–522. Mayer, E.A., Naliboff, B.D., Craig, A.D., 2006. Neuroimaging of the brain-gut axis: from basic understanding to treatment of functional GI disorders. Gastroenterology 131, 1925–1942. Neveus, T., Eggert, P., Evans, J., et al., 2010. Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children’s Continence Society. J. Urol. 183, 441–447. von Gontard, A., Nevéus, T., 2006. Management of Disorders of Bladder and Bowel Control in Childhood. Mac Keith Press, London.

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E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 155-2 Current concepts of sensory innervation of the bladder. Fig. 155-4 A, Storage phase: A model of lower urinary tract control by higher brain centers. B, Voiding phase: A model of lower urinary tract control by higher brain centers. Fig. 155-5 A, The response to bladder filling in normal controls at large bladder volumes. B, The response to

bladder filling in subjects with urge incontinence at large bladder volumes. Fig. 155-7 Current treatment options to improve bladder storage. Fig. 155-8 Child with Ochoa urofacial syndrome. Fig. 155-9 Anatomy of the rectum and its nervous supply. Fig. 155-10 Functional anatomy of storage of stool and defecation. Box 155-1 Selected Differential Diagnosis of Neurologically Induced Disorders of Micturition and Defecation

156  Poisoning and Drug-Induced Neurologic Diseases Kristyn Tekulve, Laura M. Tormoehlen, and Laurence Walsh

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Many substances are potential nervous system toxins. Manufactured and naturally occurring agents may be ingested, inhaled, injected, or absorbed, with subsequent deleterious effects on a child’s central or peripheral nervous system. Most childhood ingestions are accidental. Effects may be acute, subacute, or chronic, and may occur at any age. Neurologic dysfunction may be isolated or part of a systemic derangement. Neurotoxins are among the most commonly encountered toxins, although less common in children younger than 6 years (Mowry et al., 2014). Poisonings and drug-induced neurologic disease may mimic infection, trauma, neoplasm, psychiatric illness, or metabolic disorders. A more detailed description of the following toxins and information about additional toxins can be found in the online version.

considered when a sustained-release or enteric-coated preparation has been ingested, if the toxin cannot be removed by activated charcoal, or if illicit drugs are carried in the body. Appropriate general management steps are outlined in Box 156-1; details may be found in several references (Leikin and Paloucek, 1995). Therapy for specific toxidromes is discussed with the individual agents.

Testing The value of routine toxicologic testing in cases of possible intoxications is debated. The low sensitivity of specific tests and the inability to test for all possible agents, medicolegal concerns, cost-effectiveness, and limited use specifically for children suggest that routine testing should be limited. Ideally, history and physical examination narrow the list of possible exposures and direct specific toxicologic testing.

Emergency Evaluation

Other Ancillary Testing

Management of the poisoned child requires immediate stabilization of the patient and appropriate corrective and supportive therapy. Physicians must review the history and examine the child carefully and have a high index of suspicion. Three-quarters of poisonings are by ingestion. Medications account for most deaths. Physical examination can establish the cause and guide therapy. Neurologic findings may result from the toxin itself or its systemic effects. Systemic effects include CNS hypoxia, cardiac dysrhythmias, gastrointestinal disturbances, and metabolic acidosis.

Ancillary testing is directed by specific clinical findings. Electroencephalography (EEG) is important to exclude subtle or subclinical seizures if altered mental status is present. Neuroimaging is used if there is a suspicion of concomitant trauma or hemorrhage. It also may be helpful to detect specific radiologic patterns associated with toxins and to assess for any cerebral injury.

Management Gastric lavage has been a mainstay of treatment; however, experts now recommend against it as it does not improve outcomes and can have severe complications, including aspiration pneumonia, laryngospasm, arrhythmias, esophageal or stomach perforation, fluid and electrolyte imbalances, and small conjunctival hemorrhages. Local poison control should be consulted if gastric lavage is considered. Ipecac syrup works as an emetic, but there is insufficient data to recommend its use. The most common adverse effects are diarrhea, lethargy, prolonged vomiting, irritability, fever, and diaphoresis. If the vomiting is severe, Mallory–Weiss tears, pneumomediastinum, and aspiration pneumonia may result. Some experts argue that ipecac syrup may be used in rare circumstances, such as when medical care cannot be achieved within 1 hour, the toxin ingested was dangerous, there is no alteration in mental status, and the ipecac syrup would not affect further medical care. Many other experts disagree and recommend never using ipecac syrup. Whole-bowel irrigation with large volumes of polyethylene glycol–electrolyte solutions to prevent toxin absorption has been used. There has also not been evidence to show that this improves patient outcomes. Complications of the treatment include vomiting, diarrhea, electrolyte abnormalities, aspiration, and rarely angioedema/anaphylaxic reactions. It may be

Neurologic Examination Examination of a poisoned child includes initial and serial assessment of neurologic status. This assessment guides clinical management, predicts prognosis, and often identifies the offending agent. Please see the online version for specific examination findings associated with toxins (see Box 156-3).

COMMON TOXIDROMES The neurologic examination may indicate poisonings and drug intoxications that fit clinically into one of several toxidromes (Leikin and Paloucek, 1995). The major toxidromes include the following: anticholinergic, cholinergic, sympathomimetic, serotonergic, antihistaminic, opioid, and sedativehypnotic syndromes. The anticholinergic syndrome has peripheral and central muscarinic signs. Peripheral muscarinic signs include tachycardia, dry skin and mucous membranes, dilated pupils, decreased gastrointestinal motility, urinary retention, and hyperthermia. Central anticholinergic signs include confusion, disorientation, agitation, hallucinations, incoordination, ataxia, and frank psychosis (“mad, hot, dry, and blind”). The anticholinergic toxidrome is caused by atropine, belladonna alkaloids, plants (jimson weed), antihistamines, low-potency phenothiazines, and antidepressants, especially tricyclic antidepressants. Cholinergic toxidromes, which include both muscarinic and nicotinic effects, are produced by organophosphate

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BOX 156-1  Suggested General Management of Suspected Intoxications and Poisoning 1. Establish patent airway, adequate respirations, pulse, and systemic perfusion; monitor level of consciousness and urine output. 2. Establish intravenous access. 3. Administer oxygen, glucose, and naloxone as necessary, especially in patients with acute alteration of mental status. 4. Obtain pertinent history and perform careful physical examination, specifically looking for entry sites for envenomation, needle tracks, or other evidence of agent entry (e.g., nasal mucosa, mouth, genital orifices); examine for systemic signs of intoxication, including fever, abnormal vital signs, excessive tearing or salivation, odor, skin and nailbed color, hyperhydrosis or anhydrosis, trauma, or hemorrhages. 5. Perform age-appropriate neurologic examination, including mental status examination and cranial nerve, speech, motor, cerebellar, muscle stretch reflex, and sensory evaluations. Observe patient for posture and gait. 6. Obtain laboratory studies, such as a chemistry profile, including serum glucose and electrolyte levels, blood pH, complete blood count, urine and serum toxicologic studies (for specific agents when indicated), and drug levels, if suggested by history or physical examination. 7. Prevent further absorption or maximize elimination of the toxic agent using gastric lavage or activated charcoal only when indicated. Recent reviews suggest that both methods carry some risk and that they should be used only when there is a reasonable chance that they will reduce the load of toxin present. Furthermore, intact airway protection or intubation is required for their use. 8. Administer specific antidote when indicated. 9. Obtain electrocardiogram and, when indicated, neuroimaging studies (e.g., computed tomography, magnetic resonance imaging), electroencephalogram, and cerebrospinal fluid for examination. 10. Monitor closely; reassess the child frequently.

insecticides, carbamate insecticides, nicotine, physostigmine, and their congeners. Consciousness may be severely depressed with respiratory depression; pinpoint pupils; widespread fasciculations; salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis (SLUDGE syndrome); bronchoconstriction and bronchorrhea; pulmonary edema; hypotension or hypertension; and bradycardia. Seizures may occur. Young children may not display typical peripheral cholinergic signs and symptoms. Serotonin syndrome is traditionally described as neuromuscular abnormalities, autonomic hyperactivity, and mental status changes. The Hunter serotonin toxicity criteria are used to increase the accuracy of diagnosis. The most significant finding is clonus. Other findings associated with the syndrome include diaphoresis, agitation, hyperreflexia, and tremor (Dunkley et al., 2003). Hyperthermia is seen in severe cases (Dunkley et al., 2003). Symptoms usually occur rapidly and can be the result of a single initial medication dosage, a change in the dose, or in an overdose. Serotonin syndrome can occur after ingestion of many classes of medications. Treatment is removal of the drug source and supportive care. Benzodiazepines should be used early to control agitation. Cyproheptadine and chlorpromazine have some efficacy. Hyperthermia should be treated with sedation, intubation, and neuromuscular paralysis.

Antihistaminic agents are divided into histamine-1 and histamine-2 receptor antagonists. Both may cause significant CNS side effects at therapeutic doses, but the degree is agentspecific. Older histamine-1 blockers cause sedation, delirium, and subtle cognitive defects. Delirium is especially prominent in children. They may also have significant toxicity, including movement disorders and autonomic dysfunction. With overdose, ataxia and seizures may supervene. Toxicity may be delayed by several days. Histamine-2 blockers tend not to have significant antihistaminic side effects (except cimetidine) in children at therapeutic doses. At high doses, mental status changes predominate, especially with cimetidine. The opioid-induced toxidrome is diagnosed and treated with naloxone. It includes CNS depression with coma, pinpoint pupils, muscle flaccidity, respiratory depression, and bradycardia. All opioid-derived agents may cause this syndrome. Sedative-barbiturate toxidromes are manifested by lethargy/profound sedation, respiratory depression, miotic pupils, and generalized hypotonia with areflexia and ataxia. Signs and symptoms may be progressive, especially in intoxication with longer-acting agents, such as phenobarbital.

POISONS AND ENVIRONMENTAL TOXINS Biologic Toxins Biologic toxins include snake, arthropods (tick), insect, and fish toxins; botanic toxins; and bacterial toxins (e.g., diphtheria, tetanus, botulism) (Table 156-1, Box 156-2, and Boxes 156-4 to 156-9) (Stommel, 2008).

Snake Venom There are two major families of poisonous snakes, Crotalids and Elapids. Crotalid venom is primarly hemotoxic, whereas Elapid venom is neurotoxic. Symptoms include fever, nausea, vomiting, diarrhea, tachycardia, altered blood coagulation, and local effects of envenomation. Neurotoxins affect the neuromuscular junction and occasionally altered states of consciousness and convulsions. Initial treatment is immobilization of the bite area and transport to the hospital. Incisions, suctions, tourniquets, and ice are not recommended. Venom extraction within 5 minutes can be beneficial. Treatment should include wound cleaning, tetanus prevention, and antivenin. Exercise hastens absorption of venom. Intravenous administration of specific antivenoms is recommended. Tick Bites.  Neurotoxins from various ticks can cause acute paralysis or ataxia through impaired acetylcholine release at the neuromuscular junction. This causes restlessness and irritability followed by progressive ataxia or symmetric ascending flaccid paralysis with loss of deep tendon reflexes. Removal of the tick early leads to reversal of the clinical manifestations within 24 hours. Insect repellents may be used as a preventive measure. Botulism.  Botulinum toxin also irreversibly blocks acetylcholine presynaptic release at the neuromuscular junction. It causes three different clinical syndromes: childhood or adult food-borne, infantile, and wound botulism (Stommel, 2008). Inhalation botulism has been rarely reported. Food-borne botulism causes gastrointestinal symptoms of diarrhea and vomiting, followed by rapidly developing progressive paralytic disease associated with visual blurring and diplopia, dysphagia, dysarthria, and subsequent weakness of extremities and intercostal muscles. Onset is within 2 days. Botulinum antitoxin has been effective in shortening the length of ventilation, feeding dysfunction, and hospitalization. It must be administered within 7 days of hospital admission. Treatment



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TABLE 156-1  Selected Agents Causing Cranial Nerve Deficits Cranial Nerve Deficit

Medications

Industrial Toxins

Biologic Toxins

General

Methotrexate, vincristine

Organic mercury, ethylene glycol

Cobra venom

Olfactory

Levodopa

–

–

Optic nerve and retina

Antibiotics, phenothiazines, antineoplastics, cyclosporine, disulfiram (retrobulbar neuritis), isoniazid, minoxidil, quinines, valproic acid, vigabatrin

Cyanide, methanol, lead, thallium, organic mercury, hexachlorophene

Lathyrus

Extraocular muscles

Botulinum A toxin, bretylium, interferon

–

Clostridium botulinum toxin

Mydriasis

Antihistamines, anticholinergics, nortriptyline, barium, bromides, carbamazepine, cocaine, cyclobenzaprine, glutethimide, sertraline, sympathomimetics

Ethylene glycol, benzene, cyanide

Black nightshade (Solanum nigrum), box thorn (Lycium halmifolium), lupine, morning glory, potato (leaves, stems, immature tubers), tetrodotoxin (puffer fish, others), water hemlock (Cicuta spp.), mescaline, peyote

Miosis

Buspirone, cholinergics, narcotics

–

–

Dysgeusia

Dipyridamole, disulfiram, selegiline, ethambutol, lithium, nedocromil, tocainide, topiramate

Dimethyl sulfoxide

Ciguatera toxin (red snapper, farm-raised salmon)

Auditory

Antibiotics, especially aminoglycosides, antifungals, antineoplastics, lithium (acute), nonsteroidal antiinflammatory drugs and salicylates, quinine antiarrhythmics, angiotensin-converting enzyme inhibitors, danazol, dantrolene, dapsone, antidepressants, digoxin, dimenhydrinate, diuretics, vitamin A

Carbon monoxide, cyanide, methanol, solvents, mercury (organic)

Tobacco (acute), lathyrus

otherwise is supportive and neuromuscular effects may linger, even after recovery. Infantile botulism can be a severe paralytic disease affecting the limbs, trunk, bulbar musculature, and cranial nerves. It is preceded by a history of severe constipation without other gastrointestinal symptoms. It has been associated with ingestion of honey. Human-derived botulinum immune globulin (BIG) has also been effective in reducing hospitalization, ventilation, and enteral/parental feeding in infants, but it has not been shown to reduce adverse outcomes. Tetanus.  Pediatric tetanus is extremely rare in the vaccination era. Neonatal tetanus is reported, resulting from infection of the umbilical stump. Presentation is generalized rigidity and mortality is high, especially in neonates less than 10 days of age (Stommel, 2008).

Insecticides Organophosphate and Carbamate Insecticides.  Account for most childhood insecticide exposures. Poisoning is rare. Toxins can be absorbed through the skin and gastrointestinal tract, but most childhood poisonings are the result of ingestion. Toxicity produces a cholinergic syndrome within 12 to 24 hours. Salivation, lacrimation, bronchoconstriction, wheezing, and increased pulmonary secretions are all muscarinic manifestations. Peripheral nicotinic signs include muscle weakness, decreased respiratory effort, and muscle fasciculations. CNS signs are anxiety, restlessness, confusion, headache, slurred speech, ataxia, and generalized seizures. With low-dose organophosphate exposure, muscarinic signs predominate, but in more severe acute intoxication, the nicotinic and CNS signs appear. Long-term effects may include memory difficulties, attention problems, and brisk reflexes. With longer-acting agents, recovery is protracted and possibly incomplete. Rarely, a myopathy may occur.

Treatment includes decontamination, general supportive therapy, and administration of specific antidotes, including atropine and oximes. Single-dose activated charcoal is most effective if given within 1 hour after ingestion. Oximes, such as pralidoxime or obidoxime, are cholinesterase reactivators. They are beneficial if given soon after the ingestion, but can be harmful if treatment is delayed. Insect Repellents.  The most effective general insect repellent currently in use is diethyltoluamide (DEET). Preparations containing more than 20% diethyltoluamide are likely to cause neurotoxicity. Seizures (8 to 48 hours after exposure), ataxia, and tremor are the most common neurotoxic effects.

Metals Lead.  Acute lead poisoning is rare. Acute lead encephalopathy consists of listlessness, drowsiness, and irritability, followed by seizures and signs of increased intracranial pressure. Severe resultant cerebral edema often results in significant neurologic sequelae. Blood levels in acute pediatric lead encephalopathy exceed 90 mcg/dL (Kumar, 2008). Acute lead encephalopathy at any blood lead level constitutes a life-threatening emergency and should be managed accordingly (Kumar, 2008). The most important treatment is to remove the patient from the lead exposure. Chronic lead exposure as a result of ingestion of lead paint, inhalation of automobile exhaust fumes from leaded gasoline, or inhalation of industrial pollutants may result in high levels of blood lead and is the more common form of intoxication today. Effects can include antisocial behaviors, attention-deficit/hyperactivity disorder, learning disabilities, and reduced intelligence scores. Oral succimer, intravenous ethylenediaminetetraacidic acid (EDTA), or oral meso-2,3dimercaptosuccinic acid can be considered for children who

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BOX 156-2  Selected Agents That Cause Changes in Sensorium or Seizures MEDICATIONS • Acetylsalicylic acid (ASA) • Allopurinol • Amphetamines • Antiarrhythmics • Antibiotics • Anticholinergic agents • Antidepressants • Antiepileptic drugs • Antifungal agents • Antihistamines • Antihypertensives • Antineoplastics • Antiparasitic agents • Antipsychotics • Antitubercular drugs • Antiviral agents • Anxiolytics • Baclofen • Barbiturates • Benzodiazepines • Beta agonists • Beta blockers • Bismuth subgallate • Bromides • Bromocriptine • Carbinols • Castor oil • Chloral hydrate • Cholinergic agents • Cisapride • Clomiphene • Clonidine • Cocaine • Colchicine • Cyclobenzaprine • Cyclosporin • Dantrolene • Dextromethorphan • Digitalis • Disulfiram • Diuretics • Ergot alkyloids • Erythropoietin • Flumazenil • Glutethimide, zolpidem • Granisetron, nabilone • Guaifenesin • Hallucinogens • Hydrogen peroxide • Immunomodulators • Inhalational anesthetics • Isotretinoin • Ketamine • L-dopa • Levothyroxine • Lithium • Lovastatin • Mefloquin • Methylxanthines • Muromonab-CD3 • Nabilone • Niacin (acute) • Nitrous oxide • Nonsteroidal antiinflammatory drugs, salicylates • Omeprazole (acute) • Opiates/opiods • Steroids

• Sucralfate • Sulfasalazine • Sumatriptan • Sympathomimetics, stimulants • Tacrolimus • Vitamin A INDUSTRIAL TOXINS • Acetone • Acrylamide • Alcohols (ethanol, ethylene glycol, isopropanol, methanol) • Aluminum compounds • Ammonium chloride (toilet bowl cleaners) • Antifreeze components • Benzene • Bismuth • Boric acid (antiseptics, insecticides) • Camphor • Carbon monoxide • Cyanide • Ethylene oxide • Formaldehyde • Gasoline • Heavy metals • Hexachlorophene • Lindane • Metaldehyde (snail bait, fire starters) • Naphthalene • Nerve agents (VX, sarin) • Organophosphate and carbamate insecticides • Rodenticides • Solvents • Zinc, manganese BIOLOGIC TOXINS • Baneberry (Actaea spp.) • Box jellyfish (sea wasp) • Box thorn (Lycium halmifolium) • Buckeye (Aesculus spp.) • Copperhead, cottonmouth, some rattlesnake venom • Corn lily (Helleborus spp.) • Daphne • Death camus (Zigadenus spp.) • Foxglove (Digitalis purpurea) • Ginkgo nuts • Hyoscyamus niger • Jimson weed (Datura stramonium) • Lupine • Marijuana (Cannabis sativa) • Mayapple (Podophyllum peltatum) • Mescaline, peyote • Methcathinone • Morning glory (Ipomoea purpurea, Rivea corymbosa) • Mushrooms (especially Amanita muscaria, Pantherina, Psilocybe, Panaeolus, and Copelandia spp.) • Nutmeg • Oleander • Peony, Paeonia spp. (high doses in medicinal preparations) • Poison hemlock (Conium maculatum) • Potato (leaves, stems, immature tubers) • Shellfish (domoic acid poisoning) • Shigella toxin • Solanum spp. (Jerusalem cherry or ornamental pepper, black nightshade) • Star fruit • Star of Bethlehem, Indian tobacco (Lobelia inflata) • Strychnine (“slang nut”) • Tobacco (nicotine, acute) • Water hemlock (Cicuta maculata)



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BOX 156-3  Selected Agents Associated With Myopathies

BOX 156-4  Selected Agents Causing Peripheral Neuropathy

• Amphetamine • Amiodarone • Barium • Beta blockers • Caffeine • Chloroquine, hydroxychloroquine • Cimetidine • Clofibrate • Cocaine • Colchicine • Corticosteroids: prednisone • Cromolyn sodium • Cyclosporine • Diltiazem • Doxepin • d-Penicillamine • Ethanol • Etretinate • Heroin • Hydrogen peroxide • Licorice • Lovastatin • Minoxidil • Niacin • Phencyclidine palmitate (PCP) • Procainamide • Propylthiouracil • Pyrithioxine • Quinolones, penicillin, nalidixic acid • Salicylates • Sulfasalazine • Tiopronin • Vincristine, paclitaxel • Zidovudine

MEDICATIONS • Amiodarone • Amitriptyline (acute polyradiculopathy) • Antibiotics: nitrofurantoin, chloramphenicol, quinolones, aminoglycosides, polymyxin B • Antineoplastic agents: vinca alkaloids, paclitaxel, procarbazine (mixed), cisplatin, cytosine arabinoside • Antiparasitic agents: metronidazole, chloroquine, hydroxychloroquine • Antitubercular agents • Colchicine • Dapsone (distal motor neuropathy) • Digitoxin • Disulfiram • Ethanol • Ethionamide • Hydralazine • Interferons (sensory) • Nitrous oxide • Phenytoin, fosphenytoin • Pyridoxine (sensory) • Streptokinase (Guillain–Barré syndrome) • Thalidomide (sensory)

have elevated lead levels; however, there is no improvement in later cognitive, neuropsychiatric, or behavioral measures or blood levels. Mercury.  Mercury poisoning can result from elemental, inorganic, and organic mercury exposure. Elemental mercury exposure can occur from a laboratory exposure, broken thermometer, light bulbs, or interior paint. The majority of children are asymptomatic. Headache, abdominal pain, and nausea are the most common symptoms. Rarely visual deficits and peripheral neuropathy can persist. Inorganic mercury exposure can occur acutely after accidental ingestion of an antiseptic solution containing mercury. Chronic poisoning may follow prolonged use of mercury-containing teething powders, repeated applications of ammoniated mercury ointment to the skin, or application of mercury-containing antiseptics to the oral mucosa. Acute inorganic mercury poisoning results primarily in severe gastrointestinal problems, whereas chronic or subacute mercury toxicity causes coarse tremor, irritability, and peripheral neuropathy. Symptoms and signs of acrodynia (“pink disease”) include irritability and profound peripheral neuropathy. Organic mercury poisoning has occurred as a result of ingestion of contaminated fish, grain, or pork and in occupational exposures. Symptoms include ataxia, peripheral neuropathy, choreoathetosis, visual loss, confusion, and coma. Dimercaprol (BAL), meso-2,3-dimercaptosuccinic acid (DMSA), and 2,3-dimercapto-propanesulphonate (DMPS)

INDUSTRIAL TOXINS • Acrylamide (sensory) • Carbon monoxide • Chlorophenoxy herbicides (sensory) • Dinitrophenols • Ethylene oxide (mixed motor, sensory) • Heavy metals • Organophosphate pesticides • Solvents BIOLOGIC TOXINS • Cyanide (cassavism) • Diphtheria • Lathyrus • Podophyllum (ingestion) • Stonefish (Scorpaenidae)

effectively chelate and remove mercury from the tissues; however, this has not been shown to reduce morbidity or mortality. Thallium.  The primary sources of thallium ingestions are rodenticides and insecticides. Thallium poisoning presents with abdominal pain, alopecia, and mixed peripheral neuropathy. Abdominal pain is usually secondary to peripheral neuropathy. Other neurologic effects of thallium include cranial neuropathies, coma, dementia, delirium, and seizures. CNS levels of thallium may continue to rise for at least a few days after the initial exposure. Cardiovascular involvement includes hypertension and myocardial damage, with shock and death occurring in massive doses. Painful distal glossitis, Mees’s lines, and black thallium deposits at the base of abnormally tapered hairs may also be present. Cerebrospinal fluid protein may be elevated. Treatment is to lower thallium blood levels through hemodialysis, hemoperfusion, and/or continuous veno-venous hemofiltration. Prussian blue can help prevent absorption from the gastrointestinal tract. Arsenic.  Most arsenic toxicity occurs by contamination of the water supply. Inhalation of smoke from coal and industrial

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BOX 156-5  Selected Agents Associated With Paralysis and Muscular Rigidity PARALYSIS Medications and Industrial Toxins • Aminoglycoside antibiotics • Beta blockers • Chloroquine (with color vision shift) • Cholinesterase inhibitors: neostigmine, pyridostigmine • D-Penicillamine • Pesticides: organophosphates, carbamates • Pyrithioxine • Trimethadione BIOLOGIC TOXINS • Cobra venom • Poison hemlock (Conium maculatum) • Scorpion fish (Scorpaenidae) • Snake venom, ticks, botulinum toxin • Star of Bethlehem (Hippobroma longiflora) • Sweet pea (Lathyrus odoratus) • Tetrodotoxin (puffer fish, blue-ringed octopus, others) MUSCULAR RIGIDITY • Black widow spider venom (Latrodectus mactans) • Strychnine (Strychnos nux vomica, “slang nut”) • Tetanus toxin

wastes may also cause poisoning. Acute poisoning manifests with nausea and vomiting, abdominal pain, diarrhea, cutaneous, and neurologic findings. Severe inorganic arsenic poi­ soning also results in encephalopathy in older children. A Guillain–Barré-like neuropathy may follow. Other acute cutaneous findings may include facial edema, transient flushing, conjunctival hemorrhage, and maculopapular rash in intertriginous areas. Mees’s lines may be found several months after exposure. Unlike thallium, arsenic typically does not cause alopecia. Treatment includes removal of the exposure. Chelation is the mainstay of acute exposure treatment. It has limited efficacy in chronic exposures. Heavy-metal exposure, including cadmium, lead, arsenic, mercury, and thallium, may occur from intake of medicinals. Ernst and Coon provide a review of such metal toxicity in traditional Chinese medicines.

DRUGS OF ABUSE Cocaine Cocaine inhibits reuptake of norepinephrine, dopamine, and serotonin. Acute toxicity includes behavioral effects, hyperthermia, tremors, diaphoresis, tachycardia, cardiac dysrhythmias, myocardial infarctions, vasoconstriction, and hy­­ pertension. These effects are followed by anxiety, agitation, depression, exhaustion, and sometimes paranoid psychosis. Addiction follows continued use. Stroke, intracranial hemorrhage, vasculitis, and death have been reported. Seizures have also been reported; however, validity of the association is debated. First-line treatment for all symptoms is benzodiazepines. Alpha-antagonist treatment may follow.

Opiates There are limited data available regarding opiate use in childhood. Symptoms of intoxication include CNS depression, miotic pupils, respiratory depression/arrest, circulatory collapse, and convulsions. Morphine sulfate can rarely cause

BOX 156-6  Selected Agents Associated With Parkinsonism and Other Acute Extrapyramidal Reactions MEDICATIONS • Amiodarone • Anticholinergic agents: benztropine • Antidepressants (including selective serotonin reuptake inhibitors) • Antiepileptic drugs • Antifungal agents • Antihistamines • Antipsychotics and related drugs (including “novel” agents) • Bethanechol • Bupropion (acute) • Buspirone • Captopril (acute) • Clonazepam • Diazoxide • Digoxin (chorea) • Estrogen (chorea) • Heroin • Ketamine • L-DOPA • Lithium (chorea) • l-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) • Metronidazole (oculogyric crisis) • Ofloxacin (Tourette-like syndrome) • Opiates/opiods • Reserpine • Stimulants • Sulfasalazine (chorea) • Vinblastine INDUSTRIAL TOXINS • Carbon monoxide • Metals: manganese, thallium, aluminum • Methanol • Trichloroethylene BIOLOGIC TOXINS • Arthrinium mycotoxin

a leukoencephalopathy. Heroin can cause a spongiform leukoencephalopathy. Treatment of opiate intoxication in­cludes administration of naloxone and supportive care.

Cannabis Cannabis (tetrahydrocannabinol) is usually inhaled or ingested. Tetrahydrocannabinol intoxication produces psychomotor slowing, short-term memory loss, analgesia, pupillary dilatation, conjunctival hyperemia, tachycardia, and appetite stimulation. Coma has been reported. Long-term sequelae include mild cognitive impairment, psychiatric conditions, chronic bronchitis, bone loss, cardiovascular effects, and teratogenicity. Dependency may occur.

Gamma-Hydroxybutyrate Gamma-hydroxybutyrate is most often a “date-rape” drug. It can lead to a profound flaccid, areflexic coma. This may mimic brain death. Treatment is supportive.

Hydrocarbons “Hydrocarbons” are a broad range of substances that are organic in nature with hydrogen and carbon as their main



Poisoning and Drug-Induced Neurologic Diseases

BOX 156-7  Selected Agents Associated With Myoclonus MEDICATIONS • Antibiotics (β-lactams) • Antidepressants • Antineoplastics: busulfan, chlorambucil • Carbamazepine, vigabatrin • Clozapine • L-DOPA • Lidocaine • Lithium • Lorazepam (preterm infants) • Methaqualone • Morphine • Nitroprusside • Piperazine INDUSTRIAL TOXINS • Camphor • Chlorophenoxy herbicides • Gasoline BIOLOGICAL TOXINS • Buckeye (Aesculus spp.) • Lupine • Shellfish (domoic acid poisoning)

elements. Common examples are glue, kerosene, leaded gasoline, and Freon®. Toxicity most often occurs through inhalation. The exact mechanism of hydrocarbon toxicity is unknown. Toxicity is substance- and dose-dependent. Acute effects include euphoria, disinhibition, impulsivity, headache, dizziness, and nausea. Blurred vision, tinnitus, arrhythmias, peripheral numbness, muscle weakness, and dysesthesia of the tongue have also been described. Long-term abuse may result in neuropsychiatric alterations, cerebellar dysfunction, encephalopathy, tremor, spasticity, and dementia. White matter abnormalities on MRI have been described. Treatment is symptomatic and includes removal of exposure source.

Hallucinogens Phencyclidine (PCP) is commonly inhaled or ingested. It causes euphoria, violent behavior, extreme muscular rigidity, and exaggerated muscle strength. Vertical and horizontal nystagmus with marked pupillary dilatation is common. A syndrome of catatonic rigidity, opisthotonus, dystonic posturing, stupor or profound fluctuations in the level of consciousness, seizures, and myoclonus can occur. Extreme elevations of blood pressure are common. Intracranial hemorrhage can occur. Treatment includes sedation, hyperthermia treatment, and hypertensive management. LSD is a hallucinogen. Intoxication results in acute personality changes, hallucinations, panic reactions, and feelings of depersonalization. Ataxia, tremors, diaphoresis, convulsions, coma, and respiratory arrest may occur. Treatment is supportive care with sedation.

Amphetamines Amphetamines cause a sense of well-being and decreased fatigue. With toxic doses, acute paranoid psychosis may develop, with mania, hyperactivity, and severe sympathomimetic effects. The most common adverse effects in children are agitation and tachycardia. Less commonly hypertension,

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BOX 156-8  Selected Toxic Causes of Ataxia MEDICATIONS • Acetohexamide • Amiodarone • Anticholinergic agents • Antidepressants, including selective serotonin reuptake inhibitors • Antiepileptic drugs • Antihistamines • Antimicrobials, antifungals • Antineoplastics • Antiparasitics • Baclofen • Buspirone • Dextromethorphan • Disulfiram • Ethanol • Fenfluramine • Lithium • Lysergic acid diethylamide (LSD), phencyclidine palmitate (PCP) • Mexiletine • Sedatives, narcotics INDUSTRIAL TOXINS • Aluminum compounds • Butyl alcohol • Carbon monoxide • Carbon tetrachloride • Ethylene glycol • Formaldehyde • Gasoline • Manganese • Metaldehyde (snail bait, fire starters) • Paradichlorobenzene (moth repellent, diaper pail deodorant) • Rodenticides: aluminum phosphide, sodium monofluoroacetate • Solvents BIOLOGIC TOXINS • Belladonna, hyoscyamine • Buckeye (Aesculus spp.) • Mayapple (Podophyllum peltatum) • Mescaline, peyote • Podophyllum (ingested) • Poison hemlock (Conium maculatum)

hyperthermia, and convulsions occur. Cerebral vasculitis, cerebral infarction, subarachnoid hemorrhage, and intracranial hemorrhage have been reported. Severe agitation or seizures may be treated with intravenous benzodiazepines; hallucinations and agitation may also be treated with haloperidol or olanzapine. Hyperthermia and hypertension should be treated aggressively.

“Ecstasy” 3,4-Methylenedioxymethamphetamine (ecstasy) both stimulates and blocks reuptake of serotonin (5-HT). It also has a lesser effect on other monoaminergic neurotransmitters. It typically causes euphoria. Acutely, it commonly causes serotonergic symptoms of confusion, hyperkinesis, and increased body temperature. Rarely, these symptoms can develop into a serotonergic syndrome. Once the acute effects wear off, depressive symptoms occur. Treatment is supportive.

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BOX 156-9  Selected Agents Associated With Tremor MEDICATIONS • Aluminum compounds • Aminophylline, theophylline • Amiodarone • Antiepileptic drugs • Antihistamines • Chlorambucil • Ciprofloxacin • Cyclosporine, tacrolimus (FK-506) • Dextromethorphan • Digitoxin, lidocaine • Fenfluramine • Levothyroxine • Lithium • Nortriptyline • Piperazine • Sympathomimetics, stimulants INDUSTRIAL TOXINS • Carbon tetrachloride • Fluoride • Metaldehyde (snail bait, fire starters) • Organic mercury • Pyrethrins • Rodenticides: aluminum phosphide BIOLOGIC TOXINS • Hyoscyamine • Mescaline, peyote • Star of Bethlehem, Indian tobacco (Lobelia inflata) • Tobacco (nicotine)

Emerging Drugs of Abuse Synthetic cathinones (bath salts) can be snorted, ingested, or injected. They cause increased release and decreased reuptake of norepinephrine, serotonin, and dopamine. Sympathomimetic toxicity can result, causing symptoms of agitation, hyperthermia, tachycardia, anxiety, confusion, seizures, chest pain, nausea, palpitations, fever, diaphoresis, hypertension, dizziness, and peripheral vasoconstriction. Symptoms have a significant overlap with both serotonin and sympathomimetic syndromes. Treatment is with benzodiazepines, antipsychotic agents, and supportive care. Synthetic cannabinoids (i.e., K2 and spice) exert their effects through the CB1 and CB2 cannabinoid receptors. Their effects include mood alteration, hallucinations, conjunctival injection, tachycardia, and dry mouth. They may also provoke anxiety and psychotic reactions. Seizures have been reported. Treatment is primary supportive. Salvia is a hallucinogen that acts as an agonist at the kappa opioid receptor. Adverse effects include agitation, tachycardia, hypertension, seizures, leukocytosis, hyperglycemia, and elevated creatine kinase.

Barbiturates Barbiturate intoxication produces confusion and varying degrees of sedation and coma; lesser amounts may result in ataxia. Respiratory depression, flaccid areflexia, miotic pupils, and absent brainstem reflexes occur with more severe poisoning. Activated charcoal, given repeatedly, is the most efficacious treatment along with supportive care. Hemodialysis is of unproved value but may benefit severely intoxicated patients. Renal function monitoring is recommended.

Benzodiazepines Benzodiazepine intoxication produces ataxia and sedation at low doses, and confusion, somnolence, and coma at higher doses. Respiratory depression and hypotension may occur. The combination of benzodiazepines and other CNS depressants is potentially fatal. Treatment is supportive care and administration of flumazenil. Flumazenil-induced convulsions may occur in individuals with chronic benzodiazepine use.

Baclofen Baclofen is a GABA B receptor agonist that is most often used to treat spasticity. Mild toxicity typically results in sedation or agitation. More severe toxicity may manifest as hypothermia, hypotonia, respiratory depression, cardiac conduction abnormalities, hyporeflexia, and/or coma. Seizures or myoclonic jerks are common. A burst suppression pattern on EEG may occur and may persist for days after ingestion (Leikin and Paloucek, 1995). The clinical picture may mimic brain death. Treatment is supportive.

Antipsychotic Agents (Neuroleptics) Older neuroleptics include phenothiazines and butyrophenones. These can cause sedation, acute dystonic reactions, akathisia, pseudoparkinsonism, withdrawal, emergent dyskinesia, tardive dyskinesia, and neuroleptic malignant syndrome. Acute intoxication in a young child usually results in a confusional state or depressed level of consciousness. Acute dystonic reactions may manifest as an oculogyric crisis or sudden dystonic posturing of the head and neck, including opisthotonus, retrocollis, torticollis, facial grimacing, and tongue thrusting. These acute reactions are not necessarily dose related, and are usually readily reversed with the intravenous administration of diphenhydramine. Miosis, coma, hypothermia or hyperthermia, and hypotension may occur after ingestion of a large dose of either phenothiazines or butyrophenones. Akathisia is a dose-related neurologic complication of neuroleptic treatment and is rare in children. It usually responds to treatment with benzodiazepines, beta-adrenergic blockers, or dose reduction. Tardive dyskinesia is extremely rare in children. Neuroleptic malignant syndrome is a rare complication of neuroleptic drug therapy and is characterized by fever, muscular rigidity, autonomic dysfunction, and altered sensorium, with waxing and waning of consciousness. The patient may be in a catatonic-like stupor and may be mute. Myoglobinuria and acute renal failure may occur. Treatment consists of intensive supportive care, aggressive fluid management, and, in selected cases, dantrolene or bromocriptine administration. This syndrome can occur with both first- and secondgeneration antipsychotics (Belvederi et al., 2015). The second-generation antipsychotics, such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and sertindole, have clinically significant pharmacologic activity at multiple receptors, and fewer typical antidopaminergic side effects. They can cause acute extrapyramidal effects (clozapine and risperidone), confusion, lethargy, ataxia, seizures (clozapine), and myoclonus.

Antidepressants Tricyclic antidepressants (i.e., amitriptyline, imipramine, and desipramine) are associated with acute toxicity and significant morbidity and mortality (Qin et al., 2014). Dry mouth, palpitations, and tachycardia are typical anticholinergic effects.



An acute encephalopathy with ataxia, hallucinations, and nystagmus can occur followed by somnolence and tremor or myoclonus. Death may occur as a result of progressive coma, seizures, and cardiac conduction defects resulting in hypotension. In acute poisoning, activated charcoal with a cathartic may be helpful. Seizures are treated with benzodiazepines. Tachyarrhythmias from prolongation of the QRS interval can be treated with sodium bicarbonate and potassium. Prolonged QTc intervals should be treated with magnesium supplementation and potassium repletion. Selective serotonin reuptake inhibitors’ neurotoxicity is generally limited to accidental ingestions or intentional overdoses. This can lead to a serotonergic syndrome, including coma and convulsions. Sedation and vomiting are the most common side effects. Paradoxical behavioral reactions and SSRI-induced hyperkinetic movement disorders are the most likely adverse neurologic effects (Qin et al., 2014). Citalopram intoxication can be associated with severe encephalopathy and seizures requiring intensive care admission. Extrapyramidal symptoms can occur from duloxetine, escitalopram, and citalopram. A neonatal withdrawal syndrome has been reported. Buproprion has the highest risk for seizures.

Lithium Lithium carbonate is often used for the treatment of bipolar disorder. Most cases of lithium intoxication occur during the course of prolonged therapy. An acute encephalopathy can occur, but most chronic toxicity manifests as an irreversible cerebellar syndrome. This can be displayed as apathy, drowsiness, nystagmus, tinnitus, dysarthria, ataxia, coarse muscle tremors, vomiting, and diarrhea. Choreiform movements, dystonic posturing, and cogwheel rigidity may occur. Severity of symptoms does not appear to correlate well to serum concentrations, but instead to chronic exposure. Seizures and coma indicate severe toxicity. Treatment is supportive care and drug discontinuation.

Salicylates Salicylates are present in a myriad of medicinal preparations, ranging from aspirin tablets to oil of wintergreen and longused Chinese medicinal oils. The classic triad of acute intoxication is hyperventilation, tinnitus, and gastrointestinal irritation. Symptom onset in acute intoxications is within a few hours. Salicylates directly affect the CNS and cause central hyperventilation with respiratory alkalosis. Mortality is related to brain salicylate concentration; respiratory decompensation and subsequent worsening acidosis facilitate salicylic acid passage into the CNS. Chronic toxicity occurs after several days of use. CNS disturbances include lethargy, coma, and convulsions; however, the predominant toxicity is pulmonary edema. Isotonic alkaline solution, activated charcoal, management of hypoglycemia, early hemodialysis, and supportive therapy are the best treatments.

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gastrointestinal disturbances, and somnolence. Atomexetine overdoses have been associated with dyskinesias and seizure activity.

Diphenhydramine The antihistamine and anticholinergic diphenhydramine is contained commonly in over-the-counter cold/allergy remedies and in topical preparations. Neurologic side effects are sedation or paradoxical hyperactivity. Hallucinations, seizures, and death have been reported in a dose-dependent manner.

Drugs Used in Organ Transplantation Cyclosporine Cyclosporine is an immunosuppressant that likely has the most neurotoxicity among transplant medications (de Groen et al., 1987). It also causes nephrotoxicity and hypertension. The most common nervous system effects are headache, confusion, and seizures. Cortical blindness, hemiparesis, ataxia, and tremor are also reported. Posterior reversible encephalopathy syndrome can occur. These complications are reversible and usually dose dependent. Other factors that exacerbate cyclosporine toxicity include hypertension, fever, hypomagnesemia, hypocholesterolemia, aluminum overload, and concurrent methylprednisolone treatment (de Groen et al., 1987).

Muromonab-CD3 (OKT3) Muromonab-CD3 (OKT3) is a murine monoclonal antibody used in acute cellular allograft rejection or graft-versus-host disease. Aseptic meningitis with fever, photophobia, cephalgia, and cerebrospinal fluid pleocytosis has been described. Other complications include cerebral edema, akinetic mutism, seizures, cerebritis, and tremor.

Tacrolimus (FK-506) Tacrolimus (FK-506) inhibits interleukin-2 and is thought to act by inhibiting T-cell activation. Serum levels of tacrolimus are altered significantly by multiple drugs. Toxicity may be related to dosing. Symptoms include delirium, catatonia, dysphasia, seizures, peripheral neuropathy, and tremor. Posterior reversible encephalopathy syndrome can occur.

Antibiotics Chloramphenicol Chloramphenicol has been associated with the development of a reversible optic neuritis with long-term treatment.

Nitrofurantoin A rare, reversible polyneuropathy can develop with prolonged nitrofurantoin treatment, particularly in the presence of impaired renal function.

Stimulants

Aminoglycosides

Stimulant medications are used to treat attention-deficit/ hyperactivity disorder. They may produce increased activity and varying dyskinesias, including motor tics and chorea. Stimulants overall do not worsen tic severity or exacerbate epileptic seizures. Atomoxetine is a nonstimulant agent approved for the treatment of attention-deficit/hyperactivity disorder. Side effects are mild and can include headache, decreased appetite,

Aminoglycosides are potentially ototoxic. Symptoms may arise from oral, parenteral, or wound irrigation administration of the drug. A myasthenic-like syndrome accompanied by generalized muscle weakness may also result. This reaction usually occurs after the simultaneous administration of a neuromuscular blocking agent. It may be partially antagonized by neostigmine. These antibiotics may also cause a transient clinical deterioration in patients with myasthenia gravis.

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Beta-Lactam Antibiotics Penicillins, cephalosporins, and carbapenems may cause seizures as the result of inhibition of gamma-aminobutyric acid (GABA) receptors and are most likely to occur with renal impairment. Cefepime may provoke seizures independent of renal function, especially in those with an underlying epileptic risk. Supratherapeutic levels can lead to an acute encephalopathy and movement disorders. Effects may be magnified in a child with an altered blood–brain barrier.

Antineoplastic Drugs Vinca Alkaloids Neurotoxicity from vincristine and vinblastine is related to impaired nutrition, drug dosage, frequency of dosing, and duration of therapy. An axonal sensorimotor neuropathy is most common. It may worsen for weeks after treatment completion and can take months to recover (Armstrong and Gilbert, 2004). Muscle cramps, muscle weakness, cranial nerve palsies, ophthalmoparesis, ptosis, and olivocohlear bundle dysfunction can also occur (Armstrong and Gilbert, 2004). Autonomic dysfunction can present with colicky abdominal pain, paralytic ileus, constipation, and bladder atony. Generalized seizures and inappropriate secretion of antidiuretic hormone are rare complications. Temporary cortical blindness, ataxia, parkinsonism, and athetosis have been reported.

Methotrexate Myelopathy, headache, cognitive deficits, vomiting, nuchal rigidity with aseptic meningitis, truncal ataxia, tremor, paraplegia, delirium, and somnolence have been described as complications of both intrathecal and systemic therapy with methotrexate. Methotrexate toxicity may have a genetic component. Toxicity may be improved with leucovorin rescue. A dose-dependent leukoencephalopathy is the most common CNS complication. High-dose intravenous, prolonged lowdose oral, or intrathecal therapy can provoke a typically onetime reversible acute stroke-like syndrome (Armstrong and Gilbert, 2004). MRI can show hyperintense foci on FLAIR and DWI. Meningoencephalopathy can occur as late as several months after completion of methotrexate therapy. The most devastating effect of methotrexate therapy is a subacute and usually progressive leukoencephalopathy. Clinical manifestations include mental deterioration with dementia, seizures, and focal neurologic deficits. This complication may occur between 3 and 9 months, but can occur years, after high-dose methotrexate therapy.

L-Asparaginase L-Asparaginase

therapy may produce changes in mentation, somnolence, and EEG slowing. It produces a coagulation disorder unresponsive to corrective factors. Intracranial thrombosis or hemorrhage and peripheral arterial thrombosis with headache, obtundation, hemiparesis, and seizures are also complications.

Platinum Agents Ototoxicity is a common complication of cisplatin therapy. Dose-dependent peripheral axonal sensory neuropathy may also occur. Retinal toxicity and autonomic neuropathy are rare. Oxaliplatin typically causes an acute and chronic sensory neuropathy. Chronic oxaliplatin exposure has similar effects to

cisplatinin. Carboplatin appears somewhat less toxic to the nervous system and a neuropathy is rare. Calcium and magnesium may have some protective effects.

Cytosine Arabinoside Cytosine arabinoside is most commonly associated with cerebellar ataxia, developing within hours of treatment. This is typically self-resolving. It may also cause a change in sensorium (at high doses), and, rarely, peripheral neuropathy, myelopathy, brachial plexopathy, or transient paraplegia.

Cyclophosphamide and Ifosfamide Cyclophosphamide and ifosfamide both may cause CNS toxicity. This toxicity is manifest as an encephalopathy with mental status changes, seizures, and ataxia. Cranial neuropathies also are possible. Improvement has been reported with methylene blue administration.

Neuroteratology Drugs administered during pregnancy may affect the fetus. The effects of these drugs depend on the timing of administration; the dose, distribution, and metabolism in maternal tissues; placental transfer; and subsequent concentration and distribution of the drug in fetal tissues. Brain development from morphogenesis to terminal myelination represents a long period of developmental vulnerability. Initial recognition of structural defects associated with neuroteratogens has matured into appreciation for more subtle deleterious effects of these agents. Many neuroteratogens are best thought of as neurobehavioral teratogens that cause clinically significant cognitive and behavioral alterations but minimal structural brain changes, at least on the neuroimaging level. Despite newer clinical and imaging technologies, teratogenic risk is frequently imprecise. This discussion is limited to agents in which a neuroteratogenic effect seems likely based on human data, or in which animal data reflect a likely human scenario (e.g., some antineoplastic agents) (Table 156-2). Fetal ethanol exposure is the most common preventable chemical cause of mental retardation in the United States. There is an estimated 6% risk that an alcoholic mother will have a child with fetal alcohol syndrome (FAS); the risk is 70% for subsequent offspring. The current CDC prevalence estimate for fetal alcohol syndrome (FASD) in infants is 0.2 to 1.9 per 1000 infants in the general population, although two recent studies report FAS prevalence in 6- to 7-year-olds of 6 to 9 per 1000 and FASD prevalence of 2% to 5% in the same group. Although most studies suggest that significant risk to the fetus occurs with maternal ethanol consumption of about two drinks per day or a few “weekend binges” during pregnancy, the neurobehavioral teratogenicity of “light” alcohol consumption (defined as 1 to 2 drinks per week or per occasion) is not clear. Regardless, a safe threshold value for alcohol consumption value has not been defined. Cardinal features of FAS are 1. prenatal and postnatal growth deficiency, 2. CNS anomalies, usually involving microcephaly and mental retardation, with irritability and restlessness in infants, and 3. craniofacial anomalies that include short palpebral fissures, frontonasal alterations, midface hypoplasia with flat midface, thin upper lip, hypoplastic maxilla, and sometimes hypoplastic mandible.



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TABLE 156-2  Selected Human Neuroteratogens Drug/Toxin

Effect on Nervous System

Aminoglycoside antibiotics

Cranial nerve VIII damage (10–15%)

Antiepileptic drugs: oxazolidinediones (trimethadione), phenytoin, valproic acid, carbamazepine)

CNS malformations, mental retardation, developmental delay, microcephaly, neural tube defect; spina bifida (1–2%)

Cisplatin

Cranial nerve III

Chloroquine, hydroxychloroquine, quinine

Hydrocephalus, optic nerve hypoplasia, cranial nerve VIII damage (10–15%)

Cocaine

CNS hemorrhage, infarction

Coumarin anticoagulants

Mental retardation, microcephaly, optic nerve hypoplasia, midline CNS malformations

Ethanol (dose-related)

Mental retardation, developmental and behavioral disabilities, dyscoordination, microcephaly, CNS midline malformations and migrational errors

Folic acid antagonists (aminopterin, methotrexate)

Cranial malformations, mental retardation

Hyperthermia

Neural tube defect, migrational errors, Möbius’ syndrome

Ionizing radiation (>200 Gy)

CNS malformation, microcephaly

Lead

Learning disabilities

Maternal diabetes mellitus

Caudal regression, holoprosencephaly arhinencephalia

Organic mercury

CNS malformation, microcephaly

Solvents: gasoline, xylene, toluene (as substances of abuse)

Caudal regression malformation, CNS malformations, mental retardation

Retinoids, vitamin A

Holoprosencephaly, neural tube defect, microcephaly, posterior fossa cysts, cranial nerve palsies (II, III, VII)

Thiouracil, propylthiouracil (PTU), iodine-131

Mental retardation (congenital hypothyroidism)

Undertreated maternal phenylketonuria

Mental retardation (>90% in untreated mothers)

Partial morphologic expression of alcohol effect is referred to as partial FAS, and behavioral effects in a child without morphologic changes suggest alcohol-related neurobehavioral deficits. Fetal alcohol spectrum disorder encompasses all of these disorders. Long-term follow-up suggests that patients with FAS continue to have growth retardation, craniofacial anomalies, and cognitive and behavioral problems in school. Children with FAS had lower weight, shorter length, and smaller head circumference at 3 years of age. Decrease in intelligence quotient at 4 and 7 years of age has been reported. FAS carries worse neurodevelopmental prognosis than do the milder related phenotypes. A broad pattern of postnatal effects may occur in children with FASD, including decreased cognitive abilities, executive dysfunction, anxiety and depressive disorders, and changes in social relationships. Several antiepileptic medications are also teratogens. Phenytoin syndrome consists of facial and digital anomalies, growth deficiency, and mental deficiency. Neurodevelopmental abnormalities may occur in up to 10% of prenatally exposed children. Carbamazepine, trimethadione, and valproic acid are also teratogenic. Neural tube defects occur in about 1% to 2% of valproate- or carbamazepine-exposed fetuses. Maternal folic acid supplementation may reduce the risk for antiepileptic drug-associated neural tube defects. The 2013 NEAD study found that children with prenatal exposure to valproic acid scored 7 to 10 points lower on IQ testing and had other cognitive deficits. To date, no reports concerning other anticonvulsants marketed in the United States provide convincing evidence for injury to the prenatal central nervous system. Isotretinoin (Accutane) produces a characteristic pattern of malformation involving craniofacial, cardiac, thymic, and

CNS structures. The CNS malformations include hydrocephalus, posterior fossa defects, and focal cortical abnormalities. The syndrome is thought to relate to isotretinoin’s ability to interfere with neural crest cell development. The current recommendation is to stop oral isotretinoin at least 4 weeks before conception. There is no evidence for increased frequency of birth defects in pregnancies with topical retinoid exposures, but its use cannot be recommended. Although the evidence is strongest for the agents listed in Table 156-2, suggestive animal or human data support the teratogenicity of other substances, including antineoplastic medications (Smith et al., 2013). Severe intrauterine methylmercury exposure may result in mental retardation, visual and hearing deficits, and a cerebral palsy–like picture. Stable low-level maternal exposure to mercury also appears to have neuropsychologic consequences at least into early school age. The U.S. National Research Council has concluded that 0.1 g/kg body weight per day probably is a safe level of methylmercury exposure for maternal–fetal pairs. Finally, the effects of prenatal exposure to currently popular drugs of abuse, including cocaine, marijuana, and methamphetamine, are less defined. Despite this, at least regarding cocaine and marijuana, evidence supports some degree of neurobehavioral teratogenicity. Prenatal exposure to cocaine may have both short- and long-term CNS sequelae. Infants and children may be exposed to cocaine through transplacental transfer, breast-milk ingestion, and passive inhalation. Although a consistent dysmorphic “syndrome” in cocaine-exposed neonates is not described, congenital urogenital malformations are linked more firmly to prenatal cocaine exposure. Infants exposed to cocaine

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prenatally have intrauterine growth retardation and reduced head circumference. Sharp waves and spikes may be seen in the neonatal EEG, and there is maturational delay in the brainstem auditory-evoked response in neonates as well. Maternal cocaine use is associated with intracranial hemorrhage and antenatal or perinatal cerebral infarction. Infants frequently are irritable and tremulous, with a high-pitched cry and sometimes hypertonia and hyperreflexia. Poor feeding, abnormal sleep patterns, inappropriate response to stimulation, and difficulties with state regulation also may be present. Long-term, there is a suggestion that prenatally exposed children are highly distractible, with poorly developed verbal, language, and motor skills, despite average test scores. Microcephaly, and increased behavioral and affective symptoms, have more recently have been demonstrated in a longitudinal study of children now at age 10 years. Unfortunately, some of these studies were poorly controlled for birth weight, which also may be a predictor of cocaine neurodevelopmental effects. The role of other confounding factors is also unclear. Chronic marijuana use is associated with persistent cognitive dysfunction and other sequelae. To date, neurobehavioral sequelae of prenatal marijuana exposure are not agreed upon, although deleterious effects have been reported in behavior, attention, and overall IQ scores into adolescence. Neonates born to women using marijuana in the immediate prenatal period may be jittery and have an abnormal cry, symptoms that may persist for the first month of life. Patterns of prenatal exposure are becoming better understood, and more sensitive techniques with which to test the effects of those exposures on the developing nervous system are emerging. As increasingly subtle postnatal neurobehavioral consequences are reported, the discussion will move from “if” to “how” these agents affect neurodevelopment throughout the lifespan.

CONCLUDING REMARKS AND   ADDITIONAL SOURCES The American Association of Poison Control Centers (AAPCC) compiles Toxic Exposure Surveillance System data from regional centers in the United States. This effort, combined with educational efforts by the American Academy of Pediatrics, the National Association of Medical Examiners’ Pediatric Toxicology (PedTox) Registry, and local poison control center public and professional education, has significantly reduced pediatric poison-related deaths in this country. Other nations have similar programs and results.

New information concerning poisoning and drug effects on the nervous system appears rapidly. The following section lists several other sources of current toxicology information, and the phone number for AAPCC is 1-800-222-1222. Internet URLs are current as of 2015. The sites have links to other sites involving specific subtopics.

Internet Sites • Poison Control Centers (United States) • Toxnet: http://toxnet.nlm.nih.gov • American Association of Poison Control Centers: http:// www.aapcc.org/ • Poison Control Centers (International) • Europe: http://www.eapcct.org/ • Asia: http://prn.usm.my/ REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Armstrong, T., Gilbert, M.R., 2004. Central nervous system toxicity from cancer treatment. Curr. Oncol. Rep. 6, 11–19. Belvederi, M., Guaglianone, A., Bugliani, M., et al., 2015. Secondgeneration antipsychotics and neuroleptic malignant syndrome: systematic review and case report analysis. Drugs R D. 15, 45–62. de Groen, P.C., Aksamit, A.J., Rakela, J., et al., 1987. Central nervous system toxicity after liver transplantation. N. Engl. J. Med. 14, 861–866. Dunkley, E.J., Isbister, G.K., Sibbritt, D., et al., 2003. The hunger serotonin toxicity criteria: simple and accurate diagnostic rules for serotonin toxicity. QJM 96, 635–642. Kumar, N., 2008. Industrial and environmental toxins. Continuum (N Y) 14, 102–137. Leikin, J.B., Paloucek, F.P., 1995. Poisoning and Toxicology Handbook, second ed. Lexi-Comp, Hudson, OH, pp. 1996–1997. Mowry, J.B., Spyker, D.A., Cantilena, L.R., et al., 2014. Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 31st Annual Report. Clin. Toxicol. (Phila) 52, 1032–1283. Qin, B., Zhang, Y., Zhou, X., et al., 2014. Selective serotonin reuptake inhibitors versus tricyclic antidepressants in young patients: a metaanalysis of efficacy and acceptability. Clin. Ther. 36, 1087–1095. Smith, E.R., Borowsky, M.E., Jain, V.D., 2013. Intraperitoneal chemotherapy in a pregnant woman with ovarian cancer. Obstet. Gynecol. 122, 481–483. Stommel, E., 2008. Terrestrial biotoxins. Continuum (N Y) 14, 35–80.

157  Neurologic Disorders in Children with Heart Disease Daniel J. Licht, John Brandsema, Michael von Rhein, and Beatrice Latal

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

LIST OF ABBREVIATIONS

ANATOMIC CONSIDERATIONS

Heart Diagnosis

Abbreviation/Acronym

Transposition of the Great Arteries

TGA

Hypoplastic Left Heart Syndrome

HLHS

Patent Ductus Arteriosus

PDA

Tetralogy of Fallot

TOF

Ventricular Septal Defect

VSD

Atrial Septal Defect

ASD

Intact Ventricular Septum

IVS

Common AV Canal

CAVC

Double Outlet Right Ventricle

DORV

Interrupted Aortic Arch

IAA

Pulmonary Atresia

PA

INTRODUCTION Congenital heart defects (CHDs) are among the most common birth defects with a national prevalence estimated at about 18 per 10,000 live births. The most serious heart defects (i.e., those requiring surgery in the first week of life) occur at a national prevalence of about 8 per 10,000, with transposition of the great arteries (TGA) occurring in about 4.7 and hypoplastic left heart (HLHS) in about 2.4 per 10,000 live births. Furthermore, previously healthy children can suffer from acquired cardiac disorders including endocarditis and myocarditis. Others, including those with underlying neuromuscular disorders such as Becker muscular dystrophy and Pompe disease, may have an intrinsic abnormality of myocardial function, referred to as a cardiomyopathy. Children with cardiac disease often have neurologic complications. Acute neurologic emergencies include seizures, hypoxic-ischemic injury, arterial ischemic stroke, cerebral sinovenous thrombosis, and intracerebral hemorrhage. Evaluation and management of these neurologic conditions may be complicated due to the specific cardiac considerations and physiologic requirements. Because the risk for the various types of brain injury are closely related to the type of heart lesion, the stage of the patient’s brain development and to the perioperative management, the first part of the chapter will be organized accordingly. The second part of the chapter will cover the perioperative neurologic symptoms and will discuss the spectrum, severity, and evolution of the short-term and long-term neurodevelopmental consequences of altered fetal brain development and perioperative brain injury.

Severe CHDs may be categorized as either single ventricle lesions, biventricular lesions with or without aortic arch obstructions caused by atresia, stenosis, or coarctation (Table 157-1). These lesions can be complicated by intracardiac and extracardiac shunts such as septal defects (atrial and ventricular) or a patent ductus arteriosus (DA) respectively. Mixing of venous and arterial blood and altered flow patterns from malformed heart valves or obstructed outflow tracts (aortic or pulmonary arteries) lead to diminished oxygen delivery (the product of cerebral blood flow and oxygen content of the blood) to the brain and are the major contributors of altered brain growth and development. In addition, they increase the risk for acute brain injury in the form of hypoxic-ischemic injury to the cerebral white matter, stroke, and hemorrhage. Venous to arterial shunts (also known as “right to left shunts”) through septal defects or shunts are sources for paradoxical embolization to the brain. Furthermore, genetic syndromes that are associated with heart defects including Trisomy 21, Alagille syndrome, Noonan syndrome, and several other conditions; carry the risk for other cerebrovascular anomalies such as Moyamoya vasculopathy (Pierpont et al. 2015) (Table 157-2). The two most common diagnoses for high risk severe CHD are TGA and HLHS (Fig. 157-1). In TGA (Fig. 157-1C), the pathology results from the aortic trunk, which arises from the right ventricle shunting systemic venous blood (deoxygenated) to the ascending aorta and on to the neck vessels and coronary arteries (coronaries always arise from the aorta). The pulmonary artery arises from the left ventricle and shunts arterialized (oxygenated) blood to the lungs. In HLHS (Fig. 157-1B), the pathology results from obstruction of antegrade blood flow from the left atrium, either by developmental atresia of the mitral or aortic valve. The lack of antegrade flow from the left atrium results in profound growth failure of the left ventricle and ascending aorta. Thus all cardiac output, both pulmonary and systemic, is from the right ventricle via the pulmonary trunk. Blood flow to the neck vessels and coronary arteries is retrograde from the DA, which is just distal to the left subclavian artery. These flow patterns result in an ascending aorta that has an internal diameter of 1 to 2 mm and a large pulmonary trunk that is receiving twice the normal blood volume (pulmonary and systemic blood). Regulation of vascular resistance determines how much blood is directed to the systemic circulation and how much will flow to the pulmonary bed.

FETAL CIRCULATION At birth, infants with severe CHD have evidence of fetal growth restriction. It has been noted that head circumferences are one-half to one standard deviation lower than the mean for normal populations, and their birth weight is likewise decreased. In keeping with the smaller head sizes, a study

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using preoperative brain magnetic resonance imaging (MRI) with diffusion tensor imaging and magnetic resonance spectroscopy on infants with and without CHD, found evidence of brain immaturity that was both structural and biochemical. Using an observational scale called the Total Maturation Scale (TMS), another study demonstrated that not only was maturation delayed, but the average maturation score for infants with CHD was equivalent to infants at 35 weeks gestation (Fig. 157-2), Work from multiple centers has demonstrated that brain immaturity, as measured by the TMS, is a leading risk factor for white matter injury (WMI) and predicts functional outcomes, as measured by the Bailey Scales of Infant Development (BSID), at 2 years of age. To understand why full-term infants with CHD have delayed brain maturation, the cardiac anatomy and the effects TABLE 157-1  CHD Grading System Standard CHD Grading System

Diagnoses/Examples

Grade I— Two ventricle, no aortic arch obstruction

TGA/IVS, TGA/VSD, TOF, VSD, ASD, truncus arteriosis, CAVC

Grade II— Two ventricle with aortic arch obstruction

Coarctation of the aorta, VSD with coarctation, IAA

Grade III— Single ventricle with no arch obstruction

PA/IVS,

Grade IV— Single ventricle with arch obstruction

HLHS, DORV, unbalanced CAVC

of altered anatomy on fetal circulation must be considered. Oxygen delivery to the brain can be compromised by decreases in either cerebral blood flow (CBF) or a reduction in oxygen content of the blood (anemia or low oxygen saturations or both) or a combination of the two. Furthermore, placental circulation is dependent on fetal cardiac output, if cardiac output is abnormal, placental function may be compromised. In TGA and HLHS, alterations in fetal blood flow likely lead to decreased brain oxygen delivery defined previously. In TGA, the aorta arises from the right ventricle and receives relatively desaturated blood from the vena cavae (Fig. 157-3B). The higher saturated stream from the left hepatic veins is directed normally across the foramen ovale to the left ventricle. The left ventricle, however, is connected to the pulmonary trunk and thus this higher saturated blood (approximately 65%) is delivered to the lungs and lower body by way of the DA (Fig. 157-3B). In HLHS, the fetal circulation is characterized by increased left atrial pressure (no outlet), resulting in reversal of flow across the foramen ovale (Fig. 157-3C). Left ventricular filling is impaired or nonexistent and consequently left ventricle outflow is diminished (aortic stenosis) or absent (aortic atresia). Pulmonary venous return and blood from the placenta mix at the atrial level and are ejected into the right ventricle and into the pulmonary trunk and DA (Fig. 157-3C). Although the resulting blood saturations are not as low as with TGA, a number of factors may restrict flow to the cerebral circulation. In many cases, flow to the head and neck vessels only occurs by retrograde flow into the transverse aorta and is in competition with systemic and pulmonary vascular resistance (Fig. 157-3C). Consequences of these altered flow patterns have been demonstrated on postnatal brain MRI with the TMS evaluation but more remarkably with fetal MRI (Fig. 157-4). In the fetal MRI, Limperopoulos and colleagues performed a

TABLE 157-2  Common Genetic Syndromes With Cardiac and Nervous System Involvement (Listed According to Prevalence) Name

Omim #

Prevalence

Percent With CHD

Trisomy 21 (Down syndrome)

#190685

1 : 650–1 : 1000

Noonan syndrome

#163950

22q11.2 deletion syndrome (DiGeorge, VCF syndrome *)

Nervous System Involvement

Involved Genes

Cardiac Diagnoses

40–50

Chromosome 21, particularly 21q22.3

AVSD, VSD, ASD

Muscular hypotonia, mental retardation, expressive language disorder, impaired hearing, Alzheimer disease

1 : 1000–2500

80–90

12q24.13

PS, AVSD, hypertrophic cardiomyopathy

Mental retardation, speech and articulation difficulties

#611867

1 : 6000

75

22q11.2

Interrupted aortic arch, truncus arteriosus, TOF, aortic arch anomalies

Feeding disorder, nonverbal learning disability, behavioral and psychiatric disorders (adulthood)

Williams-Beuren syndrome

#194050

1 : 8000

50–85

7q11.23

Supravalvular and valvular aortic stenosis, PS

Mental retardation/cognitive delay, sociable personality

CHARGE syndrome

#214800

1 : 10,000

75–80

8q12.2 (7q21.11)

TOF (33%), PDA, DORV, ASD, VSD,

CHARGE acronym: Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness)

Alagille syndrome 1

#118450 (#610205)

1 : 70,000

85–95

20p12.2 (1p12 in Alagille syndrome 2)

Peripheral PA, TOF, PS

In some mental retardation or mild, learning disability

*Patients with a clinical diagnosis of DiGeorge, VCF syndrome (velocardiofacial), or Shprintzen syndrome most often have a 22q11 deletion (Pierpont et al., 2007). Abbreviations: ASD–atrioventricular septal defect; AVSD–atrioventricular septal defect; DORV–double outlet right ventricle; PA–pulmonary atresia; PDA–patent ductus arteriosus; PS–pulmonary stenosis; TOF–tetralogy of Fallot; VSD–ventricular septal defect. For a full list of genetic syndromes associated with CHD see Pierpont et al., 2007. Trisomy 13 and 18 are not listed as children usually die within the first year of life, both defects have various forms of CHD and manifest with severe mental retardation.



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157 Atretic aorta artery

Aorta

Pulmonary artery Left atrium

Right atrium

A

B

Pulmonary Artery

Ascending aorta

Coronary artery

C Figure 157-1.  Anatomy and orientation of the great arteries. A, Normal orientation with the pulmonary artery crossing in front of the aorta. B, HLHS, a very large pulmonary artery crossing in front of an atretic aorta. C, TGA, aorta in front of the pulmonary artery, both normal size. (Courtesy of Dr. Gil Wernovsky)

cross-sectional analysis of three-dimensional brain volumes from fetal brain MRIs performed prospectively on mothers carrying fetuses with and without CHD. Starting early in the third trimester, it is clear that, in fetuses with CHD, there is a divergence from normal of total brain volume and intracranial volume growth, resulting in the postnatal phenotype of lower brain volume (Fig. 157-4).

POSTNATAL CIRCULATION Heart Surgeries It is convenient to think of cardiac surgery as being the sole risk for brain injury. However recent research suggests that the primary/major risks for injury are the abnormal

anatomy and circulatory patterns in the fetus and newborn. Most surgical repairs and palliative procedures require cardiopulmonary bypass (CPB), whereby the chambers of the heart are isolated from the circulation by inflow (i.e., right atrium) and outflow (i.e., aortic trunk) surgical clamps, and the systemic circulation is diverted to a roller pump equipped with a membrane oxygenator via large, centrally placed cannulae. For the more delicate surgeries involving repair of the aortic arch or the pulmonary veins, a different strategy is required. Here the suturing of the vascular structures must be accomplished in a bloodless, unencumbered field. The patient is cooled to 18°C (64.4°F) to reduce systemic and cerebral oxygen metabolism to zero (Fig. 157-5). The bypass pump is stopped and blood is drained from the body into a reservoir

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68%

68%

53%

53%

60%

IVC UA

DV PV

A

UV Placenta Normal

B

C

d-TGA

AAo

DA 41

Head Upper limbs

16 PBF

57 40

3

MPA RV

29 SVC

HLHS

Lungs LV

FO 27 RA

LA

DAo 52

IVC UV 29

D

Placenta

UA

Abdo Lower limbs

Figure 157-3.  Comparative fetal circulations. A. Normal fetal circulation with oxygenated blood (red color) from the placenta streaming across the foramen ovale into the left-sided heart structures and out to the ascending aorta. Venous deoxygenated blood (blue) returns to the right-side of the heart. B, TGA anatomy with oxygenated blood circulating to the transposed pulmonary artery and on to the ductus arteriosus. Venous blood circulates to the right side of the heart and to the ascending aorta. C, HLCS anatomy with complete blood mixing at the level of the common atrium. All cardiac output is through the pulmonary artery to the ductus with retrograde flow to the transverse arch, neck vessels and the ascending aorta. D, Normal distribution of blood flow measured by phase contrast fetal MRI. (With permission from Prsa, M., Sun, L., van Amerom, J., et al., 2014. Reference ranges of blood flow in the major vessels of the normal human fetal circulation at term by phase-contrast magnetic resonance imaging, Circ Cardiovasc Imaging 7(4), 663–670.)

on the circuit. The cannulae are then removed from the field. Developed in the 1950s, this strategy is called Deep Hypothermic Circulatory Arrest (DHCA) was rapidly adopted in the 1970s. The use of DHCA continues today and is particularly useful for complex adult and pediatric cases involving aortic repairs. The effect of the use of DHCA on cognitive outcomes has been hotly debated, and surgical strategies therefore altered with the stated goal of improving outcomes. There are several surgical strategies that allow for continuous cerebral blood flow throughout the case, and these have been adopted in many centers. These new surgical strategies still require cooling to 18°C, but there is continuation of antegrade cerebral circulation. The trade-off for these modifications is longer surgical and

bypass times. Both piglet and human studies have examined DHCA and continuous flow strategies and suggest that there does not seem to be a demonstrable difference between the two strategies. A randomized controlled trial of DHCA versus continuous antegrade cerebral perfusion was performed in Europe and also failed to show significant differences. A recent retrospective collaborative study examined how BSID scores changed as a result of surgical modifications over the past decades (Gaynor et al., 2015). BSID data collected from 1770 subjects from 1996 to 2009 at 22 international institutions found that, although scores have increased over time, the clinical significance of this change was dubious (0.39 points/ year or less than one-third of a standard deviation over a decade).



Neurologic Disorders in Children with Heart Disease

Perioperative Considerations A detailed discussion of the risks associated with each surgical intervention is beyond the scope of this chapter. Typical surgical risks involving anesthetics, mechanical ventilation, bleeding, and infection are always present. Some of the perisurgical neurologic morbidity is specific to the type of heart defect or postoperative management, and not simply the conduct of the surgery itself. The following discussion is focused on specific risks related to the care of infants and children with critical CHD regardless of diagnosis. The management of other complications such as arterial ischemic stroke, intracranial hemorrhage, and venous thrombosis are discussed in other chapters (Chapters 108–113).

White Matter Injury Neonatal heart surgery refers to surgical procedures performed on infants less than 30 days old. Survival beyond the neonatal period for these infants depends on surgical correction or palliation of their heart defect. For such patients, the mortality from these early surgeries has decreased dramatically since the late 1980s. In the more experienced centers with the highest surgical volumes, survival approaches 90% for the most complex and technically challenging surgeries. With this increase in survival, the focus of care has shifted to long-term neurologic morbidity.

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Infants with severe CHD are prone to hypoxic-ischemic white matter injury (Fig. 157-6) that is not distinguishable from WMI, an injury seen primarily in premature infants. In infants with multiple forms of CHD, this injury is seen in 17% to 40% before surgery and in as high as 80% after surgery (Licht, 2015; Morton et al., 2015). Research has now demonstrated that the primary vulnerability for this injury is the brain-specific IUGR that arises as a consequence of the alterations in fetal hemodynamics created by the CHD, reviewed previously. Recent research supports the notion that not only is the surgery not the cause of WMI, but that delaying the correction/palliation of the native anatomy may increase the risk for postoperative WMI (Lynch et al., 2014). Brain MRI is required to diagnose WMI as the lesions may be missed on CT or cranial ultrasonography. The typical white matter lesion occurs in the white matter watershed zone, is hyperintense on T1 imaging (Fig. 157-6) and may have susceptibility signal on T2* sequences, reflecting hemorrhage or mineralization. If imaging is acquired acutely, the lesions may demonstrate restricted water diffusion. MRI slice thickness is an important consideration when assessing this injury as thick slices or large interslice gaps may obscure lesions. There exist some controversy in nomenclature of these white matter lesions; some researchers view lesions with restricted water mobility on diffusion-weighted imaging as arterial ischemic stroke whereas others consider these lesions part of the spectrum of WMI. An international consortium of neurologists,

A

B

C Figure 157-6.  Three dimensional segmentation. (A) The T1-weighted image before manual PVL segmentation, (B) the manual segmentation, and (C) the volumetric reconstruction colored by quadrant, are shown in the transverse (left), sagittal (middle), and coronal (right) plane. PVL, periventricular leukomalacia. (With permission from McCarthy, A.L., et al., 2015. Scoring system for periventricular leukomalacia in infants with congenital heart disease. Pediatr Res 78(3), 304–309.)

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cardiologists, and radiologists is in the process of establishing a universal nomenclature and standardized imaging protocol for this population. The prevalence of preoperative and postoperative injury is different for individual cardiac diagnoses. Across centers, there appears to be a higher preoperative prevalence seen in TGA and higher rates of postoperative injury seen in HLHS. For patients with TGA, systemic oxygen saturations are lowest before surgery and rapidly normalize after corrective surgery. Proceeding to surgical correction at the earliest time possible should be protective against WMI. Conversely, for patients with HLHS or other single ventricle heart lesions, systemic oxygen saturations are typically in the mid 80% range before surgery and are not significantly higher after initial surgical palliation. In infants with ductal dependent physiology, cerebral oxygen saturations decrease on a daily basis from birth to surgery. This decrease, coupled with increasing oxygen extraction and failure of a compensatory increase in CBF, results in an increasing risk for WMI after surgery.

Arterial Ischemic Stroke Classically, arterial ischemic stroke (AIS) is defined by a focal neurologic deficit that is related to a known arterial territory of the brain (Chapter 109). In children this definition has been expanded to include confirmatory neuroimaging (usually MRI). As infants with AIS are likely to be asymptomatic, the diagnosis is dependent on neuroimaging. The risk for AIS in CHD is not limited to the neonate requiring heart surgery. In fact, the risk for AIS in patients with single-ventricle heart defects increases with time and is reported to be greatest after the final stage of surgical palliation (the Fontan circulation, total cavopulmonary connection). There is sparse literature on subsequent stroke occurrence in infants with severe CHD requiring newborn heart surgery. In a retrospective study, symptomatic stroke was identified in 12 of 122 infants (10%). Seizures were mostly identified after a clinical change or the occurrences of clinically observable seizures. Of these 12 infants, 6 had arterial ischemic stroke and 6 had watershed stroke. This low prevalence rate is congruent with the rate of stroke seen in another study and with the authors’ experience of 2% to 4% preoperatively and 8.6% postoperatively, in mixed populations of infants with severe CHD. With such small numbers, investigation of risk factors is unlikely to be fruitful. Centrally placed catheters, such as umbilical catheters, right atrial catheters, and femoral artery catheters, are potential thrombus sources. Intracardiac and extracardiac shunts allow for paradoxical embolization and stroke. Poor heart function is another important source for intracardiac thrombus formation (discussed later). Older children with single-ventricle heart lesions are highly predisposed to arterial ischemic stroke due to their unique anatomy. Lower extremity vascular access should be avoided if possible in patients with bidirectional Glenn physiology (superior cavopulmonary connection, Stage 2 palliation) as the inferior vena cava remains in direct communication with the systemic circulation. Fenestrations placed surgically at the time of Fontan completion act as a pressure pop-off valve but are obligate right-to-left (venous to arterial) shunts that may also allow for paradoxical emboli. Simple monitoring of systemic oxygen saturations will inform the clinician of the size of the right-to-left shunt. Long-term structural changes in the common atrium, higher central venous pressures resulting in sluggish venous blood flow, and failing ventricle function lead to increased risk for right atrial thrombi (and stroke), chylous effusions, protein losing enteropathies, congested liver, and plastic bronchitis. At the Children’s Hospital of Philadelphia, it is the clinical practice to manage the single-ventricle patients

with prior unprovoked thrombotic events with life-long anticoagulation to prevent recurrence.

Intracranial Hemorrhage Detection of intracranial hemorrhage before surgery is of obvious importance, as the cardiac surgery with cardiopulmonary bypass requires aggressive anticoagulation. At the time of birth, some amount of intracranial hemorrhage has been commonly found. These include subdural hemorrhages along the tentorial membrane and choroid plexus hemorrhages, which may have intraventricular extension. It is important to note that these hemorrhage types do not extend during the conduct of infant heart surgery with cardiopulmonary bypass despite the requirement for systemic anticoagulation. Intraparenchymal hemorrhages found on preoperative head ultrasound or incidentally as part of a research protocol must be managed on a case-by-case basis because there is a paucity of information on the risk of hemorrhagic extension on cardiopulmonary bypass with this finding. At the Children’s Hospital of Philadelphia, if an incidental parenchymal hemorrhage is found, surgical postponement is discussed with the surgeon and intensivist. This frequently results in the postponement of surgery. If the decision is made to postpone surgery, the patient is returned to the intensive care unit and surgery is rescheduled in 1 week with a second preoperative brain MRI. Subdural hemorrhages are the most common clinically significant hemorrhages in the postsurgical patient, and these can occur acutely or subacutely after surgery. Anticoagulation, elevation in central venous pressures, and brain atrophy (from other injury) are all putative contributors to increased risk. Subdural hemorrhages requiring surgical intervention are uncommon in the cardiac ICU population. Punctate microhemorrhages seen on brain MRI (Fig. 157-7) after heart surgery with cardiopulmonary bypass or after catheter-based interventional procedures are of unclear clinical significance. These microhemorrhages are unlikely to be hemorrhages at all and may be the result of micro thromboembolic material from bypass cannulation. The lesions are common, occurring in 30% to 50% of postsurgical patients. There is a single report that these lesions may contribute to the neurodevelopmental impairment that is seen in survivors of infant heart surgery.

Cerebral Sinovenous Thrombosis Cerebral sinovenous thrombosis has been described in the CHD population, particularly in children or infants with dehydration and/or protein loss through pleural effusions or protein losing enteropathy. Management is described in Chapter 110 and includes hydration, elevation of the head of the bed when possible to promote venous drainage, and systemic anticoagulation.

Seizures Seizures after infant heart surgery were identified as one of the significant predictors of a poor neurocognitive outcome in The Boston Circulatory Arrest Trial (BCAT). In that trial, electroencephalography (EEG) monitoring was performed on paper tracings, which were then read retrospectively. As a result, clinically silent seizures (electrographic only) were not treated. As a consequence of the findings in the BCAT, many centers have started to perform EEG monitoring (full montage or amplitude integrated EEG) after infant surgery. Seizure prevalence is quite variable after infant surgery and ranges from 5% to 26% of infants. The majority of seizures are electrographic



only (as was seen in the BCAT), and status epilepticus occurs in the majority of seizures detected by EEG monitoring (85% to 100% of patients with seizures detected). Most seizures that occur after infant heart surgery are acute symptomatic seizures, and neuroimaging commonly shows WMI or AIS. Recent results from one study showed that longer duration of DHCA and/or returning to the cardiac ICU with an open chest were the most predictive risk factors for postoperative seizures after infant heart surgery.

Neurologic Sequelae of Heart Failure Heart failure is the syndrome that results from the inability of the heart to meet the body’s metabolic demands. Heart failure may be primary or secondary—that is, due to congenital or acquired cardiomyopathy or due to high flow states as seen in large hemangiomas, arterial-venous malformations (AVM), or severe anemia, among other causes. During heart failure, a child is at increased risk of neurologic injury: low cardiac output decreases cerebral perfusion, sudden arrests can lead to watershed infarction, hypoxic-ischemic brain damage, and secondary seizures or encephalopathy. Furthermore, decreased ventricular systolic function can result in stasis of blood in the heart chamber and increase the child’s risk of cardioembolic events including AIS. The degree of thrombotic risk associated with severe ventricular dysfunction is poorly defined in children. There are no guidelines to recommend the use of anticoagulation versus antiplatelet therapy. Current American College of Cardiology/ American Heart Association adult heart failure guidelines (Monagle et al., 2008) suggest anticoagulating adults with heart failure and no history of atrial fibrillation or prior thromboembolic events (class IIb recommendation with level of evidence B). In children, recent guidelines suggest that anticoagulation should be considered in children with cardiomyopathy awaiting heart transplantation. Neither guideline specifies a threshold level of ventricular dysfunction where antiplatelet or anticoagulant agents would be strongly recommended. Further investigation is needed to help define the risk-to-benefit ratio of these therapies in various heart failure scenarios. At the Children’s Hospital of Philadelphia, it is the clinical practice to use anticoagulation when the cardiac ejection fraction falls lower than 30%, unless there are contraindications such as a large AIS (i.e., greater than one-third of a specific vascular territory) or hemorrhage.

Mechanical Circulatory Support Devices Children with severe heart failure may require support devices to maintain cardiopulmonary circulation. These support devices often require maintenance on anticoagulation, antiplatelet agents, or both. Complications from the underlying cardiac failure, the device itself, or the medications used to maintain the device may arise, most commonly stroke.

Extracorporeal Membrane Oxygenation (ECMO) ECMO has been the most commonly used form of mechanical cardiopulmonary support and is a form of heart-lung bypass. There are two types of ECMO: veno-arterial ECMO supports both oxygenation and circulation and veno-venous ECMO supports oxygenation alone. For veno-arterial ECMO, a vascular cannula is placed into an artery (usually the right carotid artery, but it can also be the femoral artery) and a large vein. Systemic venous return is shunted into the pump and the blood is passed through an oxygenator that then returns the oxygenated blood to the arterial cannula in the patient. It is important to know that the carotid cannula is pointed down,

Neurologic Disorders in Children with Heart Disease

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toward the aortic arch, so that blood flows away from the brain on the right side. An intact circle of Willis allows for collateralization of blood flow. Survival of “cardiac” ECMO is improving and is listed as 66% (https://www.elso.org/Registry/ Statistics.aspx) by the Extracorporeal Life Support Organization (ELSO), with 51% surviving to discharge or transfer (inferring heart transplant or other destination therapy). Neurologic complications can arise from ischemia due to carotid cannulation, hypoxic-ischemic damage, embolic arterial ischemic stroke, or intracranial hemorrhage. Sequelae including seizures and encephalopathy can arise in any of these settings. There are many other types of ventricular assist devices (VAD) that support circulation only (without a membrane oxygenator). The FDA recently approved the Berlin Heart EXCOR Pediatric VAD under the Humanitarian Device Exemption Program. They can be used to assist the left ventricle only (systemic flow), right ventricle only (pulmonary flow), or both ventricles. Most cases involve direct cannulation of the ventricle for flow to the pump and aortic cannulation for systemic outflow. VADs are more compact than ECMO, thus providing a longer-term option for mechanical circulatory support so that the patient can be an active participant in rehabilitation. In pediatric centers, VADs are currently used almost exclusively as a bridge to cardiac transplantation, although newer impeller devices are beginning to be considered as “destination therapy” for special populations such as Duchene muscular dystrophy and other nontransplantable cardiomyopathies and in patients in whom heart transplant is not an option due to anatomic considerations. Similar to ECMO, children supported by VADs are at significant risk of neurologic complications including AIS and intracerebral hemorrhage. The prevalence of neurologic complications varies by case series. In one study, children with short-term VAD devices were significantly more likely to suffer a stroke than those with long-term VAD devices (35% versus 13%, p = 0.02). In another series, children with left atrial cannulation were more likely to develop embolic arterial ischemic stroke than were those with left systemic apical cannulation. There are relatively few studies of neurologic complications in children supported with ECMO versus VAD; one nonrandomized study reported a higher rate of neurologic complications with ECMO than for VAD. However, in a different study that compared an institutional experience between ECMO and the Berlin EXCOR device, the incidence of stroke was not significantly different between the two devices. A child placed on ECMO who is suspected of needing more long-term support is generally transitioned to a more mobile VAD device.

NEUROLOGIC MANAGEMENT SPECIFIC   TO CARDIAC CARE The intensivist must choose medications and management with the child’s underlying cardiac status in mind when managing neurologic complications of cardiac disease. For example, a child with acute arterial ischemic stroke or cerebral sinovenous thrombosis is often placed on isotonic fluids at 1 to 1.5 times the maintenance rate for age and weight. In the child with heart failure, the fluid rate may require modification in order to avoid iatrogenic worsening of heart failure. In the management of seizures with or without status epilepticus, anticonvulsant choices should take into account the child’s cardiac status. Although phenobarbital is often the medication of choice for infants and phenytoin or fosphenytoin the choice for older children, these medications can cause hypotension. Furthermore, phenytoin is a class 1B sodium channel blocker

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with both arrhythmogenic and antiarrhythmic properties. There are little data to guide anticonvulsant choice. Indwelling vascular catheters are a likely source for most clots in patients cared for in the cardiac intensive care unit. For these patients, if ultrasound confirms the presence of a clot, a complete thrombophilia work up and consideration for anticoagulation is recommended in those patients with an arterial ischemic stroke (Chapter 109). An echocardiogram is helpful to evaluate for a residual intracardiac clot or fibrin stranding, as can be seen after removal of a right atrial catheter. Rarely is a transesophageal approach required for this assessment, as a transthoracic approach can usually provide adequate images in the pediatric population. For patients with significant residual right to left shunting (assessed by knowing the pulse-oxygen saturations in a patient without pulmonary disease), Doppler flow ultrasonography of the lower extremity venous system is also indicated.

SHORT AND LONG-TERM OUTCOMES Postoperative Neurologic Findings With improved surgical techniques and perioperative care, the prevalence of immediate postoperative complications has significantly decreased over the last decades. In the 1980s, the prevalence of perioperative neurologic abnormalities, mostly consisting of postoperative seizures, was as high as 25%. The significance of postoperative seizures as a risk factor for adverse long-term outcome has been documented already in the 1990s. Importantly, the prevalence of perioperative neurologic symptoms has dropped to around 2%, again mostly consisting of a decline in clinical seizures. However, despite this reduction, neurologic complications, often moderate to mild in severity, are still common when looking at early neurodevelopmental outcome. The reported overall rate of neurologic complications developing in the postoperative period is quite broad, ranging from 2.3% to over 50%. This heterogeneity may be explained by different patient characteristics in the studies, including all different types of CHD or only severe ones, by the definitions of neurologic impairments, and by the variability across centers in surveillance. To address this, Bird and colleagues proposed a consensus list and definitions to help standardize terminology across centers (Bird et al., 2008). Preoperative abnormalities can persist after surgical repair or accentuate. Newly occurring neurologic abnormalities have also been described and manifest by changes of muscle tone, reflexes, or power or by movement abnormalities such as choreoathetosis. Seizures are important neurologic symptoms that may occur preoperatively, but more frequently occur postoperatively. Postoperative seizures may have a significant influence on mortality and morbidity. The Boston Circulatory Arrest Trial demonstrated a negative effect of postoperative seizures on neurodevelopmental outcome in newborns with TGA. This has also been shown for children with a large variety of CHD diagnoses. Recently a study confirmed that postoperative seizures on amplitude integrated EEG (aEEG) predicted motor, but not cognitive, outcome at 2 years of age. Cerebral MRI cannot always be performed during the immediate postoperative period. Thus studies have examined the use of functional bedside tools such as aEEG and NIRS to assess brain injury. Furthermore, the bedside clinical diagnosis of neurologic dysfunction may be complicated by their subtle manifestations, and further impaired by the use of sedating medications. These confounding factors can delay the accurate diagnosis of perioperative brain dysfunction. The aEEG is increasingly used as a routine monitoring, but its prognostic value for abnormal outcome remains unclear. One study

demonstrated a relationship between delayed recoveries of the background pattern on postoperative aEEGs and motor outcome. When summarizing clinical outcome predictions for early childhood and school-age outcome, the strongest predictors are postoperative neurologic abnormalities, including seizures, as well as lower preoperative and postoperative head circumference.

Short-Term Outcome Recent reviews summarized neurodevelopmental outcomes in children with CHD, showing a consistent pattern of global developmental impairment, characterized by motor and cognitive delay in the first 2 to 3 years with motor delay and neuromotor abnormalities being more affected than cognitive and language functions (Marino et al., 2012; Snookes et al., 2010). Of note, children with genetic disorders are at particular risk for poorer neurodevelopmental outcome (Table 157-2). In a recent large multicenter retrospective analysis, neurodevelopmental outcome of 1700 children from 22 institutions who had undergone cardiac surgery using cardiopulmonary bypass at ages less than 9 months showed significant neurodevelopmental impairments (Gaynor et al., 2015). At a mean age of 14.5 months, the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development II (BSID II) were lower (PDI: 77.6±18.8; MDI: 88.2±16.7) than normative means. In that study, time trends over two decades were analyzed. The rate of survivors with more complex CHD and genetic/extracardiac abnormalities increased over time. Despite this, a modest improvement of motor and cognitive function was observed after correction for a variety of cofactors. However, this improvement is not substantial and is counterbalanced by the high rate of children with complex CHD and genetic comorbidities. Another study reported on children with various types of CHD who were assessed every 6 months until the age of 36 months. Of this group, 75% had scores in the “at risk” or “delayed” range in more than one domain at more than one assessment. Nineteen percent of children who had cognitive, language, and motor scores in the average range at 1 year of age were later found to be at risk or delayed in more than 1 area. In this study, parents reported that 74% of the children had received or were actively receiving early intervention services from the state-based “Birth to 3” programs or private therapy. Importantly, although motor delay improved in children without genetic syndrome, cognitive and language delay became more evident in nonsyndromal children. In addition, in children with syndromal disorders, developmental scores decline over time, and developmental delay become more apparent. The ability to successfully achieve oral feeding was an important clinical predictor for a favorable developmental course, indicating neuronal integrity. An increase of developmental delay within early childhood has also been shown in another study in which children were followed between 8 and 24 months. The most pronounced increase in the odds to have impairments was found in the problemsolving and in the personal-social dimension.

Long-Term Outcome School-age children with CHD may exhibit a wide range of long-term developmental impairments (Latal, 2016; Marino et al., 2012) (Table 157-7). They affect all areas of development, are most frequently mild to moderate in severity. Though they often occur in combination and can lead to significant school problems and academic difficulties. Mean IQ scores are in the low-average range, and motor difficulties



Neurologic Disorders in Children with Heart Disease TABLE 157-7  Potential Long-Term Neurocognitive and Behavioral Problems in Children and Adolescents With CHD Developmental Domain

Impairment

Neurology

Cerebral palsy (rare, only if significant perioperative insult has occurred) Microcephaly Mild muscular hypotonia

Motor function and visuomotor function

Fine and gross motor coordination disorder Visuoperceptual and visuomotor problems

Cognition/intellectual function

Reduced overall IQ Working memory Processing speed Poorer academic achievement

Higher order intellectual function

Higher order language functions Executive functions

Behavior

Attention-deficit disorder Emotional disorders Social interaction problems

in gross and fine motor domains occur in around 20% to 40% of the children tested. Children with motor difficulties at school age will have a higher need of therapeutic support. Language problems may manifest themselves as impaired reading abilities. The Boston Circulatory Arrest Trial, one of the largest and most comprehensive studies of long-term neurodevleopmental outcomes, showed that at age 4 and 8 years after surgery, neurodevelopmental outcomes were independent of surgical strategy (ie DHCA). In addition, hearing problems and abnormalities on neurologic examination were more frequent than in the group that did not receive DHCA. This pattern of impairment seems to persist without much “outgrowth” occurring. When these children were reexamined at adolescent age, performance scores were lower in both treatments with a significant proportion of adolescents performing lower than average, who were in need of academic or behavioral services. The pattern of mild to moderate impairments in a variety of developmental domains has been shown also in other CHD populations with varying diagnoses, persisting into adolescence. These findings consolidate the impression that regardless of type of CHD, there seems to be an increased risk for long-lasting neurodevelopmental impairments in this population.

Adolescent and Adult Outcome The number of studies examining adolescent and adult outcome is small but growing. There is consistent evidence that with increasing academic challenges, children with CHD may be faced with more difficulties. One of the first studies examining long-term outcome demonstrated a persistence of lower IQ at 13 years of age in a small group of children with TGA. More studies followed and confirmed this finding in larger populations of children with TGA, TOF, after Fontan procedure or with mixed cardiac diagnoses. Overall IQ and other developmental domains such as executive functions and visuospatial, and motor performance remained affected (Calderon and Bellinger, 2015; Marino et al., 2012). These difficulties went along with an increased need for remedial academic or behavioral services. Of note, one study demonstrated flexibility and problem-solving executive skills to be impaired in all CHD patients in a large sample of patients aged 10 to 19 years, whereas visuospatially mediated executive

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abilities were preserved in adolescents with TGA. Overall, adolescents seem to score worse on academic achievement tests, to need more supportive help, and to have a lower chance of completing mandatory schooling. The transition into adulthood is an important phase and CHD survivors may be particularly vulnerable. There are very few studies examining this period. A recent study demonstrated that Swiss adolescents with a variety of CHD diagnosis had similar school educations and that patients were satisfied with their educational career. Only those patients with severe CHD were more likely to attend lower level education. One explanation for this favorable outcome may be the good educational support system allowing for a relatively easy transition into adulthood. Overall, the trend of poorer academic achievement described for adolescents with CHD seems to persist into adulthood, resulting in a higher rate of early unemployment and a lower rate of full-time employment. Patients with complex CHD seem to be at particular risk.

SUMMARY As mortality rates for children and adolescents with CHD have decreased significantly, the focus has shifted toward potential acute and chronic neurologic and developmental sequelae. Infants with CHD requiring cardiac surgery may show a combination of delayed intrauterine cerebral maturation and acute preoperative and postoperative brain injuries, associated with clinical neurologic symptoms such as seizures and abnormalities on neurologic examination. The mechanisms are complex and most likely multifactorial, consisting of altered fetal hemodynamics and cerebral perfusion, leading to a delay in brain maturation that in turn seems to be a risk factors for neonatal WMI. Children may present with mild neurologic abnormalities in early childhood (typically muscular hypotonia) and may continue to show motor deficits (balance and fine motor problems). In addition children with CHD may have cognitive impairments and attention problems, as well as deficits in working memory and higher language functions, which in turn influence school performance and academic achievement. Studies in this area of the longterm outcome up to adolescence and young adulthood are needed to shed light onto the full spectrum of potential problems, as well as their effect on personal well-being, on quality of life, and on societal financial burdens. Also, parents and caregivers need to be informed about the potential shortterm and long-term neurodevelopmental and behavioral problems their children may face, and interdisciplinary follow-up clinics need to be established to detect developmental problems early in order to provide timely therapeutic interventions and parental guidance. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bird, G.L., Jeffries, H.E., Licht, D.J., et al., 2008. Neurological complications associated with the treatment of patients with congenital cardiac disease: consensus definitions from the Multi-Societal Database Committee for Pediatric and Congenital Heart Disease. Cardiol. Young 18 (Suppl. 2), 234–239. Calderon, J., Bellinger, D.C., 2015. Executive function deficits in congenital heart disease: why is intervention important? Cardiol. Young 25, 1238–1246. Gaynor, J.W., Stopp, C., Wypij, D., et al., 2015. Neurodevelopmental outcomes after cardiac surgery in infancy. Pediatrics 135, 816–825.

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Latal, B., 2016. Neurodevelopmental outcomes of the child with congenital heart disease. Clin. Perinatol. 43 (1), 173–185. Licht, D.J., 2015. The path forward is to look backward in time—fetal physiology: the new frontier in managing infants with congenital heart defects. Circulation 131 (15), 1307–1309. Lynch, J.M., et al., 2014. Time to surgery and preoperative cerebral hemodynamics predict postoperative white matter injury in neonates with hypoplastic left heart syndrome. J. Thorac. Cardiovasc. Surg. 148 (5), 2181–2188. Marino, B.S., Lipkin, P.H., Newburger, J.W., et al., 2012. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation 126, 1143–1172. Monagle, P., Chalmers, E., Chan, A., et al., 2008. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133, 887S–968S. Morton, P.D., Ishibashi, N., Jonas, R.A., et al., 2015. Congenital cardiac anomalies and white matter injury. Trends Neurosci. 38, 353–363. Pierpont, M.E., Basson, C.T., Benson, D.W. Jr., et al., 2007. Genetic basis for congenital heart defects: current knowledge: a scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115, 3015–3038. Snookes, S.H., Gunn, J.K., Eldridge, B.J., et al., 2010. A systematic review of motor and cognitive outcomes after early surgery for congenital heart disease. Pediatrics 125, e818–e827.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 157-2 Total Maturation Score (TMS) in full-term infants with CHD. Fig. 157-4 Differences in brain volumes in fetuses with and without CHD. Fig. 157-5 The temperature dependency of cerebral metabolic rate. Fig. 157-7 Microhemorrhages. Fig. 157-8 Complications of infectious endocarditis. Table 157-3 Neurologic Conditions Associated with Acquired Heart Disease Table 157-4 Clinical Neurologic Scoring Assessment for Infant Examination Table 157-5 Preoperative Neurobehavioral Abnormalities Table 157-6 Suggested Ages and Tests to Assess Neurodevelopmental Outcome in CHD Patients

158  Neurologic Disorders Associated With Renal Diseases Cheryl P. Sanchez, Rita D. Sheth, Robert S. Rust, Jessica L. Carpenter, and Stephen Ashwal

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Advances in the treatment of children with kidney disease with new antihypertensive medications, dialysis, transplantation, and immunosuppressive agents have resulted in improved long-term survival and quality of life. Still, children present acutely with neurologic symptoms, and they may develop long-term neurologic disorders because of currently available treatments. This chapter reviews various aspects of the complex interrelationships between the kidneys and the brain. Four areas are discussed: (1) renal diseases that secondarily affect the nervous system, (2) diseases that affect both the kidneys and the nervous system, (3) neurologic drugs that may affect renal function in individuals with normal kidneys, and (4) drug therapy in renal disease.

RENAL DISEASES SECONDARILY AFFECTING THE NERVOUS SYSTEM Acute Kidney Injury Acute kidney injury (AKI) is a common problem occurring in as many as 10% to 25% of all hospital admissions in the United States, and approximately 25% to 50% of these admissions may require critical care management. Neurologic decompensation occurs as a result of the following: (1) disturbances in water homeostasis, electrolyte abnormalities, and acid–base metabolism; (2) impairment in the blood–brain barrier (BBB); (3) changes in neurotransmitter activity; and (4) derangements in drug metabolism.

Sodium and Water Disorders Neurologic abnormalities associated with water intoxication may arise in AKI. The kidney’s capacity to excrete water as dilute urine is the chief mechanism for prevention of water intoxication. In AKI, this mechanism is impaired, and neurologic dysfunction can develo p within hours to days. Individuals with sodium values as low as 120 to 125 mEq/L can remain asymptomatic. Neurologic symptoms become more prevalent once the serum sodium is less than 120 mEq/L. Signs and symptoms of water intoxication are variable and include mental status changes (e.g., apathy, agitation, or confusion to obtundation), headache, nystagmus, vomiting, diaphoresis, weakness, generalized tremulousness, and seizures. Children are at high risk for the development of brain edema from hyponatremia. Systemic aspects of water intoxication include cardiovascular compromise and pulmonary edema. These complications further jeopardize brain function. Hyponatremia may result in seizures, increasing cerebral energy demand and the rate at which toxic by-products of metabolism accumulate. Brain edema may increase intracranial pressure, further impairing cerebral circulation. Medical conditions that can lead to sodium disorders should be addressed (Table 158-1). Hyponatremia can also be seen with acute neurologic disorders. Low serum sodium can result from excess renal sodium losses, as in cerebral salt wasting (CSW), or free-water retention, as in the syndrome of inappropriate antidiuretic hormone

(SIADH). CSW is characterized by a negative fluid balance, whereas SIADH is associated with a state of euvolemia or positive fluid balance. Distinguishing between these disorders is critical for management. Treatment of CSW is with sodium replacement and fluids and/or mineralocorticoids, whereas SIADH is treated with fluid restriction. A high index of suspicion for these disorders should exist for patients with acute brain dysfunction and down-trending or low serum sodium levels to minimize complications. Correction of serum sodium should be done slowly to prevent complications associated with rapid osmolar shifts. Maintenance of circulation may require acute administration of fluid, in which case isotonic sodium is permissible. Volume expansion with hypotonic saline in a hyponatremic patient poses risks if the patient is actually in a sodium-depleted state. The decision to restrict fluids is appropriate if there is evidence of SIADH. Hypertonic saline should be administered in any symptomatic hyponatremic patient. Dialysis is often not necessary unless the patient is anuric or oliguric and fluid overload is the major cause of the sodium abnormality. The rate of sodium correction is crucial. Excessively rapid correction poses the danger of central pontine myelinolysis. In children, correction at approximately 0.5 to 1 mEq/L/hour should be implemented, until the patient becomes alert and seizure-free, plasma sodium becomes 125 to 130 mEq/L, or the serum sodium level increases by 10 to 15 mEq/L, whichever occurs first. If seizures persist, or if there are signs of increased intracranial pressure (especially if these signs are worsening), the sodium concentration may be corrected at a rate of 4 to 8 mEq/L for 1 hour (if tolerated) or until seizures stop. Assuming that total body water comprises 50% of body mass, administration of 1 ml/kg of 3% NaCl solution will increase plasma sodium by approximately 1 mEq/L.

Potassium Abnormalities During the first 48 hours of anuric AKI there is loss of as much as 70% to 80% of renal outer medullary potassium secretory channels and 35% to 40% of the activity of potassium channel inducing factor. Cardiac and pulmonary manifestations of hyperkalemia generally precede and are greater threats to survival than neurologic ones. Cardiac dysfunction is usually the earliest and most ominous sign. However, there are rare instances of hyperkalemia that present with neurologic signs such as striated muscle paralysis. Other important causes of acute hyperkalemia include rhabdomyolysis and succinylcholine administration to susceptible individuals in the setting of acute muscle damage. Catecholamine elevation in the setting of hypothermia may produce hyperkalemia. A list of causes of potassium disorders is given in Table 158-2.

Calcium and Magnesium Abnormalities Neurologic symptoms associated with calcium and magnesium disorders vary and depend on the rate with which these levels change. Typical symptoms of hypocalcemia in­­ clude mental status changes, muscle irritability, and seizures.

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TABLE 158-1  Causes of Hyponatremia and Hypernatremia

TABLE 158-2  Causes of Hypokalemia and Hyperkalemia

Mechanism

Mechanism

Source

CAUSES OF HYPONATREMIA Excessive NaCl Gastrointestinal loss tract Skin Urinary tract Excessive water intake

Oral Parenteral Rectal

Defective water excretion

Inappropriate antidiuretic hormone secretion

CAUSES OF HYPERNATREMIA Excess sodium intake

Water deficit

Water deficit in excess of sodium deficit

Causative Factor/Disorder Diarrhea Cystic fibrosis Heat stress Salt-losing renal disease Adrenal insufficiency Diabetes mellitus Psychogenic Acute kidney injury Therapeutic error Coma Tap water enema Improperly mixed formula Anesthetic drugs Craniocerebral trauma Infection Malignancy Improperly mixed formula or rehydration solution Excessive sodium bicarbonate or chloride administration during resuscitation Saltwater drowning Diabetes insipidus Diabetes mellitus Excessive sweating Increased water loss Adipsia Inadequate water intake Diarrhea Osmotic diuretics Obstructive uropathy Renal dysplasia

Hypercalcemia can present with lethargy, weakness, and confusion. Box 158-1 lists some of the common causes of hypocalcemia, hypomagnesemia, and hypermagnesemia. The interactions between calcium and magnesium are complex, and each must be considered in situations where the other is present. Hypomagnesemia is a serious condition. Acute deficiency of magnesium is the cause of cramps and tetany. In critically ill patients, development of hypomagnesemia is associated with a twofold to threefold increased risk of death. Hypomagnesemia may be found in as many as 47% of patients with hypokalemia, 27% of individuals with hyponatremia, and 22% of those with hypocalcemia. Hypermagnesemia may cause neurologic manifestations in AKI, although it is uncommon because normal renal magnesium regulation is efficient.

Chronic Kidney Disease Current estimates of the incidence of end-stage renal disease (ESRD) in children is approximately 16 per million in the United States.

Uremic Encephalopathy The syndrome of uremic encephalopathy is a spectrum of brain abnormalities resulting from the failure of the kidney to do the following: 1. Regulate fluids and electrolytes 2. Excrete protein catabolites and toxic substances 3. Balance endocrine secretion (Seifter and Samuels, 2011)

HYPOKALEMIA Deficient intake Renal loss Renal disease

Extrarenal disease

Shift (extracellular to intracellular) Extrarenal loss

HYPERKALEMIA Excessive intake

Causative Factor/Disorder Protein-calorie malnutrition Parenteral nutrition Distal tubular acidosis Proximal tubular acidosis (Fanconi’s syndrome) Bartter’s syndrome Interstitial nephritis Diabetes mellitus Cushing’s syndrome Aldosteronism Drug administration (diuretic, aspirin, steroids) Hypomagnesemia Hypercalcemia Alkalosis Drugs (insulin, catecholamines) Parenteral nutrition Vomiting, diarrhea Fistula drainage Laxative abuse Ion-exchange resins Congenital alkalosis Increase urine output Potassium-containing salt substitutes Parenteral administration (excessive infusion, outdated blood) Gastrointestinal bleeding

DECREASED RENAL EXCRETION Renal disease Oliguric kidney injury Chronic hydronephrosis Potassium-sparing diuretics Extrarenal causes Addison’s disease Congenital adrenal hyperplasia Diabetes mellitus Drugs (beta blockers, heparin) Shift (intracellular to Rapid cell breakdown (trauma, infection, extracellular) cytotoxic agents) Acidosis Freshwater drowning

In developed countries, severe uremia is rare because of the availability of dialysis or renal replacement therapy. Clinical symptoms usually do not occur until the estimated glomerular filtration rate (GFR) is less than 10% of normal. High levels of uremic toxins, advanced glycation end products, inflammatory mediators, excess of parathyroid hormone, and acid–base imbalance may contribute to the development of uremic encephalopathy. Brain edema is uncommon in uremic encephalopathy. Disturbances of endocrine function occur in uremia, with elevations of parathyroid hormone (PTH), insulin, growth hormone, glucagons, thyrotropin, prolactin, luteinizing hor­ mone, or gastrin. Secondary hyperparathyroidism may contribute to the development of uremic encephalopathy because elevated PTH levels have been clearly linked to the reduction of mental capacity. Clinical Features of Uremia.  Clinical symptoms include seizures, encephalopathy, poor feeding, lethargy, tremulousness, and gastrointestinal autonomic dysregulation. Twitching, muscular weakness or tetany, apnea, and paresthesias also may occur. Altered mental status, tremulousness, and muscle cramping tend to occur. Uremic encephalopathy remains a complicated condi­ tion, the pathophysiology of which is likely multifactorial.



Neurologic Disorders Associated With Renal Diseases

BOX 158-1  Causes of Calcium and Magnesium Abnormalities HYPOCALCEMIA • Vitamin D deficiency • Hypoparathyroidism • Pseudohypoparathyroidism • Hyperphosphatemia • Magnesium deficiency • Acute pancreatitis • Alkalosis • Rapid correction of acidosis HYPERCALCEMIA • Vitamin D excess • Hyperparathyroidism • Malignancy • Medications • Infections • Sarcoidosis HYPOMAGNESEMIA • Malabsorption • Hypoparathyroidism • Renal tubular acidosis • Diuretic therapy • Primary aldosteronism • Neonatal tetany HYPERMAGNESEMIA • Decreased renal function • Magnesium-containing laxatives or enema preparations • Maternal magnesium sulfate treatment

Encephalopathy is more common in children than in adults with uremia and may present with subtle psychiatric manifestations such as moodiness or depression. Hypocalcemic tetany and a peculiar movement disorder termed “uremic twitching” occur more commonly in children. Neurologic manifestations to which hypermagnesemia might contribute include lethargy, depression, paresthesias, muscle weakness, and neuropathic changes in cardiac conduction, autonomic cardiovascular regulatory abnormalities, and autonomic aspects of gastrointestinal function. Conditions that might worsen uremic hypermagnesemia are hypothyroidism, Addison’s disease, familial hypercalciuric hypercalcemia, and milk alkali syndrome. As with other electrolyte disturbances, clinically significant hypomagnesemia is found more commonly in infants and elderly individuals, usually in association with chronic kidney disease. Pathophysiology of Uremia.  See online version of the chapter. Diagnostic Considerations in Patients With Uremia.  Most cases of chronic uremia are seen in those on dialysis for ESRD. In patients with new-onset renal failure and uremia, there is a wide differential diagnosis to consider for possible causes of neurologic deterioration. Acute uremic encephalopathy produces deterioration of higher cortical function that varies from slowly progressive to fulminant. The earliest changes include inattention, irritability, and diminished intellectual agility and are often more apparent to caregivers than to the patient. Cognitive deficits may worsen as a consequence of the duration of hemodialysis. Tremor and asterixis are reliable early signs of uremic encephalopathy and should prompt careful mental status

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evaluation. With progressive obtundation, encephalopathy becomes less intermittent, and severe disturbances of orientation, memory, cognition, judgment, and primitive reflexes (e.g., snout, root, grasp) may emerge. Transient loss of hearing or vision may develop. Seizures occurring in the later stages of acute uremia generally signify the development of other complications. Muscle twitching or fasciculations, especially in the distal extremities, are common in acute renal failure. Such activity may be preceded by muscle aches or cramping. Restlessleg phenomenon is not uncommon in uremic encephalopathy. Tetany may develop and may not respond to calcium supplementation. Moderate to severe motor weakness may follow. Multifocal stimulus-sensitive myoclonus emerges as uremic stupor develops. In patients with chronic kidney disease, acute weakness must be distinguished from preexisting changes related to neuropathy or hyperparathyroidism. Endocrinopathies and vitamin deficiency states should be considered because most are treatable. Cardiovascular autonomic dysregulation in uremia is a cause of considerable morbidity and increases mortality risk. Some abnormalities (e.g., emotional and intellectual) may respond quickly to dialysis, whereas others (e.g., motor and sensory) respond more slowly. Brain imaging is often normal. When present, abnormalities may be transient and of uncertain significance. Elevated lumbar cerebrospinal fluid (CSF) pressure may be found and usually resolves with dialysis. CSF protein concentration may be elevated, and pleocytosis may be found. These changes may occur without identification of any treatable process and may be a result of uremic alteration of BBB function. Management of Uremic Encephalopathy.  The primary treatment of uremic encephalopathy is dialysis. Seizures should suggest reevaluation for hypertension, electrolyte or water imbalance, infection, or intoxication (commonly, penicillin or a phenothiazine). Persistent seizures should be treated with antiseizure drugs.

Congenital Uremic Encephalopathy Most infants with congenital uremic encephalopathy have inherited forms of nephrosis, particularly congenital nephrosis of the Finnish type. It is possible that some of the neurologic abnormalities in these infants are independently inherited developmental abnormalities or a result of the prenatal metabolic effects of nephrosis. The appearance of abnormalities may present after a latent interval. Early provision of dialysis has not been shown to prevent development of congenital uremic encephalopathy. Infants with seizures and developmental arrest in the first year of life are at a high risk for developing epilepsy and moderate to severe motor, cognitive, language, and psychosocial delay in later childhood. Neurologic abnormalities include ataxia, choreoathetosis, facial myoclonus, hypotonicity, weakness, and hyperreflexia. If language develops, it is often compromised by dysarthria and lingual apraxia. Renal transplantation may reverse progression of uremic encephalopathy.

Stroke and Vasculopathy Vascular accidents may cause acquired neurologic injuries in children with congenital nephrotic syndrome. Ischemic lesions appear to correlate with a history of pretransplantation hemodynamic crises and with greater duration of dialysis before renal transplantation. Attention devoted to ensuring hemodynamic stability in infants undergoing dialysis for chronic renal failure and early consideration of transplantation may improve

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outcome. There may be a beneficial effect of folate, pyridoxine, and cobalamin supplements for the prevention of stroke in individuals undergoing peritoneal dialysis.

Dialysis-Associated Complications Dialysis is efficacious in the remediation or prevention of acute uremic encephalopathy and is also beneficial in the treatment of uremic peripheral neuropathy. Dialysis is associated with many potential complications. Problems related to the preparation of dialysis fluids are now seldom encountered. When they occur, they tend to manifest as seizures or decline in mental status. Dialysis side effects include headache, fatigue, allergic reactions, and hypotension. Mild to moderate headache is not uncommonly reported by older children. It is likely that dialysis headache is prompted by water and electrolyte shifts or by other aspects of dialysis disequilibrium. Risk can be reduced by adjustment of dialysis parameters. Patients with higher predialysis systolic and diastolic blood pressure may be at greater risk for headache, in addition to those who experience dialysis-related hypotension or weight loss. Metabolic abnormalities should be excluded. Headaches tend to occur after 3 to 4 hours of dialysis and often respond to acetaminophen. Hypertension or subdural hemorrhage should be considered when headache is more severe or persistent, particularly if mental status changes or new focal neurologic signs are present.

Dialysis Disequilibrium Syndrome Dialysis disequilibrium syndrome is a rare but serious complication mostly associated with aggressive hemodialysis. Manifestations include irritability, fatigue, headache, nausea, blurred vision, muscle cramps, and tremulousness. Hypertension, elevated intraocular pressure, and asterixis are sometimes seen. The syndrome is likely to occur with recently initiated dialysis, utilization of a rapid dialysis protocol, or dialysis with ultrafiltration, especially when initial serum osmolality is high. The term osmotic demyelination has been applied to some patients who experience neurologic deterioration after dialysis and are found to have pontine abnormalities on T2-weighted magnetic resonance imaging (MRI). These changes may be found with dialysis-associated seizures or mild alterations of consciousness. Repeat scans usually demonstrate the rapid and complete disappearance of these changes. Dialysis removes osmotically active molecules from blood more rapidly than they can diffuse out of the brain. This movement results in an osmotic gradient that provokes net flow of water into the brain, resulting in cerebral edema, increased intracranial pressure, and encephalopathy. Modifications in dialysis protocols have reduced the frequency of dialysis disequilibrium. The most important element in preventing dialysis disequilibrium is early diagnosis of uremia and initiation of dialysis, so that profound azotemia (blood urea nitrogen ≧ 200 mg/dl) is not encountered.

Dialysis-Associated Seizures Dialysis-associated seizures occur in 7% to 10% of children (newborn to 21 years) with ESRD. Most are generalized tonicclonic seizures that occur during or shortly after dialysis. Risk factors include previous seizures, young age, malignant hypertension, uremic encephalopathy, dialysis disequilibrium, and congenital uremic encephalopathy. Seizures occur during the early phases of dialysis. Hemodialysis poses a greater risk for seizures than peritoneal dialysis because of more rapid clearance of electrolytes and other osmotically active solutes.

The efficacy of antiseizure drugs in treating or preventing dialysis-associated seizures is poorly defined. In individuals chronically treated with antiseizure medications, dialysisassociated seizures may be a result of dialysis-related reduction of antiseizure medication concentration.

Aluminum Toxicity and Encephalopathy (Including Dialysis Dementia) Aluminum toxicity and dementia related to dialysis and use of aluminum phosphate binding agents in chronic kidney disease have declined over the last decade; however, aluminum can still be found in total parenteral nutrition (TPN) and some drug preservatives. Infants, children, and adults with chronic kidney disease are at risk for aluminum toxicity. See the online chapter for further discussion.

Vitamin and Cofactor Deficiencies The B vitamins are water soluble, and most are readily dialyzable. A single dialysis session may reduce plasma thiamine concentration by as much as 40%. Patients with ESRD continue to be at risk for thiamine deficiency, which causes Wernicke’s encephalopathy. Symptoms include a triad of ophthalmoplegia, encephalopathy, and ataxia. Symptomatic thiamine deficiency has been reported rarely in children probably because stores of thiamine accumulated before the development of renal disease are only gradually depleted, and considerable effort is expended by parents and caregivers to ensure good nutrition. Response to intravenous thiamine may confirm the diagnosis. Pyridoxine deficiency is a risk factor for seizures. Hyperhomocystinuria is an important indicator of vitamin B12 deficiency. If found, it is associated with higher risk for preeclampsia, neural tube defects in offspring, atherosclerotic arterial disease, stroke, and venous thrombosis. Supplementation with B vitamins is routine to avoid these various complications. Chapters 46 and 47 review the vitamin and other micronutrient deficiency states seen in children.

Intracranial Hemorrhage Individuals requiring chronic dialysis for renal failure have an 11-fold greater risk for cerebral hemorrhage and 4-fold greater lifetime risk for subarachnoid hemorrhage. Replacement of generalized with regional anticoagulation and use of nonheparin-based anticoagulation have reduced the risk of this serious complication. Intracranial hemorrhage must be considered in renal patients with persistent drowsiness, headache, vomiting, persistent focal neurologic signs, or meningismus.

Milder Forms of Encephalopathy Neuropsychologic studies of children on dialysis have shown lower cognitive functioning. Abnormalities of performance IQ, short-term visual and auditory memory, attention span, memory, and speed of decision making have been documented. The risk is greatest if ESRD developed in early childhood (particularly during the first year of life) or if renal failure is of very long duration. Subtle intellectual and behavioral abnormalities, responsive to dialysis, have been detected. Sensorineural hearing abnormalities may occur in some patients with ESRD as a result of ototoxic medications given during the course of illnesses and multiple hospitalizations. Drugs used for treatment of ESRD and its complications may contribute to encephalopathy. There is a high prevalence of depression, anxiety, and emotional stress in patients with chronic renal failure. Other



confounding effects include developmental dysmaturity related to chronic hospitalization. A long-term outcome study of individuals who started dialysis before 16 years of age reported good overall quality of life despite coexistent conditions and disabilities. Poor intellectual function should lead to identification and scrupulous correction of metabolic abnormalities. Moderate uremia may result in disturbances ranging from mild encephalopathy to mild chronic delirium or psychosis. Intellectual dysfunction, deafness, and neuropathy, unresponsive to dialysis, may improve after successful transplantation.

Uremic Peripheral Polyneuropathy Peripheral neuropathy occurs in 65% of patients with ESRD. Somatic and autonomic nerves may be involved. As with other neurologic complications, the duration and severity of chronic kidney disease are important determinants of the occurrence and severity of neuropathy. Electrophysiologic abnormalities consistent with neuropathy are detectable in two thirds of adults with long-standing chronic kidney disease, whether or not dialysis has been initiated. Restless-leg syndrome is among the most common presenting complaints of sensorimotor neuropathy, associated with an unpleasant sensation of crawling skin or a dull ache in the legs that is worse in the evening. Pruritus is common more likely in individuals who also complain of paresthesias. Hearing is an important modality to be monitored in individuals with chronic kidney disease. Hearing loss may be the result of uremic axonal neuropathy, although other incompletely cleared endogenous or administered ototoxic substances may contribute to this and other neuropathic abnormalities. Loss of deep tendon reflexes (especially the ankle jerk), diminished vibratory sense, and weakness of great toe extension are among the earliest signs of uremic neuropathy. Paradoxical heat sensation, the tendency to identify a lowtemperature stimulus as being hot, is also a sensitive early sign of uremic polyneuropathy. Fully developed uremic neuropathy is a distal, symmetric polyneuropathy that involves sensory and motor modalities. Diminished sensitivity to all modalities in a glove-stocking distribution gradually develops. Pressure palsies, to which chronic renal failure/neuropathic renal disease patients are particularly subject, may alter the expected distribution of abnormalities. In adolescents and adults on dialysis for ESRD, sudomotor changes and postural hypotension are common consequences of autonomic neuropathy. Delayed gastric emptying can occur in children with chronic kidney disease independent of age, gender, duration of disease, or blood urea nitrogen or creatinine levels. Successful renal transplantation may reverse sympathetic and parasympathetic dysfunction. The mechanisms of nerve injury in association with endstage kidney disease remain incompletely understood and are discussed in the online chapter.

Uremic Myopathy (Myopathy of Chronic Kidney Disease) Muscle weakness is common in patients with ESRD. The pathogenesis is incompletely understood, and the definition and diagnostic features of the term uremic myopathy remain controversial. Diagnosis is often made on the basis of loss of endurance or ability for muscular exercise without muscle physiologic testing or biopsy. Muscle enzymes and electromyography tend to be normal. Chronic and progressive muscular weakness may be the secondary consequence of “uremic” neuropathy. Uremic vasculopathy is another cause of secondary myopathy. Vascu-

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lar myopathy is a necrotic process that has been ascribed to severe hyperparathyroidism with calcification of blood vessels, rather than representing a consequence of autonomic neuropathy. Muscle biopsy abnormalities include atrophy, type grouping, lipidosis, glycogen depletion, and mitochondrial proliferation. Caution is needed to avoid excessive use of calcium-based phosphate binders and vitamin D analogs in the treatment of secondary hyperparathyroidism and hyperphosphatemia in patients with chronic kidney disease. Sudden cardiac death occurs in approximately 25% of adult dialysis patients as a result of multifactorial etiologies, including vascular calcification, calcium abnormalities, and high prevalence of arrhythmias. The rate in children is unknown.

Malnutrition Protein and energy wasting are a serious problem in children with chronic kidney disease. Tube feedings and special formulas have improved growth, although motor, speech, and fine motor delays remain evident, especially in the very young. Nutritional disorders are often difficult to dissociate from the metabolic and endocrine dysfunction of chronic kidney disease.

Endocrinopathy Secondary hyperparathyroidism with hypercalcemia or hypocalcemia may directly injure the nervous system. Parathyroid hormone excess may directly affect central neurotransmission. Studies in animals and human adults have found that en­­cephalopathy may be prevented or ameliorated with parathyroidectomy.

Complications Associated With   Renal Transplantation The quality of life, including certain aspects of neurologic function, is generally improved after renal transplantation. Dialysis-associated complications are avoided, and neuropathy usually improves. Cognitive function, head growth, and psychomotor development also improve in many children. Survival also has been extended with kidney transplantations from deceased donors and living relatives. Transplantation entails risk for a particular set of neurologic complications that are usually associated with infection, hypertension, and medications including immunosuppressive agents.

Infection Infections may be related to the donor organ, surgical procedure, or presence of a foreign body, including urinary stents. Infections can be severe as a result of immunosuppression during the first few weeks after transplantation. Common gram-positive bacterial infections include Staphylococcus aureus, coagulase-negative staphylococcus, and enterococcus; gram-negative organisms include Escherichia coli, Pseudomonas, Klebsiella, and Enterobacter. Donor-derived or naturally acquired fungal infections can be fatal after renal transplantation. It is important to know the endemic areas where these infections can occur, travel history, and donor history. Central nervous system (CNS) infections account for 4% to 29% of CNS lesions in transplant recipients. Given the gravity of these infections, early biopsy of brain lesions and CSF collection for viral polymerase chain reaction (PCR) should be considered. Meningoencephalitis in transplant recipients is often caused by viral infections, including Epstein–Barr virus (EBV), cytomegalovirus (CMV), West Nile virus, varicella zoster, polyoma virus JCV, and BK virus. EBV and CMV infections

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in the first few months after renal transplantation are less common than previously because of the use of antiviral prophylaxis.

Malignancy Newer and more powerful immunosuppressants have decreased allograft rejection, but increased the risk of infections and malignancy. In adults, posttransplant malignancies are at least double in transplant recipients compared with the general population. The risk of developing a solid tumor is 6.7-fold higher in pediatric kidney recipients compared with the general pediatric population. Posttransplant lymphoproliferative disorders (PTLDs) are more common in children than in adults who have received renal allografts and constitute the majority of neoplasms for which these children are at risk. Approximately 1% to 2% of pediatric kidney recipients will develop PTLD within 5 years. The use of lymphocyte-depleting antibodies has been associated with an increase in the incidence of PTLD in children, and CNS involvement carries a poor prognosis. Management includes reduction or cessation of immunosuppression and treatment with a combination of chemotherapy including rituximab (specific anti-CD20 monoclonal antibody), cranial irradiation, and intravenous (IV) ganciclovir. Approximately 72% of pediatric patients achieve CNS remission with the use of intrathecal/intraventricular rituximab in posttransplant EBV associated CNS lymphoma.

Drugs Drug-related complications include hypertension, immunosuppression, oncogenesis, and direct neurotoxicity. The use of corticosteroids and calcineurin inhibitors, cyclosporine A and tacrolimus, can lead to posterior reversible encephalopathy syndrome (PRES). Cyclosporine A is a calcineurin inhibitor most commonly associated with neurologic side effects, including paresthesias, peripheral neuropathy, ataxia, tremor, encephalopathy, sympathetic overactivation, headaches, and seizures. Cyclosporine neurotoxicity occurs more frequently in younger children and in those who develop hypertension. There is evidence that tacrolimus, a more potent immunosuppressant than cyclosporine A, may also have a greater tendency to engender neurotoxicities of the same variety as that associated with cyclosporine use. Tacrolimus has been associated with a posttransplantation encephalopathy that includes MRI-discernible changes in gray and white matter. This syndrome may subside without discontinuation of tacrolimus. Patients who developed neurotoxicity with calcineurin inhibitors have been safely treated with mTOR inhibitors and mycophenolate mofetil without recurrence of their neurologic symptoms. Calcineurin-treated patients also have a higher prevalence and severity of neuropathy. Administration of the CD3 monoclonal antibody, orthoclone OKT3, to prevent renal allograft rejection may provoke headache, fever, vomiting, a flulike syndrome, hypotension, seizures, or aseptic meningitis in as many as one third of patients. These changes may be severe and can progress to coma. Severe symptoms associated with OKT3 have precluded its use in the majority of renal transplant centers, in lieu of newer and safer medications and biologic agents.

Hypertension Hypertensive Encephalopathy The designation hypertensive encephalopathy is generally reserved for hypertensive patients with alteration of consciousness with diffuse or multifocal CNS dysfunction, in whom there is no better or more complex etiologic explanation. Malignant

hypertension leading to hypertensive encephalopathy can arise in association with a number of underlying illnesses, including aortic coarctation (30%) and polycystic kidneys (30%), nephritis (16%), and hemolytic-uremic syndrome (7%). The causes of malignant hypertension in children are age dependent. Increased sophistication in imaging has led to increased recognition of PRES and concomitant redesignation of cases that would previously have been designated as hypertensive encephalopathy. More than 40% of patients with malignant hypertension develop significant neurologic complications. The risk for hypertensive encephalopathy is related to the rapidity and severity of blood pressure increases from any given baseline. Risk is higher in patients with acute renal failure. When hypertensive encephalopathy occurs in children, it carries a high risk of morbidity and mortality. Clinical Features of Hypertensive Encephalopathy.  Clinical symptoms include a combination of hypertension, headache, encephalopathy, and visual disturbances. The headache typically develops hours to days after the initiating blood pressure crisis and may be accompanied by lethargy, projectile vomiting, meningismus, or edema of the eyelids and ankles. Ophthalmoscopic findings include funduscopic evidence of arteriolar spasm or ischemic nerve fiber infarction. Papilledema is present in one third of children with hypertensive encephalopathy. Newborns and infants with hypertensive encephalopathy can present with irritability, lethargy, and unresponsiveness. Encephalopathy in older children may consist of fluctuating confusion, irritability, and restlessness that may progress to coma. Mental status changes typically develop 12 to 36 hours after headache onset. Seizures may occur and are more commonly generalized. Focal neurologic signs may signify more permanent injury. Unilateral infarction of some portion of the anterior optic pathways is especially characteristic. Infarction may be more common in patients who have had long-standing unrecognized hypertension. It also may occur in individuals who experience hypotensive episodes as a result of overly aggressive management of blood pressure elevation. Pathophysiology of Hypertensive Encephalopathy.  The exact nature of the pathophysiology of hypertensive encephalopathy is not fully understood, but two major theories are advocated. Both propose dysfunction of cerebral autoregulation, with one favoring excessive vasoconstriction with secondary ischemia. The other theory proposes a vasoconstrictive threshold that is exceeded, resulting in the development of transudative perivascular edema, which then compresses the regional microvasculature. Microinfarction, edema, and loss of autoregulation can occur, necessitating caution in blood pressure reduction and manipulation of cardiac output because rapid changes may result in acute cerebral infarction. Diagnostic Considerations in Patients With Hypertensive Encephalopathy.  The differential diagnosis for hypertensive encephalopathy is broad. Structural CNS lesions, encephalitis (infectious or immune mediated), and seizures should all be considered in the initial evaluation. Focal lesions, such as infarction, intracranial hemorrhage, or tumor, may be the cause of the hypertension. Alternatively, focal lesions, such as PRES or cerebral ischemia, may be the consequence of the hypertension.

Outcomes From Hypertensive Encephalopathy Outcome in hypertensive encephalopathy is generally favorable. Encephalopathy and seizures resolve with correction of



blood pressure. Visual disturbances are typically reversible but occasionally can persist. The degree and duration of the hypertensive phase are important elements in the risk for visual dysfunction, underlining the importance of early diagnosis and treatment.

Posterior Reversible Encephalopathy Syndrome PRES is thought to represent a disorder of cerebral autoregulation occurring in the setting of acute hypertension and manifest as acute neurologic symptoms associated with stereotypical radiographic changes. The phenomenon was first described in patients with hypertension, but it is now thought to be associated with a variety of conditions and may occur in children with or without hypertension. Populations known to be at risk for PRES include children with autoimmune disease, renal or hematological disorders, and bone marrow or solid-organ transplantation. An increasing number of medications are associated with PRES. Risk is highest with immunosuppressive medications, including monoclonal antibodies, calcineurin inhibitors, steroids, and cytotoxic medications. Clinical Features of Posterior Reversible Encephalopathy Syndrome.  Clinical features of PRES include fairly sudden onset of severe headache, encephalopathy, seizures, and visual disturbance. Symptoms typically resolve spontaneously or after correction of blood pressure. Recurrent PRES is not uncommon. Brain imaging usually illustrates fairly symmetric and extensive abnormalities within 24 hours of clinical onset that are much more apparent on MRI than on computed tomography. Changes are both cortical and subcortical and generally without diffusion restriction. Diagnostic Considerations in Patients With Posterior Reversible Encephalopathy Syndrome.  A broad differential diagnosis should be considered when making a diagnosis of PRES. Other considerations include vasculitis, hypoxic ischemic injury, infectious or immune-mediated encephalitis, acute disseminated encephalomyelitis, toxic leukoencephalopathy (e.g., methotrexate toxicity), and/or osmotic demyelination syndrome. Management of Posterior Reversible Encephalopathy Syndrome.  Management of PRES largely consists of supportive care. Severe blood pressure elevation should be treated aggressively. Blood pressure reduction is likely to be well tolerated except in the setting of chronic hypertension or cerebral vasculopathy. Seizures should be treated aggressively, and continuous electroencephalogram (EEG) monitoring should be employed to assess for subclinical seizures. Medications should be renally dosed for children with renal insufficiency/failure. Electrolytes should be normalized, with close attention to sodium, calcium. and magnesium. Chronic anticonvulsant therapy is seldom required.

DISEASES AFFECTING BOTH KIDNEY AND NERVOUS SYSTEM Diseases that affect both the kidney and the nervous system can be divided into four general categories: 1. Inflammatory/vascular 2. Infectious 3. Toxic or metabolic 4. Heritable disorders with brain and renal anomalies The inflammatory/vascular illnesses, which are considered first in this section, include thrombotic thrombocytopenic

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purpura, hemolytic-uremic syndrome, and other thrombocytopenic microangiopathies. Additional disorders such as hepatorenal syndrome, Henoch–Schönlein syndrome, and familial amyloidosis are also reviewed. Systemic lupus erythematosus, polyarteritis nodosa, and Wegener’s granulomatosis are examples of other illnesses that produce inflammatory changes in both the nervous and renal systems. The details of these illnesses are covered in Chapter 121. Infections with a predilection for renal and neurologic involvement include bacterial infections, such as Shiga-toxinproducing E. coli–associated hemolytic-uremic syndrome (STEC-HUS) and S. aureus infections; infections with viruses such as adenovirus, enteroviruses, coxsackieviruses, and echoviruses; and infections caused by fungi such as Candida spp. and Aspergillus. A variety of toxins ranging from metals (e.g., lead, mercury, aluminum) and illicit substances (cocaine and heroin) to household products (e.g., ethylene glycol) and insecticides such as malathion, chlorpyrifos, and dichlorvos are known to cause brain and kidney dysfunction. Rare inherited metabolic diseases are a vast category of diseases with potential for multiorgan involvement. Examples of subtypes with a predilection for kidney and brain disease include glycogen storage and lysosomal storage disorders (e.g., Gaucher disease and Fabry disease). Many inherited disorders include brain and kidney involvement. Polycystic kidney disease is associated with an increased risk for cerebral aneurysms and arachnoid cysts. Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome (HANAC) includes kidney disease, cerebral aneurysms, and myopathy. Von Hippel–Lindau disease is a genetic disorder with a predisposition to malignancies, including CNS neoplasms, such as endolymphatic sac tumors and craniospinal hemangioblastomas, and renal masses, such as renal cysts and carcinomas. Sickle-cell disease is a chronic hematologic disorder with a high risk for cerebral vasculopathy, stroke, and kidney abnormalities ranging from proteinuria to ESRD.

Thrombotic Thrombocytopenic Purpura The clinical diagnosis of thrombotic thrombocytopenic purpura (TTP) requires at least two major (thrombocytopenia, Coombs-negative microangiopathic anemia, or neurologic dysfunction) and two minor (fever, renal dysfunction, or circulating thrombi) manifestations, permitting the diagnosis to be made in the absence of either renal or neurologic dysfunction. Determining the boundaries between TTP and a number of other microangiopathic conditions, collectively termed thrombotic microangiopathies, was challenging until recently. It is now understood that TTP and HUS are distinct entities. TTP-associated thrombi are rich in platelets and are found in the heart, pancreas, kidney, adrenal glands, and brain, in decreasing order of severity. HUS-associated thrombi are rich in fibrin/red cells, and they tend largely to be confined to the kidney. TTP thrombi are found in the brains and kidneys of 50% to 75% of individuals with fatal TTP. Brain thromboses of TTP occur in small arterioles, capillaries, and venules and are associated with microinfarction. Small petechial hemorrhages may be widely scattered in gray matter. Diagnostic tests are available that reliably designate most heritable and acquired TTP cases. Classification of thrombotic microangiopathies is described in the online version of the chapter (James et al., 2014). Signs and symptoms of acute TTP usually evolve quickly and quite noticeably over 7 to 10 days. Skin purpura is the initial manifestation in more than 90% of patients. Fever usually develops early. Hemorrhage (retinal, choroidal, nasal,

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gingival, gastrointestinal, and genitourinary), abdominal pain, arthralgia, or pancreatitis may also develop. Neurologic findings include fatigue, confusion, headache, and varying degrees of dysfunction of vision or language. Significant laboratory findings include microangiopathic hemolytic anemia, thrombocytopenia, elevated lactate dehydrogenase, proteinuria, and microscopic hematuria. CSF chemistry, cell counts, and pressure are usually normal. Other findings associated with disseminated intravascular coagulopathy are not usually found. MRI of brain is often normal. Plasma exchange is the therapy of choice. A survival rate of at least 80% has been found for plasma exchange, compared with 60% survival for patients randomized to plasma infusion. Plasma infusions may be used as a temporizing measure in patients with suspected TTP until plasma exchange can be instituted because of the high risk for morbidity and mortality if therapy is delayed. In addition to therapeutic plasma exchange, immunosuppressant therapy with corticosteroids is indicated in patients with acquired TTP (Blombery and Scully, 2014). Most cases of TTP are monophasic, but 11% to 28% of patients experience one or more recurrences. Relapses can occur weeks to years after initial remission. For severe or recurrent cases, chronic plasmapheresis is useful. Rituximab can be used for initial therapy and in refractory or relapsing cases.

Hemolytic-Uremic Syndrome HUS is a Coombs-negative thrombocytopenic microangiopathy, the onset of which is typically in early childhood. Classic HUS, also known as D + HUS or STEC-HUS, occurs with a prodrome of diarrhea and is secondary to infections with Shiga-toxin-producing E. coli, although other bacterial infections have been associated with D + HUS. HUS that occurs in the absence of a diarrheal illness is labeled D-HUS or atypical HUS (aHUS). aHUS is considered to be a disorder of the alternate complement pathway involving dysregulation and increased terminal complement pathway activation. Multiple genetic mutations in the complement pathway have been identified as risk factors for the development of aHUS. Other forms of D-HUS include infection-related HUS that occurs with nondiarrheal illnesses, such as HUS associated with Streptococcus pneumoniae infections or drug-induced HUS. Most cases occur in children younger than 5 years of age; however, HUS associated with E. coli outbreaks can occur in patients at any age (Trachtman, 2013). HUS that presents in infancy is often noninfectious and is secondary to familial or genetic mutations. HUS can have multisystem involvement with associated cardiac, liver, and pancreatic dysfunction (Trachtman, 2013). Neurologic manifestations of HUS—most commonly, seizures, stroke, and varying degrees of encephalopathy—are seen in 30% to 40% of patients. Occurrence of neurologic abnormalities predicts a worse outcome, with enhanced risk for ESRD or death. It is not always clear whether such neurologic changes are the result of cerebral microangiopathy or are secondary to metabolic disturbances and hypertension. MRI of the brain may disclose focal areas of infarction with swelling and, in some patients, hemorrhage.

Treatment Management of patients with D + HUS is supportive, with attention to fluid and electrolyte management, hypertension control, and judicious use of blood transfusions. HUSassociated renal failure usually persists for several weeks. Dialysis is required in 30% to 50% of patients and is indicative of a poorer prognosis. Patients with aHUS are more likely to

develop severe AKI requiring dialysis. Most patients with D + HUS will recover renal function, as opposed to patients with aHUS, who often develop chronic kidney disease or dialysis dependency. Patients with aHUS have a more prolonged course with a higher incidence of morbidity and mortality. Eculizumab, a complement inhibitor, has been used successfully in the treatment of patients with aHUS and is considered the first line of therapy in patients with suspected complement-mediated aHUS (Loirat et al., 2016). Renal transplantation is indicated in patients with chronic kidney disease secondary to HUS; however, patients with aHUS are at a high risk for HUS recurrence posttransplantation.

Vasculitic Diseases With Neurologic-Renal Presentations Extended consideration of the various inflammatory disorders can be found in Chapters 109, 112, 121, 142, and 150.

Hepatorenal Syndrome Hepatorenal syndrome (HRS) is defined as the presence of functional, potentially reversible AKI that occurs in patients with various forms of liver failure in the absence of hypovolemia or other identifiable causes for AKI. It is divided into two types. Type 1 includes patients with AKI with rapidly deteriorating renal function in association with acute severe hepatic dysfunction. It can be fulminant and carries a high risk for death. Encephalopathy is common in type 1. Type 1 hepatorenal syndrome is rare in childhood. Type 2 includes patients who manifest the combination of less severe liver and renal disease with a slow progressive course and evidence of chronic liver and concurrent kidney disease. Encephalopathy is less common in type 2 cases. Some form of hepatorenal syndrome develops in as many as 20% of patients who are in their first year of acute or subacute hepatic failure. Clinical features include ascites, jaundice, and low arterial blood pressure, despite increased plasma volume. The hepatorenal syndrome is often precipitated by infections such as spontaneous bacterial peritonitis or with aggressive diuresis or paracentesis. Laboratory findings consistent with AKI include a rise in serum creatinine from baseline values with concurrent evidence of a prerenal state in the form of a normal urine analysis, a low urinary sodium clearance, and a high urine osmolarity. Therapy is based on replenishing the low effective circulatory volume with fluids, albumin infusions, and correction of the vasomotor dysregulation with vasoconstrictors. Other supportive therapies include the institution of renal replacement therapies, such as hemodialysis in patients with severe hyponatremia, azotemia, or other metabolic disturbances. Combined liver–kidney transplantation may be considered when patients remain dialysis dependent or have evidence of chronic kidney disease (Sampaio, Martin, and Bunnapradist, 2014; Eason et al., 2008).

Amyloidosis Amyloidoses are a group of rare disorders of amyloid proteins that affect the kidney and the brain. They can be divided into the heredofamilial (primary) type and those that constitute the secondary (reactive) group. Renal amyloidosis is uncommon in children and is often secondary to chronic infectious or inflammatory diseases such as familial Mediterranean fever (Bilginer, Akpolat, and Ozen, 2011). These disorders are discussed in the online chapter.



Metabolic Diseases Producing Generalized Renal and Neurologic Dysfunction Both acute and chronic generalized nephron dysfunction may result from metabolic diseases that have primary effects on the kidney and nervous system. Diseases that are most likely to result in encephalopathy are those that produce the combination of chronic metabolic and catabolic dysfunction in association with acute renal failure. Under such conditions, the metabolic perturbation worsens more rapidly and often achieves greater severity. Systemic diseases that can provoke encephalopathy, even without renal failure (e.g., sepsis, burns, fever, ethylene glycol, lactic acidosis, or ketoacidosis), produce more fulminant, severe, and difficult-to-treat nervous system dysfunction when renal failure also occurs or was previously present. Therapeutic interventions must include attention to cerebrovascular dynamics because cardiac output is often low, and cerebral autoregulation is often compromised.

Selective Tubular Dysfunction Many inherited diseases and intoxications produce characteristic patterns of renal tubular acidosis in association with neurologic abnormalities; glomerular function is usually preserved in these diseases. Renal tubular acidosis is generally characterized by hyperchloremia and reduced plasma bicarbonate, and is further divided into proximal (bicarbonate-wasting) or distal (defective acid-excreting) renal tubular varieties. Selective tubular dysfunction itself produces far fewer clinical manifestations than are observed in uremia. In many instances, the neurologic dysfunction is more apparent than the associated renal dysfunction, which is often overlooked.

Proximal Renal Tubular Acidosis Proximal renal tubular acidosis (proximal RTA) refers to the condition characterized by urinary bicarbonate loss secondary to an isolated proximal tubular dysfunction, which leads to hyperchloremic non-anion-gap metabolic acidosis. Proximal RTA can occur as an adverse effect of medications, such as carbonic anhydrase inhibitors. It can occur transiently in infants and preterm babies as a result of lack of renal tubular maturation. Isolated proximal RTA can be primary in origin as a result of inherited genetic mutations, but it is more commonly seen secondary to medications or other systemic illnesses (Haque, Ariceta, and Batlle, 2011). Clinical presentation includes a history of recurrent dehydration and failure to thrive, along with polyuria and polydipsia in older children. Laboratory evaluation will a reveal normal anion gap and metabolic acidosis. Urinary acidification will be impaired with a urine pH less than 5.5. Fractional excretion of urinary bicarbonate will be high, providing evidence of urinary bicarbonate loss. In patients with the Fanconi’s syndrome, hypophosphatemia and hypokalemia may be seen. Urine studies will confirm the presence of generalized aminoaciduria along with glycosuria despite normal serum glucose.

Nephropathic Cystinosis Nephropathic cystinosis, caused by a defective lysosomal membrane transport protein, is the most common identifiable cause of renal Fanconi’s syndrome in children. Mutations in the CTNS gene located on 17p13.2 result in defective cystinosin. Presentation is usually that of symptoms of failure to thrive and recurrent dehydration. Laboratory evaluation is consistent with Fanconi’s syndrome with progressive renal dysfunction. The diagnosis is confirmed by detection of

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elevated white blood cell (WBC) cystine levels, genetic analysis, and/or the presence of cystine crystals seen on slit-lamp examination (Emma et al., 2014). Before renal transplantation was available, it was thought that neurologic abnormalities occurred only as consequences of renal dysfunction. With the prolonged survival, it has become clear that the infantile and juvenile forms may be associated with visual, intellectual, and motor abnormalities that result from cystine accumulation in the eye (cornea, conjunctiva, retina) or brain (choroid plexus, cortex). Other neurologic consequences develop at various ages from childhood to adulthood. They may include headache; autonomic abnormalities (heat intolerance, hyperthermia, abnormal sweating); poor vision and deficient visual memory; short, raspy, repetitive speech; tremor; pyramidal or extrapyramidal motor defects; and weakness. Selective impairment of visual processing is a frequent finding. Abnormal tactile recognition with astereognosis has been discerned in some patients. These subtle deficits are the likely basis of some of the school difficulties experienced by children with nephropathic cystinosis. Intellectual deficits are mild and may be static or slowly progressive. Some patients experience severe and strikingly progressive neurologic complications. Cystinosis-related encephalopathy is an entity characterized by cerebellar and pyramidal signs, with ensuing mental deterioration, and then development of pseudobulbar or bulbar palsy with a prominent swallowing disorder. Evidence suggests that cysteamine may reverse cystinosis-related encephalopathy, improve the radiologic appearance of the brain, and prevent paroxysmal episodes. One quarter of patients with long-standing nephropathic cystinosis develop distal lipid inclusion myopathy. This result may be the direct effect of cystine toxicity, although carnitine deficiency and other potential causes may contribute. Patients with cystinosis-related myopathy develop weakness and wasting of small hand muscles, facial weakness, and muscular dysphagia. Biopsies may indicate a vacuolar myopathy of lysosomal origin. Additional heritable diseases that may result in a combination of neurologic and renal manifestations are listed in Table 158-6.

NEUROLOGIC DRUGS THAT MAY AFFECT   RENAL FUNCTION IN INDIVIDUALS WITH NORMAL KIDNEYS Some drugs commonly used in the management of neurologic diseases may produce disturbances of renal function that range from mild transient effects on the regulation of freewater clearance to severe parenchymal kidney injury. Important effects of selected neurologic drugs on renal function are summarized in Table 158-7. It is well known that carbamazepine and oxcarbazepine can produce hyponatremia. Prevalence with carbamazepine treatment is approximately 5%. Mild hyponatremia is seen in 18% to 25% of oxcarbazepine-treated children, with more severe hyponatremia (i.e., 9–12 yr; max 60 mg/day >12 yr; max 90 mg/day; divided twice a day to three times a day; increase weekly

1–2 + sedation 1–2 + weakness

DBPC (adult)

Clonazepam

Facilitates GABA

10 yr or 30 kg; max 20 mg/kg/day; divided twice a day to three times a day; increase every 3 days

3 + sedation 2 + weakness

Open trial only

Diazepam

Facilitates GABA

12 yr; 6–30 mg/day; divided three times a day to four times a day; increase weekly

3 + sedation 2 + weakness, dizziness

DBPC (child/adult)

Dantrolene

Interferes with skeletal muscle contraction by interruption of calcium release from sarcoplasmic reticulum

>5 yr; 12 mg/kg/day divided twice a day to four times a day Adult; max 400 mg/day; increase every 4–7 days

1 + sedation 3 + weakness, hepatotoxicity, GI complaints

DBPC (child/adult)

Tizanidine

Alpha-2 adrenergic agonist with presynaptic inhibition

0.2–0.3 mg/kg/day divided three to four time a day; night dosing helpful for sleep Adult max 36 mg; increase weekly

2 + sedation 1 + weakness, hypotension

DBPC (adult)

DBPC: double-blind, placebo-controlled; GABA: gamma-aminobutyric acid; GI: gastrointestinal.

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in which meaningful functional goals can be achieved, as opposed to mere clinical ones—i.e., decreased resistance to stretch. Exceptions to the above “rule” include medications to facilitate hygiene, improve positioning, reduce caregiver demands and ease proper fitting of orthotics. Commonly employed medications treating spasticity in pediatrics include diazepam, baclofen, tizanidine, and dantrolene (Table 162-1). Baclofen usually is well tolerated and has been moderately effective in reducing spasticity in spinal cord injury, with lesser benefit in brain injury from trauma or stroke. In cerebral palsy, baclofen studies have demonstrated significant reduction in spasticity and improved use of extremities. Sudden withdrawal of the medication has been associated with seizures and hallucinations. Although there have been numerous controlled trials of tizanidine in adults with spasticity, studies in children are few (Table 1621). The usefulness of clonidine is limited mainly to patients with acute brain injury resulting in hypertension, tachycardia, and autonomic dysfunction, given its propensity to cause hypotension and bradycardia. Dantrolene sodium is the least sedating of the antispasticity medications, but requires careful titration to minimize the potential for severe generalized weakness and a limited duration of treatment due to the risk of hepatic injury (Noetzel, 2012). Newer agents such as gabapentin and pregabalin, both GABA analogs, as well as modafinil lack convincing data to establish that any of them reduce spasticity or improve quality of life in children (Noetzel, 2012).

Neuromuscular Blockade: Alcohol, Phenol, and Botulinum Toxin Injections Neuromuscular blockade with phenol and alcohol causes axonal degeneration, with tone reduction lasting up to 1 to 3 years, but they are utilized relatively infrequently due to the need for sedation or anesthesia, as electrical stimulation is necessary to identify the target nerve (Noetzel, 2012). Intramuscular injection of botulinum toxin inhibits the release of the neurotransmitter acetylcholine responsible for transforming nerve impulses into muscle contraction. Studies on children with cerebral palsy have documented reduction in spasticity and modest functional improvement after injections in the arms and legs (Noetzel, 2012). The limitation in movement must be the result of spasticity and not from a fixed contracture (Box 162-3). In addition, there should be sufficient underlying strength so that weakening of the problem muscle does not produce paresis. A clinically apparent effect is most notable 2 to 4 weeks after injection, and ongoing benefit typically lasts 3 to 4 months or longer. The total maximum dose of botulinum that can be administered at a single time is limited, and there must be appropriate spacing between injections in order to minimize antibodies developing to the toxin. Botulinum injections can be employed with other therapies and typically are coupled with an intensification of therapy and/or serial casting in order to secure maximum benefit (Fig. 162-1) (Noetzel, 2012). Pain on injection and transient flu-like syndromes have been noted; with increasing use, systemic botulism, resulting in deterioration in respiratory and oral-motor function, has occurred.

Intrathecal Baclofen Therapy In patients with more extensive spasticity, intrathecal baclofen pump (ITB) therapy can be employed. Components include: a pump implanted under the skin on the abdomen, which infuses the drug at a predetermined rate; a catheter, which delivers drug to the intrathecal space of the spinal cord (with

the tip placed between T2 and C6 for maximum efficacy); and a programmer for adjustable and precise dosing (Noetzel, 2003). ITB therapy should be considered in children whose spasticity interferes with function or care, those who have painful spasticity-related spasms, and individuals unable to tolerate side effects from oral medications (Box 162-4). Because intrathecal baclofen diffuses directly into the spinal cord, the doses are much smaller than those taken orally, and the potential for systemic side effects is reduced. ITB therapy is not the optimal treatment if: spasticity predominantly affects the arms or is focal; trunk control is poor; and families cannot fully commit to the requirements of therapy maintenance (Box 162-4) (Noetzel, 2012). The pump reservoir is refilled percutaneously every 2 to 6 months, and the battery life of 5 to 7 years mandates pump replacement at the end of that time. Contraindications in patient selection include hypersensitivity to baclofen, unrealistic expectations of benefit, and small size/low weight. ITB therapy complications due to surgical implantation and refilling procedures include CNS infection and peritonitis; device-related complications also may occur (Box 162-5). Side effects, such as somnolence, dizziness, and hypotonia, have been reported. Signs of overdose range from itching, excessive weakness, and ascending low tone to respiratory depression, seizures, and coma. Withdrawal is a medical emergency, presenting as altered mental status, spasticity and rigidity that may advance to rhabdomyolysis, organ failure, and death. Management of withdrawal is predicated on prompt recognition, institution of oral baclofen or tizanidine, and, in severe cases, intravenous benzodiazepines or propofol. Cyproheptadine can be a useful adjunct in the management of serotonergic syndrome symptoms.

Selective Dorsal Rhizotomy Selective dorsal rhizotomy (SDR) is designed to reduce moderate to severe lower-extremity spasticity by minimizing aberrant muscle spindle input believed to trigger muscle overactivity. Bone covering the first two lumbar segments is removed. Afferent fibers in the dorsal roots from L1 to S2 are dissected, and those rootlets that demonstrate excessive activity are severed. Studies have demonstrated that the combination of SDR and intensive post operative PT is beneficial in reducing spasticity in children with diplegic cerebral palsy and produces gains in strength, gait speed, and overall gross motor function (Noetzel, 2012). Patients most suitable for SDR are those between the ages of 4 and 10 with spastic diplegia or mild quadriplegia who have some degree of ambulatory capability (Box 162-6) (Noetzel, 2003). Most have a history of prematurity or evidence of periventricular leukomalacia on imaging studies. Those unsuitable for SDR include patients with spasticity from congenital or neonatal CNS infection and head trauma or hypoxic brain injury outside the newborn period (Box 162-6). In addition, children with very weak abdominal muscles and those with predominant dystonia or ataxia are less likely to benefit from SDR.

Orthopedic Surgery Even with optimal treatment, spasticity may progress to cause contractures and bony deformities necessitating orthopedic intervention such as tendon releases for fixed contractures at the ankle, surgery to correct hip subluxation or dislocation, and instrumentation for scoliosis. The benefit of orthopedic surgery is most pronounced in patients who have achieved some degree of skeletal maturation.



Treatment of Dystonia and Other Hyperkinetic Movement Disorders A number of movement disorders have been recognized in children after traumatic brain injury and stroke (Dosenbach and Noetzel, 2014). Management is predicated upon the type of movement disorder, but unfortunately most medications have proven to be ineffective or of minimal benefit. For children with acquired dystonia, trihexyphenidyl, tetrabenazine, and botulinum toxin injections often are utilized.

ACQUIRED BRAIN INJURY Traumatic brain injury, together with stroke, hypoxic/ischemic injury, brain tumor, and CNS infection, account for about 75% of all pediatric admissions to an acute neurorehabilitation service (Noetzel, 2012). Even though the primary injury may be focal, brain damage is typically widely distributed in most patients. Secondary injury from cerebral edema, hypoxia, or ischemia, often in the setting of elevated intracranial pressure, may inflict additional diffuse damage, especially in infants with nonaccidental trauma. Although the pathology of acquired brain injury is variable, certain neurorehabilitation issues require attention in almost every child recovering from this type of injury.

Behavioral Disturbances Behavioral aberrations are a nearly universal consideration and can be observed in all stages of recovery (Noetzel, 2012). Agitation, characterized as nonpurposeful, random, motor and verbal activity, is common early in recovery. Emotional regression and impaired information processing likewise often are observed and may persist for weeks or months. Sedative medications usually are without benefit and, in fact, symptoms may be aggravated by further clouding the sensorium. In the middle stages of recovery, patients often have limited understanding of their own deficits and intolerance to sensory stimulation (Noetzel, 2003). Hyperactivity and impulsivity are typical manifestations seen in a child 3 to 8 years old; in older children and adolescents, the behavioral theme is one of decreased motivation and poor initiation of action, combined with lethargy. Therapeutic intervention and management strategies require ongoing careful assessment of the patient’s attention and arousal patterns. Medications with adverse cognitive or behavioral side effects should be withdrawn when possible. Careful modulation of a child’s surroundings may be beneficial, avoiding either overstimulation or prolonged sensory deprivation. Alerting, orienting, and preparing a child for any therapy activity is important. In addition, it is essential to monitor the child’s response so as to determine which environmental adaptations are beneficial (Noetzel, 2003). In some children with acquired brain injury, aberrant behavior persists and medication may need to be prescribed, recognizing that the use of pharmacologic agents to manage behavior in this clinical setting has not been investigated in a scientifically rigorous manner. The most pressing behavioral issues of aggression and severe agitation have been treated with beta blockers, carbamazepine, and tricyclic antidepressants, as well as clonidine, amantadine, and buspirone (Noetzel, 2012). Stimulants may have a role in children with underarousal and slow cognitive processing.

Communication and Cognitive Deficits Deficits in communication and cognition are exceedingly common and represent the largest cause of long-term

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disability, most often affecting memory and learning of new information. Agents acting upon the various neurotransmitter systems have been employed to establish an appropriate level of arousal and sustained attention. Although not overwhelming, the results do demonstrate a likely overall beneficial effect. Efficacy of pharmacologic intervention with respect to memory and learning has not been demonstrated (Noetzel, 2012). Therapeutic interventions for communication and cognitive impairment should be initiated in the acute care setting, with the main focus on providing sensory modulation. Cognitive retraining should pervade all aspects of the therapy process. Finally, rehabilitation should be predicated not only on enhancing preserved function, but also on remediating residual deficits, utilizing standardized tests to establish a structured intervention program (Noetzel, 2003).

Postinjury Seizures Seizures resulting from brain trauma commonly occur within the first 7 to 10 days after injury. The risk is highest in children under the age of 3 years and those with a severe injury or any nonaccidental brain injury. The incidence of posttraumatic epilepsy (PTE) is less than 1%; severity of brain injury and the presence of early seizures are the most important predictive factors for PTE (Noetzel, 2012). Early seizures do not mandate treatment, but recurrent seizures can be treated with levetiracetam, especially in patients with raised intracranial pressure and those with risk factors for late seizures, such as intraparenchymal hemorrhage and penetrating cerebral injury. There is, however, no convincing evidence in children that prophylactic therapy prevents PTE. In contrast, epilepsy as a long-term complication occurs in 15% to 20% of childhood acute ischemic stroke patients, with large cortical infarcts imposing the highest risk. In patients with seizures at stroke onset, anticonvulsants are warranted, with the choice of medication dictated by seizure semiology and EEG findings.

PEDIATRIC STROKE There is increasing recognition of the incidence, severity, and functional impact of pediatric stroke and of the consequent rehabilitation needs of survivors. Disability caused by pediatric stroke and its influence on a child’s quality of life endures over decades (Dosenbach and Noetzel, 2014). Although brain damage from a stroke is not progressive, the resultant functional deficits typically evolve over time, commensurate with nervous system maturation. Permanent motor and cognitive dysfunction is seen in the majority of pediatric stroke survivors, with deficits ranging from 50% to 90%.

Novel Rehabilitation Strategies-Overview Fueled by a growing understanding of brain reorganization stategies, various novel rehabilitation treatments are currently in different stages of development and efficacy testing, mostly in adults (Carmichael, 2010). Because stroke recovery utilizes some of the same systems-level, neuronal and molecular mechanisms as learning, theraputic interventions demonstrated to improve learning are being applied to stroke patients. Novel stroke rehabilitation treatments can be grouped into three basic categories. First, many are practice programs that build on existing therapy paradigms but incorporate novel technologies or vary some of the specifics of training. A second group has as its foundation electrical stimulation of the nervous system. Finally, medications are being tested in the hope that they might boost recovery from stroke. Although most novel rehabilitation treatments have focused on improving motor outcome, efforts are under way to extend

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PART XIX  Care of the Child with Neurologic Disorders

these therapies into other domains such as the restoration of sensory, language, attentional, and executive deficits (Dosenbach and Noetzel, 2014). However, these interventions have not demonstrated any lasting benefit over convential therpies in the small number of pediatric patients enrolled. There is increasing interest in the potential use of stem cell therapy (Chapter 15).

Practice Based Therapies—Constraint   Induced Movement Therapy and Robot Assisted Therapy In pediatrics, intervention with CIMT has focused on children with hemiparesis from presumed perinatal stroke, utilizing a bivalvedcast to restrain the more functional arm (Fig. 162-5). CIMT can result in lasting improvements in motor function compared with standard, less intense treatment. A recent study found slightly better outcomes for CIMT compared with dose-matched bimanual intensive therapy immediately after the treatment period, but these differences were not sustained at 12-month follow up (Sakzewski, et  al., 2011). Robot-assisted therapy may eventually allow convenient delivery of the high volume of repetitions needed to effect use-dependent neural plasticity (Noetzel, 2012) and currently is being investigated in children with cerebral palsy and stroke.

Stimulation of the Nervous System to Improve Stroke Recovery Numerous studies have demonstrated that functional neuroanatomy of the brain’s distributed systems can be reshaped by task practice (Lewis, et al., 2009), but repetitive training is time consuming. Thus there is significant interest in directly stimulating the nervous system to bypass or at least enhance task practice. Transcranial magnetic stimulation (TMS), which uses rapidly shifting magnetic fields to induce small currents, has been well studied in pediatric patients. Repetitive TMS (rTMS) can increase or decrease the excitability of underlying cortex and appears to induce a local state of heightened usedependent neuroplasticity via several molecular and cellular mechanisms, including both GABA and glutamate levels. Evidence for clinical efficacy of rTMS is limited to small-scale studies in children with chronic paresis after stroke (Kirton,

et al., 2008). More research is needed before it can become a mainstream treatment, but rTMS appears to have great potential.

Medications to Improve Stroke Recovery Efforts to find neurorehabilitative medications have focused on compounds shown to improve use-dependent neuroplasticity and learning, including selective serotonin reuptake inhibitors, stimulants, and agents that increase dopamine. In the best trial to date, adults with moderate to severe motor deficits who were randomized to 90 days of standard rehabilitative care plus 20 mg of fluoxetine daily had significantly better outcomes compared with standard care plus placebo. Thus it may be reasonable to consider fluoxetine treatment in teenagers who have suffered a motor stroke (Dosenbach and Noetzel, 2014). Stimulant medications and dopamine also induce neuroplasticity and improve stroke recovery in animal models, but no data exists to determine whether pediatric patients might benefit from their use during stroke recover.

SPINAL CORD INJURY About 20% of acute SCI patients are under 20 years of age. Although trauma accounts for the vast majority of SCI in children, demyelination, infarction, and tumors contribute to cases of myelopathy. The neurologic examination with suspected SCI entails a sensory evaluation of dermatomes and strength assessment in key muscles in the arms and legs. An understanding of motor movement and reflexes, as they relate to spinal level, aids in the examination (Table 162-2). The assigned level of injury is the lowest segment at which sensory and motor responses are intact bilaterally. The American Spinal Injury Association provides criteria defining the extent of injury that not only informs rehabilitation decisions (Box 162-7), but also has predictive value because mobility and independence in activities of daily living outcomes correlate with the level of functional motor activity.

Medical Issues Pulmonary complications such as ventilator failure, pulmonary edema, pneumonia, and aspiration are a major source of morbidity and mortality in the acute stage of SCI. Patients with high cervical injuries (C1–C4) typically require lifelong

TABLE 162-2  Neurologic Examination to Determine the Spinal Level of Injury Spinal Level

Cutaneous Sensation

Motor Function

Working Muscles

Reflex

C5

Lateral upper arm

Elbow flexion

Biceps, deltoid

Biceps

C6

Anteromedial arm/thumb

Wrist extension

Extensor carpi ulnaris/radialis

Brachioradialis

C7

Posterior forearm/middle finger

Elbow extension

Triceps

Triceps

C8

Fourth/fifth fingers

Finger flexion

Flexor digitorum sublimis

T12

Lower abdomen

None

None

L1

Groin

Weak hip flexion

Iliopsoas

L2

Anterior upper thigh

Full hip flexion

Iliopsoas and sartorius

L3

Anterior distal thigh/knee

Knee extension

Quadriceps

Knee jerk

L4

Medial leg

Knee flexion/hip adduction

Medial hamstrings

Knee jerk

L5

Lateral leg/medial knee

Foot dorsiflexion/eversion

Anterior tibial/peroneals

Ankle jerk

S1

Sole of foot

Foot plantar flexion

Gastrocnemius/soleus

Ankle jerk

S2

Posterior leg/thigh

Toe flexion

Flexor hallucis

Anal wink

S3

Middle of buttock

None

None

Anal wink



ventilator support because respiratory muscles are innervated by cranial nerve XI and C2–C4. Individuals with injuries from C3–C5 have varying degrees of ventilator compromise depending on diaphragmatic function, whereas damage at the C6–C7 level usually allows for eventual discontinuation of ventilator support. Once spinal shock resolves, bladder spasticity with detrusor hyperreflexia produces elevated voiding pressures and impaired emptying, with the potential for renal damage. Treatment consists of intermittent catheterization and anticholinergic medications. Bowel dysfunction in SCI almost always takes the form of constipation and incomplete evacuation of stool, thus a bowel management program, with stool softeners and suppositories, as well as digital stimulation, is important. Other concerns in children with SCI include heterotopic ossification, hypercalcemia, and deep vein thrombosis (DVT), the latter of which occurs in 10% of adolescents. In adults with SCI, thromboprophylaxis with low molecular weight heparin is recommended for the first 3 months; data are less compelling in children.

Rehabilitation Strategies Childhood SCI produces greater disability than a similar injury in an adult. In addition to the profound multisystem trauma that often occurs in an SCI, in a child there is secondary impairment created by the disruption of normal development, physical growth, and psychosocial maturation. Although rehabilitation goals are dictated by specific deficits in bodily function, the overriding aim is to treat the needs of the whole child and maximize the potential for future independence. Patients with C1–C4 injuries require significant adaptive equipment, typically with activating switches. In most cervical cord injuries, a power wheelchair is indicated, with the method of control determined by the level of injury. Appropriate splinting and orthotics may facilitate greater independence in feeding and upper-extremity dressing. With slightly lower injury levels, patients have adequate arm extension and improved hand function, which are critical for wheelchair propulsion (Fig. 162-6), the ability to self-transfer, and participation in bowel and bladder training programs. Programs and equipment designed to assist ambulation are predicated on residual muscle function in the trunk and legs. Finally, regardless of injury level, pressure relief is necessary, and patients, as well as their caretakers, need to be instructed in this maneuver to minimize development of decubitus ulcers.

FUTURE DIRECTIONS Pediatric neurorehabilitation has improved dramatically over the last quarter century. Our understanding of the mechanisms of recovery has accelerated, leading to the hope that this knowledge can be translated into specific neurologic therapies that can serve as the basis for restorative rehabilitation. The more immediate need is to upgrade the neurorehabilitation treatments we provide for our patients. Few of the currently employed interventions, medications, and physical modalities implemented in the rehabilitation of children have been subjected to rigorous scientific research with appropriate control subjects. Most investigations involve limited populations, with little regard for the influence of normal development on recovery; many fail to recognize that achievement of functional goals is the only meaningful outcome. Double-blinded protocols, utilizing quantifiable clinically relevant outcomes,

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are essential for the growth of rehabilitation and improving the care we provide to neurologically injured children. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Carmichael, S.T., 2010. Translating the frontiers of brain repair to treatments: starting not to break the rules. Neurobiol. Dis. 37 (2), 237–242. Carter, A.R., Shulman, G.L., Corbetta, M., 2012. Why use a connectivitybased approach to study stroke and recovery of function? Neuroimage 62 (4), 2271–2280. Delgado, M.R., Hirtz, D., Aisen, M., et al., 2010. Practice parameter: pharmacological treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review); report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 74, 336–343. Dosenbach, N.U.F., Noetzel, M.J., 2014. Rehabilitation of children after stroke. In: Stein, J., Harvey, R.L., Winstein, C.J., et al. (Eds.), Stroke Recovery and Rehabilitation, 2nd ed. Demos Medical, New York, pp. 699–734. Johnston, M.V., 2009. Plasticity in the developing brain: implications for rehabilitation. Dev. Disabil. Res. Rev. 15 (2), 94–101. Kirton, A., Chen, R., Friefeld, S., et al., 2008. Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomized trial. Lancet Neurol. 7 (6), 507–513. Lewis, C.M., Baldassarre, A., Committeri, G., et al., 2009. Learning sculpts the spontaneous activity of the resting human brain. Proc. Natl. Acad. Sci. U.S.A. 106 (41), 17558–17563. Noetzel, M.J., 2003. Acute pediatric neurorehabilitation. In: Winn, H.R. (Ed.), Youman’s Neurological Surgery, 5th ed. Elsevier Science, Philadelphia, pp. 3783–3791. Noetzel, M.J., 2012. Pediatric neurorehabilitation medicine. In: Swaiman, K.F., Ashwal, S., Ferriero, D.M., et al. (Eds.), Swaiman’s Pediatric Neurology: Principles and Practice, 5th ed. Elsevier Science, Philadelphia, pp. e234–e249. Sakzewski, L., Ziviani, J., Boyd, R.N., 2011. Best responders after intensive upper-limb training for children with unilateral cerebral palsy. Arch. Phys. Med. Rehabil. 92 (4), 578–584.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 162-1 Treatment options for a child with spasticity. Fig. 162-3 Assistive equipment. Fig. 162-4 Assistive recreational devices. Fig. 162-5 Constraint-induced movement therapy. Fig 162-6 A wheelchair enables most patients with paraplegia mobility within the community. Box 162-1 Principles of Pediatric Neurorehabilitation. Box 162-2 Criteria for Admission to a Comprehensive Pediatric Rehabilitation Program. Box 162-3 Botulinum Toxin—Patient Selection. Box 162-4 Intrathecal Baclofen Therapy—Patient Selection. Box 162-5 Intrathecal Baclofen Therapy—Complications. Box 162-6 Selective Dorsal Rhizotomy—Patient Criteria Selection. Box 162-7 American Spinal Injury Association Classification of Spinal Cord Injury.

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163  Pain Management and Palliative Care John Colin Partridge and Elizabeth E. Rogers

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

PAIN MANAGEMENT Introduction Pain has been defined as “an unpleasant sensory and emo­ tional experience associated with actual or potential tissue damage, or described in terms of such damage” from thermal, chemical, or mechanical stimuli. Nociception, or pain percep­ tion, is the series of electrochemical events after the tissue damage or injury, excluding any emotional correlates of the noxious sensation. Acute pain is common in pediatric medical encounters, and chronic pain affects an estimated 15% to 30% of children. Only 20% of patients achieve effective relief of chronic pain.

Historical Background Studies from the 1970s into the 1990s documented under­ treatment of pediatric patients compared with adults under­ going uncomfortable diagnostic procedures (e.g., lumbar puncture) and even for major surgical procedures. Newborn infants have both the neurophysiologic basis necessary to experience and remember pain and an intact and functional opiate receptor system. Appropriately, routine pain assessment is now standard of care, and there is consensus on the need to prevent and treat pain in pediatric patients (Hall and Anand, 2014).

Physiology Nociceptors transduce a noxious stimulus into electrical sensory nerve activity, and the sensory information is pro­ jected to the central nervous system via several types of fibers to the dorsal root and on to the medial and lateral divisions of the dorsolateral fasciculus, then forming synapses within the laminae of spinal cord gray matter (Simons and Tibboel, 2006). Neurons within the spinal cord relay information via the long ascending tracts to various portions of the brain, including the locus ceruleus, thalamus, hypothalamus, ante­ rior and posterior cingulate gyrus, amygdala, insular cortex, and somatosensory cortex, forming what has been termed the “pain matrix.”

Developmental Differences Fetal stress responses to pain have been documented as early as 18 weeks’ gestation, with peripheral, spinal, and supraspi­ nal capacity for afferent pain transmission by 26 weeks’ gesta­ tion (Lee et al., 2005). Neonates demonstrate characteristic facial expressions, aversive body movements, alterations in cardiac activity, and changes in cry in response to painful stimuli. Nociceptive receptors are fewer in number in children; so tissue damage must be more significant before a pain response is elicited. Young infants may perceive pain more intensely than older children or adults because inhibitory pathways develop later than afferent excitatory pathways. Inadequately treated pain in premature infants is associated with adverse short-term effects (e.g., more postoperative com­

1256

plications); the accompanying physiologic changes (increases in heart rate, blood pressure, cardiac variability, autonomic tone, venous pressure, cerebral blood flow, and intrathoracic and intracranial pressure) may augment the risks for intraven­ tricular hemorrhage or white-matter injury in the immature brain. Repetitive pain may lead to accentuated neuronal apop­ tosis, wind-up, pain syndromes, long-term behavioral changes, and diminished visual-perceptual abilities at school age (Grunau et al., 2009).

Clinical Assessment Infants and children demonstrate nonspecific but consistent behavioral, physiologic, and autonomic responses to pain (Box 163-1). There is no single, uniform, standard technique for assessing pain in neonates or children. Biochemical responses to pain, (cortisol, catecholamines, beta-endorphins, insulin, glucagon, renin-aldosterone, growth hormone, and prolactin) are not specific to pain. Self-report, usually by linear analog scale, is regarded as most reliable among children having sufficient cognitive capacity. For preverbal patients, pain assessment is best achieved using multidimensional scales, including behavioral, physiologic, and autonomic responses. Behavioral observa­ tional scales are used for pain assessment with children under the age of 4 or with cognitive impairment. Toddlers and pre­ school children can often use standardized, semiquantitative pain assessment tools (poker chips, cartoons of faces, a pain thermometer, and colors or words) to rate pain intensity. Chil­ dren of 8 years or older can effectively use questionnaires or visual analog scales designed for adults. Newer studies are investigating the use of near-infrared spectroscopy and EEG to monitor neonatal cortical pain responses.

Management Pain, acute or chronic, should be assessed regularly and treated aggressively with nonpharmacologic methods and appropri­ ate analgesics with around-the-clock dosing tailored to indi­ vidual patient needs. In neonates, nonnutritive sucking (with or without sucrose), distraction, breastfeeding, swaddling, kangaroo care, contralateral tactile stimulation, massage, acu­ puncture, music therapy, and multisensorial stimulation can decrease the pain severity and needs for pharmacologic treat­ ment. Nonpharmacologic interventions should be develop­ mentally appropriate for older patients. When pharmacologic management is required, regular doses should be ordered at appropriate intervals with added “as necessary” medication for breakthrough pain (Howard et al., 2008). Doses should be titrated according to response. Mild pain that is unresponsive to cognitive techniques or sucrose in neonates can be treated with nonsteroidal antiin­ flammatory (NSAIDs) drugs or acetaminophen. For moderate pain, oral “weaker” opioids or combinations of opioids and NSAIDs or acetaminophen can be used. Severe pain requires more aggressive parenteral opioids such as morphine or



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Pain Management and Palliative Care

BOX 163-1  Responses to Painful Stimuli BEHAVIORAL RESPONSES TO PAIN 1. Crying, whimpering 2. Facial expressions: brow bulge, eye squeeze, and deepening of the nasolabial folds 3. Active movement and attempts to withdraw from the painful stimulus a. Thrashing b. Tremulousness c. Limb withdrawal, flexion d. Bicycling e. Arching 4. Disorganized behavior; limpness and flaccidity 5. Flexor reflexes; leg withdrawal 6. Exaggerated reactivity 7. State changes a. Decreased sleep periods b. Rapid changes in state cycles c. Decreased rapid eye movement (REM) sleep PHYSIOLOGIC/AUTONOMIC RESPONSES 1. Changes in heart rate and variability 2. Respiratory rate and quality 3. Fluctuations in blood pressure 4. Decreased transcutaneous oxygen and carbon dioxide levels 5. Oxygen desaturation 6. Increased intracranial pressure 7. Palmar sweating 8. Pallor 9. Flushing 10. Pupillary dilatation 11. Increased catabolic state

fentanyl. Intractable pain or unacceptable toxicities of pain medications may require nerve blocks or intraspinal anes­ thetic infusions. For prolonged pain, neuropathic pain, addic­ tive behavior, history of addiction, or complicated family or psychosocial issues, referral to a multidisciplinary pain service consultation may be helpful.

Types of Pain Medications Aspirin, Acetaminophen, and NSAIDs Aspirin is used less commonly as an analgesic in pediatrics because of its association with Reye’s syndrome. NSAIDs are most effective as preemptive agents or for treatment of mild to moderate pain of somatic origin. Acetaminophen is used widely for minor pain and discomfort. Ibuprofen and naproxen have gained wide acceptance in pediatric use and are equally effective. For children who cannot tolerate oral dosing, ketorolac is available. Concurrent use of NSAIDs can reduce opioid dosing needed for effective analgesia. The use of more than one NSAID concurrently offers little therapeutic advantage and increases side effects. Dosage guidelines and maximal doses are summarized in Table 163-2.

Opioids Opioids are the mainstay of treatment of severe pain, opera­ tive procedures, postoperative pain relief, and chronic painful medical conditions in neonates and children. Agonistantagonist drugs are not recommended as they may precipi­ tate withdrawal if given concomitantly with full agonists, and they have have limited routes of administration. Suggested guidelines for opiate-naive patients are shown in Table 163-2.

TABLE 163-2  Dosage Guidelines for Analgesics Drug

Dose

NONOPIOID ANALGESICS Sucrose 0.2 mL of 30% solution* 10–15 mg/kg Acetaminophen Maximal daily dose Infants: 32 wks: 60 mg/kg Neonates 28–32 wks: 40 mg/kg Ibuprofen 6–10 mg/kg Naproxen 5–6 mg/kg Aspirin† 10–15 mg/kg Ketorolac 0.5 mg/kg

Interval (Hr)

Route

4

PO PO, PR

6 8–12 4–6 8

OPIOID ANALGESICS (INITIAL DOSES AND INTERVALS) Bolus: 0.1 mg/kg 2–4 Morphine‡ Infusion Children: 0.03 mg/kg/hr Infants: 0.01–0.03 mg/ kg/hr Term neonates: 0.005–0.02 mg/kg/hr Preterm neonates: 0.002–0.01 mg/kg/hr Oral immediate release: 3–4 0.3 mg/kg Oral sustained release 20–35 kg: 10–15 mg/kg 8–12 35–50 kg: 15–30 mg/kg 8–12 0.1–0.2 mg/kg 3–4 Oxycodone Methadone 0.1 mg/kg 4–8 Fentanyl Bolus: 0.5–1.0 µg/kg 1–2 Infusion Children: 0.05–2.0 µg/ kg/hr Infants: 1–2 µg/kg/hr Term neonates: 0.05–2 µg/kg/hr Preterm neonates: 0.05–1 µg/kg/hr Transdermal: Children: 12.5 µg/hr Hydromorphone Bolus: 0.02 mg/kg 2–4 Infusion: 0.006 mg/kg/ hr Oral 0.04–0.08 mg/kg 3–4

PO, PR IV IV IV IV IV IV PO PO PO PO IV, PO IV IV IV IV IV TD IV IV PO

*Optimal dose not established. † Restricted use for antiplatelet or anti-inflammatory effect. ‡ No ceiling effect for severe pain. IV, intravenous; PO, by mouth; PR, rectal; TD, transdermal. (Adapted from: Berde, C.B., Sethna, N.F., 2002. Analgesics for the treatment of pain in children. N Engl J Med 347, 1094–1103; Stevens, B. et al., 2000. Treatment of pain in the neonatal intensive care unit. Pediatr Clin North Am 47, 633–650; Holder, K.A., Patt, R.B., 1995. Taming the pain monster: pediatric postoperative pain management. Pediatr Ann 24, 164–168; Tobias, J.D., 2000. Weak analgesics and nonsteroidal anti-inflammatory agents in the management of children with acute pain. Pediatr Clin North Am 47:527–543.)

As opiate agonists have no therapeutic ceiling, dosages should be adjusted to meet the patient’s individual needs. Clinicians should not hesitate to treat pain aggressively out of fear for later addiction. Increased risks for respiratory depression in young infants younger than 6 months of age require close cardiorespiratory, and oxygen saturation monitoring. Metha­ done, a long-acting opioid agonist, has been utilized in com­ bination therapy for children with cancer pain. Fentanyl is the drug most often used for short procedures because of its rapid onset, peak effect, and short duration of action.

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PART XIX  Care of the Child with Neurologic Disorders

Opioids may be administered subcutaneously, orally, rec­ tally, transdermally, or intranasally, or by patient-controlled analgesia in children over age 7 years. For some procedures, oral transmucosal or transdermal fentanyl provides an alterna­ tive for conscious sedation, although emesis is a frequent side effect. Rectal administration can be utilized when oral dosing is contraindicated; intramuscular injection should be a last resort. Tolerance may develop more rapidly with continuous infusions and with use of synthetic opioids. Opiate with­ drawal can occur when opioids are discontinued abruptly after several days of exposure. Although considered safe, bolus opioids are associated with an increased incidence of severe intraventricular hemorrhage, white matter injury, and shortterm neurodevelopmental abnormalities.

Procedural Sedation and Analgesia Methods such as perioperative preparation, relaxation train­ ing, distraction, guided imagery, cognitive interventions, and hypnosis may reduce the need for pharmacologic treatment for minor procedures. More uncomfortable procedures require deeper sedation, more appropriately performed by anesthesi­ ologists, intensivists, or emergency physicians experienced in deep sedation techniques and monitoring. The American Academy of Pediatrics has defined two levels of sedation for procedures that are less deep than general anesthesia: 1) con­ scious sedation, a medically controlled state of depressed consciousness that preserves protective reflexes, airway, and responses to physical stimuli or verbal commands; and 2) deep sedation, involving depressed consciousness or uncon­ sciousness when the patient is not easily aroused, cannot protect the airway, or respond to physical stimuli or verbal commands (Committee on Drugs, 2002).

Analgesia Topical analgesia such as EMLA (eutectic mixture of topical anesthetics, prilocaine, and lidocaine) can reduce the discom­ fort of minor procedures. For very brief procedures, ethyl chlo­ ride or fluoromethane can provide limited analgesia. Local anesthetics or peripheral nerve blocks should be used for lumbar punctures, difficult intravenous cannulation, suturing, or procedures involving prolonged pain. For surgical proce­ dures, fentanyl is preferable because of its faster onset, shorter duration, and lack of a histamine-inducing effect. For longer duration procedures, morphine remains the preferable agent. Ketamine induces profound analgesia while maintaining spontaneous respiratory activity, airway tone, and protective reflexes; it may be the drug of choice for emergency procedures when the patient has not fasted. When used in conjunction with propofol for short-term procedural sedation, doses and side effects are reduced.

Sedation Benzodiazepines are the most commonly used drugs for sedat­ ing children, particularly in pediatric intensive care. Mid­ azolam is the preferred drug for procedural sedation given its rapid onset of action, short half-life, and potent sedative and anxiolytic effects. For painful procedures, benzodiazepine sedation should be accompanied by opioid analgesia, and patients should be monitored for hypoxia or respiratory depression. Barbiturates are regarded as the sedatives of choice for diagnostic imaging in children younger than 3 years of age but provide no analgesia. Chloral hydrate, an acceptably safe sedative without analgesic efficacy, can be used for nonpainful procedures such as electroencephalograms and diagnostic imaging in children younger 3 years of age, although it has a long half-life and concerns about potential carcinogenicity.

Given at subanesthetic doses, intravenous ultrashort-acting agents (etomidate, methohexital, propofol, remifentanil, and thiopental) can be used for procedural analgesias but should be used only by certified practitioners due to risks for overse­ dation or rapid swings in consciousness.

Types of Pain Neuropathic Pain Neuropathic pain is seldom responsive to opioids, often requiring multiple modalities for effective pain relief. Analge­ sic agents recommended for first-line medications for neuro­ pathic pain in pediatric patients are gabapentinoids, tricyclic antidepressants, and serotonin noradrenaline reuptake inhibi­ tors. For moderate to severe pain, tramadol and controlledrelease opioid analgesics are recommended as second-line medications, with cannabinoids now recommended as thirdline treatments. Other drugs for management of neuropathic pain include methadone, less efficacious anticonvulsants (e.g., lamotrigine), tapentadol, or botulinum toxin. Phantom pain after amputation may respond to preemptive regional anes­ thesia, antiepileptics, tricyclic antidepressants, calcitonin, topical agents, or intrathecal medication. Nerve trauma may be treated with injected local anesthetics, steroids, neurolysis, antiepileptics, tricyclic antidepressants, or mexiletine. Neu­ ropathies after chemotherapy can be treated with antiepilep­ tics, tricyclic antidepressants, or mexiletine.

Pain in Children With Significant Neurological Impairment Children with cerebral palsy or developmental delays do expe­ rience pain despite some reports of blunted pain responses or insensitivity to pain. Pain from spasticity and muscle spasms can be treated with diazepam, dantrolene, oral baclofen, or botulinum toxin. Oral analgesia is the preferred route as intra­ muscular injections may be more painful in children with decreased muscle mass. Subcutaneous and transdermal administration can be used for chronic administration. Patients with neurologic impairment are more likely to have pain discounted or denied and thus may have pain treated ineffectively. In patients too impaired to communicate pain levels, behavioral responses should be regarded as effective surrogate indications for analgesic treatment. Analgesic needs must be balanced by the recognition that systemic opioids may have undesirable side effects such as respiratory depres­ sion or constipation.

Migraine and Headache NSAIDs or weak analgesics can be given for mild to moderate pain from tension headaches and to many children with migraine attacks. Once a chronic pattern is established, cognitive-behavioral techniques such as biofeedback and relaxation therapy may help alleviate headaches. Practitioners should be aware of the possible development of medication overuse headache when NSAIDS or opiates are used chroni­ cally (Lewis et al., 2002, Lewis et al., 2004). Sumatriptan is an effective and safe abortive treatment; dihydroergotamine and ibuprofen may help interrupt episodes. Other drugs studied for prevention of migraine include beta-blockers, calciumchannel blockers, and antidepressants. For migraine, the hall­ mark of effective control is treatment early in an attack.

Summary Pain in pediatric patients is often underrecognized and under­ treated. Relief of pain is one of the most important aspects of



ethical pediatric care. Judicious use of nonpharmacologic modalities, analgesics, and anxiolytics to treat pain is recom­ mended until further research indicates the medications and dosing schedules that relieve pain and pose the least side effects or neurodevelopmental risks.

PALLIATIVE CARE Introduction At least 500,000 children suffer life-threatening medical con­ ditions such as extreme prematurity, heritable disorders, or acquired diseases warranting palliative care services; of these, 15,000 die each year (Feudtner et al., 2011; Himelstein et al., 2004). Nearly half of pediatric deaths and over 70% of deaths from chronic complex conditions occur in hospital; of these, nearly half occur in an intensive care setting. It is estimated that only 5000 to 7000 children receive hospice care or formal palliative care services and that another 10,000 to 15,000 children could benefit from them. Recent population-based studies have documented that 15% of pediatric hospital deaths are from neurologic or neuromuscular diseases. Neu­ romuscular disorders cause 3% to 4% of childhood deaths in all age groups but account for 18% of deaths of children with complex chronic conditions (Feudtner, 2007). A third of the children referred for palliative care have neuromuscular condi­ tions, and another 41% have genetic or congenital conditions that may have neurologic consequences (Ho and Straatman, 2013). Children with neuromuscular disorders tend to be referred for palliative care earlier than those with other chronic dis­ eases (cancer, human immunodeficiency virus, cystic fibrosis, sickle cell disease, or chronic lung disease); however, 30% to 35% of children with metabolic diseases, muscular dystrophy, severe cerebral palsy, and posttraumatic brain injury receive only end-of-life care. Some neurologists may feel they lack the training or experience in addressing the complex needs of dying children or communicating bad news to young patients and their families.

Historical Background Palliative care as an adjunct to modern medical care began with the founding of St. Christopher’s Hospice by Cecily Saun­ ders in 1967. Although the first pediatric hospices started in 1982, it is only recently that widespread institution of pediat­ ric palliative care has been recommended, including in inten­ sive care settings. Pediatric palliative care is a cost-effective way to care for dying children, decreasing procedures and intensive care days, increasing support, and facilitating withholding or withdrawing aggressive measures.

Definitions of Palliative Care Best provided by a multidisciplinary team (Box 163-3), the focus of palliative care is to provide comprehensive, compas­ sionate, and developmentally appropriate care that optimizes the quality of life by meeting the physical, psychological, emo­ tional, social, and spiritual needs of the child as the disease progresses. The intent is a decent or good death, free from avoidable distress and suffering for patients, families, or caregivers.

Components of Palliative Care Identifying the Need Children with neuromuscular diseases and their family members have palliative care needs that differ from those of

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BOX 163-3  Interdisciplinary Team for Palliative Care • Primary care provider, community pediatricians, subspecialists • Pediatric registered nurses/case managers • Pediatric social worker • Child life therapist • Spiritual care counselor • Home health aides • Pediatric medical consultants • Physical/occupational therapists • Clinical pharmacist • Clinical dietitian • Volunteers • Insurers/payers • Other providers • Regional centers • Durable medical equipment companies • Community pharmacies

dying adults. A series of questions can help inform the coun­ seling process and considerations about the appropriateness of further interventions of changing the goals of care when necessary. First, what has been the child’s health status and quality of life previously? Second, how likely is the child to survive the current life-threatening condition? Third, what degree of suffering is entailed if the child survives in the short term? Fourth, what is the anticipated quality of life in the future and how long is it expected to endure? Fifth, how likely are future crises or deteriorations? Discussions about treat­ ment options should assist the child and parents in selecting which measures should or should not be done (Feudtner 2007). Critically ill or dying children benefit from being with and comforted by their parents. Providers should allow time for the family to nurture their child and recognize the emotional stress of anticipating neurologic compromise or death. Provid­ ers should attempt to give parents and, when appropriate, children some sense of control in their care.

Transition in Goals of Care Palliative care should not be restricted to children expected to die soon when therapeutic interventions fail or are withdrawn. Providers should learn to recognize when needs for palliative care become more salient with neurodegenerative diseases or progressive neuropathies or as complications from a static encephalopathy impinge on quality of life. In conditions asso­ ciated with a predictably shortened life span (e.g., trisomy 13 and 18, neurodegenerative diseases, anencephaly, and many inborn errors of metabolism), the primary focus of care is limited to optimizing quality of life. For diseases with less certain prognoses (for example, traumatic or hypoxic brain injury, some central nervous system or spinal tumors, congeni­ tal myopathies and neuropathies), it is appropriate to intro­ duce palliative care at an early stage that can soften the effect of nonintervention discussions later in the disease trajectory. With older children, it is important to address future choices for care before the neurologic status deteriorates and bars them from participating in healthcare decisions. Parents must be given the information necessary to decision making and be made aware of the limits of our prognostic ability. An essential step is to clarify, and reassess periodically, the goals of continu­ ing, rather than limiting, ongoing interventions as the chances for cure lessen.

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Levels of Care A shift from curative to palliative treatment goals does not imply that all ongoing medical interventions must be aban­ doned. It is important to clarify specific measures that will continue to be utilized, as well as what level of noninterven­ tion appears most appropriate. An order proscribing all or selected resuscitative measures in the event of a cardiac or respiratory arrest (a “Do not resuscitate” or “Do not attempt resuscitation” order) is often an appropriate first step; it is not a half-hearted resuscitation (“slow code”) order. It should be discussed with parents and the healthcare team before being written. Withholding of life-sustaining measures involves an agreement not to institute medically indicated measures given that more aggressive interventions would not improve a grim prognosis or quality of life. Interventions deemed futile are not required and should be discontinued. Withdrawal of lifesustaining measures involves the discontinuation of current medical interventions deemed either futile or no longer appropriate to the child’s best interests.

Communication Patterns of communication sensitive to the child’s develop­ mental status and to the parents’ emotional state are critical to good palliative care. The degree to which the child can participate in decision making increases as children develop sufficient cognitive capacity (over the age of 7). Pictures, stories, toys, music, or other family rituals can help younger children communicate their preferences. Whenever the child has the cognitive capacity to participate, it is important for providers to allow the child the time to express hopes, dreams, and fears. Infections of the nervous system, hypoxia-ischemia, neurodegenerative diseases, or traumatic brain injury may limit older children’s decision-making capacity. Conversations about changing the goals of care when the disease progresses are best held by continuity providers over a period of time, allowing patients or parents time for ques­ tions, second opinions, reflection, and informed decision making. To minimize the sense of giving up or abandoning their child, it is critical that parents understand that the goal of care will be to do everything that should be done rather than everything that can be done. The primary focus is what is important to the child and the family: longer life, pain-free, time with family members, spe­ cific desires, environment and setting, time to say goodbye in ways that respect family values. A structured approach can help physicians deliver difficult news and negotiate goals of care (Box 163-4). Communications should be simple, direct, clear, and honest explanations that relate the expected outcomes of each treatment option. It is critical to avoid promising outcomes

that are not reasonably feasible, overwhelming the parents, or leaving them in despair.

Healthcare Decision Making Children usually have no previously documented preferences for healthcare decisions; the first issue is to identify who will be making healthcare decisions. In general, advanced direc­ tives are not relevant in pediatrics; parents are assumed to be the primary proxy decision makers for young children, although their discretion is not limitless. Older children them­ selves have the right to determine what quality of life means to them, with support from their parents and physicians. Parents (or competent adolescents) determine the quantity of information necessary for to informed decision making. If decisions seem not to reflect a full understanding of the disease, the goals of care and expected outcomes should be readdressed. Decisions that do not concur with the provider’s choices should be respected when taken in the child’s best interests. Ethics committee consultation can help clarify impediments to decision making, the limits to parental deci­ sion making, or the need to advocate for the child or refer to child welfare. The resulting care plan should be disseminated to the healthcare team and any limitations to care clearly documented.

Persistent Vegetative State Although there is no consensus as to whether children in a persistent vegetative state experience pain and suffering, it seems prudent to treat suggestive signs and symptoms. Deci­ sions to withdraw or withhold life-sustaining measures should be made only when neurodiagnostic testing and a sufficient period of observation suggest there is no chance for a mean­ ingful recovery. Decisions involving the withholding of fluids or hydration remain controversial, even when deemed appro­ priate responses to the child’s medical situation.

Environment for Death and Dying When parents prefer continued inpatient care, a private space for families to gather before and after the child’s death is rec­ ommended (e.g., a separate comfort care room) but should not impede nursing medical attention to pain and symptoms. Elective transfer to a lower level of care or to a hospice may be preferred and feasible despite concerns about changing care providers late in their child’s disease. Death at home from neuromuscular disorders is preferred by an increasing propor­ tion (25%) of children and parents. Plans for a death at home require a continuity provider skilled in managing pain and suffering and able to provide 24-hour coverage from discharge through the child’s death and the parents’ bereavement.

Support During Dying BOX 163-4  Protocol for Palliative Care Communications SPIKES: A PROTOCOL FOR DELIVERING BAD NEWS AND NEGOTIATING GOALS OF CARE • Setting: create environment conducive to communication • Perception: determine what the family knows • Invitation: determine how the family would like information delivered • Knowledge: provide information • Emotions: empathetically support patient • Summarize: set realistic goals, make a treatment plan, and follow through • Repeat: review and revise frequently

When death is near, providers can commit to aggressive treatment of pain or suffering and help parents envision the child’s imminent death and the likely timing. Overall support when a child is dying involves a balance between respect for privacy and close, but noninvasive, attention to the child’s and the family’s needs in collaboration with primary care pediatricians, social workers, clergy, and psychologists or psychiatrists.

Assessment and Treatment of Symptoms Providers should reevaluate the efficacy of pain and symptom management as the disease progresses. Many neurologists will feel comfortable treating seizures, insomnia, and depres­ sion in dying patients but may prefer to have primary care



Pain Management and Palliative Care Practice sphere Physical concerns

Area of assessment

Plan

Identify pain or other symptoms

Create and disseminate pharmacologic and nonpharmacologic treatment plan Place emergency medications in the home Refer child to pain and palliative care specialists as needed

Identify child and family’s fears and concerns

Address child and family’s fears and concerns honestly Assure child and family they will not be abandoned Address concerns of child’s siblings and extended family

Identify child’s coping and communication styles

Adjust care plan to meld with child and family’s coping and communication styles Communicate with child in a developmentally appropriate fashion Explain death concepts and developmental stages of death understanding

Discuss previous experiences with death, dying, other traumatic life events, or special issues such as substance abuse or suicidality

Modify care plan and choices on basis of child’s previous experiences Consider referring child and family to mental health professionals as needed

Assess resources for bereavement support

Make plan for follow up of family after child’s death Assure family members they will not be abandoned

Perform a spiritual assessment (review child’s hopes, dreams, values, life meaning, view of role of prayer and ritual, beliefs regarding death)

Consider referring child to culturally appropriate spiritual care provider Offer to help explain child’s illness to spiritual provider, with family’s permission Allow time for child and family to reflect on life’s meaning and purpose

Identify decision makers

Include key decision makers Communicate decision-making information to entire team

Discuss illness trajectory

Provide information as necessary to make the subject understandable Establish consensus regarding illness trajectory Identify effect of illness on child’s functional capacity and quality of life Identify probable time until death

Identify goals of care

Establish whether goals are curative, uncertain, or primarily comfort Communicate goals to healthcare team

Think about issues regarding care or concerns near end of life

Create or disseminate medical plan (including do-notresuscitate orders as necessary), reflecting choices for specific interventions related to change in health status Provide anticipatory guidance regarding physical changes at time of or near death, whom to call, who will manage child’s symptoms

Establish means of communication and coordination with healthcare team

Identify care coordinator and route of contact that is always available Recruit new personnel as needed to achieve goals (such as hospice or palliative care specialists) Make plan-of-care information available to team

Establish child and family’s preference for location of care

Assure child or family that stated goals of care can be achieved in preferred environment Create and disseminate plan for location of death, contacts at time of death, and pronouncement of death

Become familiar with child’s home or school environment

Create and disseminate care plan for all relevant environments Try to visit care sites such as school to provide education and support, if possible in partnership with community agencies

Address child’s current and future functional status

Order medical equipment such as wheelchair, suction, commode, or hospital bed for anticipated needs

Inquire about the financial burden child’s illness places on family

Offer assistance from social services, financial counselors, or other supports as available in the community

Psychosocial concerns

Spiritual concerns

Advance care planning

Practical concerns

Figure 163-3.  Essential elements in the approach to pediatric palliative care.

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pediatricians or palliative care specialists manage other fre­ quently encountered end-of-life symptoms (dyspnea, anxiety, fatigue, fever, bleeding, nausea, skin breakdown, anorexia, dehydration, and constipation). Pain should be treated aggressively with analgesics. Termi­ nal sedation with opioids is effective and justifiable in alleviat­ ing severe or unremitting pain at the end of life despite risks of suppressing respiratory drive and thereby hastening death. Fears of addiction to opioids are unwarranted. Paralytics are not appropriate when life support is being withdrawn. Anxio­ lytics may help terminal agitation and perhaps air hunger experienced in the terminal phases.

Developmental, Emotional and Spiritual Concerns Care for a dying child requires candor, openness, and an emo­ tional availability to the child’s experience of illness and imminent death in a developmentally appropriate manner. Children come to understand death as a change of being by age 3 and as a universal fact of living by age 5 to 6; by age 8 to 9, they have gained a concept of their personal mortality. Developmentally appropriate interactions that respect the children’s spiritual nature will allow providers to explore issues of love, hope, security, loneliness, and concepts of the legacy that the child will leave to family and friends. Family routines and rituals add structure and a sense of normality and should be encouraged as the medical condition worsens.

Bereavement Children are aware of dying and disease; they understand much more about death and dying than adults often realize and do not need to be protected from death and dying as much as they need help making it understandable. Parents often regret not having talked with the child about death. Dying children may grieve about their impending death, the loss of functional status, or the inability to participate in current or future events. They may fear how their family members will cope after their death. When heritable neuro­ muscular disorders pose a future risk to affected siblings, par­ ticular care is necessary to deal with concerns about subsequent pregnancies or fears of future illness. Providers should allow family members the opportunity to spend time grieving with their deceased child alone, with time to talk and time to be silent. It may be helpful to celebrate their child’s life, recap the family’s experience, value their loss and emotions, and help them contact family members and friends. Parents should be offered religious observances, social services support, family support groups, or other supportive measures to help them cope. Funerals can help siblings remember and value the dead child. Psychological counseling may help parents and siblings work through the emotional trauma.

Follow-Up Conference Many physicians arrange a postdeath conference to see how the parents are coping. Clarification of the diagnosis, etiology, end-of-life events, and (when relevant) autopsy results can provide solace, an opportunity to address parents’ questions about their decisions, a method of reducing guilt, time to detail the implications of heritable neurologic disorders and to offer referrals for counseling or support.

Barriers to Palliative Care Providers may encourage treatments with little hope of a favorable outcome, abandoning them only when death seems inevitable. A late transition from curative care to palliative care is a frequent problem. For many pediatric neurologic diagnoses, it is difficult to predict which children will die of

their disease or the quality of life as the disease progresses. Parents’ recognition that death is inevitable often lags behind their understanding of the diagnosis.

Summary Neurologists can offer children and their families the compre­ hensive palliative care that can improve children’s and fami­ lies’ experience of end-of-life care (Fig. 163-3). Primary-care neurologists should develop expertise in the palliative care of children with life-threatening neuromuscular conditions. Consultant neurologists should coordinate their palliative care efforts with primary pediatric providers, palliative care specialists, and the interdisciplinary team. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Committee on Drugs, American Academy of Pediatrics, 2002. Guide­ lines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures. Pediatrics 110, 836–838. Feudtner, C., Kang, T.I., Hexem, K.R., et al., 2011. Pediatric palliative care patients: a prospective multicenter cohort study. Pediatrics 127, 1094–1101. Feudtner, C., 2007. Collaborative communication in pediatric pallia­ tive care: a foundation for problem-solving and decision making. Pediatr. Clin. North Am. 54, 583–607. Grunau, R.E., Whitfield, M.F., Petrie-Thomas, J., et al., 2009. Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants. Pain 143, 138–146. Hall, R.W., Anand, K.J., 2014. Pain management in newborns. Clin. Perinatol. 41 (4), 895–924. [Epub 2014 Oct 7]. Himelstein, B.F., Hilden, J.M., Boldt, A.M., et al., 2004. Pediatric pal­ liative care. N. Engl. J. Med. 350, 1752–1762. Ho, C., Straatman, L., 2013. A review of pediatric palliative care service utilization in children with a progressive neuromuscular disease who died on a palliative care program. J. Child Neurol. 28, 40–44. Howard, R., Carter, B., Curry, J., et al., 2008. Analgesia review. Paediatr. Anaesth. 18 (Suppl. 1), 64–78. Lee, S.J., Ralston, H.J., Drey, E.A., et al., 2005. Fetal pain: a systematic multidisciplinary review of the evidence. JAMA 294, 947–954. Lewis, D.W., Ashwal, S., Dahl, G., et al., 2002. Practice parameter: evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 59, 490–498. Lewis, D.W., Ashwal, S., Hershey, A., et al., 2004. Practice parameter: pharmacologic treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology 63:2215–2224. Simons, S.H., Tibboel, D., 2006. Pain perception development and maturation. Semin. Fetal Neonatal Med. 11 (4), 227–231. [Epub 2006 Apr 18].

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 163-1 Questions to address prognostic uncertainty in palliative care decisions for children. Fig. 163-2 Model for concurrent components of palliative care. Box 163-2 Examples of Neuromuscular Conditions that may be Appropriate for Pediatric Palliative Care. Table 163-1 Examples of Pain Assessment Scales for Differing Developmental Ages.

164  Ethical Issues in Child Neurology David L. Coulter

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION The task of ethics in general is to understand how human beings should behave in regard to other persons and to society: to understand what is right and what is wrong. The philosophic study of ethics parallels the growth and development of human society. Morality is understood as the set of generally accepted rules and guidelines for acceptable conduct in society. These social conventions about what is right and wrong constitute the common morality (Beauchamp and Childress, 2012). Philosophic ethics can be thought of as the attempt to develop a rational basis for morality. Although ethics (as a form of philosophy) strives for universal truth, it is inextricably linked to the realities of the human societies whose morality it seeks to understand. Distinguishing between “moral” and “ethical” behavior is often difficult (Bernat, 2008). Perhaps moral behavior may be thought of as a personal attempt to conduct one’s life in conformity with the common morality, whereas ethical behavior may be thought of as a more theoretical or rational attempt to apply philosophic thinking to what is right and wrong. In other words, ethics is a systematic attempt to understand how to live and act morally in a social context. Ethics addresses all aspects of human behavior. Bioethics considers the interaction between biology and ethics. It is defined as the systematic study of the moral dimensions of the life sciences and health care, and it includes consideration of the health- and science-related moral issues in the areas of public health, environmental health, population ethics, and animal care. Clinical ethics is a subcategory of bioethics that refers to the day-to-day moral decision making of those caring for patients. More specifically, clinical ethics refers to the identification, analysis, and resolution of moral problems that arise in the care of a particular patient (Jonsen, Siegler, and Winslade, 2015). Medical ethics is a subcategory of clinical ethics that refers to the moral behavior of physicians (and is thus distinguishable from nursing ethics, social work ethics, and pastoral ethics). Neuroethics is a concept that cuts across most of these distinctions. As an area of bioethics, it considers the interaction between the neurosciences and clinical neurology and ethics in all of the same areas of study as for bioethics, noted previously. As a clinical discipline, it addresses the care of patients with neurologic disorders. As an area of medical ethics, it refers most directly to the moral behavior of neurologists and neurosurgeons. Thus child neurologists interested in ethics need to be knowledgeable about the general approaches to ethics, the emerging scope of bioethics, and the more specific approaches to ethics in medicine, nursing, and other health-related disciplines. The goal of this chapter is to provide child neurologists interested in ethics with the tools they need to identify, analyze, and resolve moral problems they may encounter in the care of children and adolescents with neurologic disorders. The first part covers the most significant theoretical approaches to ethics as they apply to child neurology. The second part considers the varied duties of the child neurologist working

with patients with morally problematic issues. These tools should help child neurologists to frame the ethical problems that arise in their work. Developing a framework for the analysis and identifying the key ethical question or questions are the first step in approaching these cases. The next step is to consider the most relevant and appropriate ethical approach, which may vary considerably from case to case. The final step is to synthesize all of the available information (usually through discussion with colleagues, patients, and family) and attempt to answer the question as it was framed.

THEORETICAL APPROACHES TO ETHICS Philosophy may be a search for truth, but the fact is that there is no one, true, universal approach to ethics. Physicians who want to act ethically should be aware of the several major ethical theories that compete for attention in contemporary medical practice. Two ethical theories in particular dominate thinking in Western philosophy. Utilitarianism is derived from the writings of Jeremy Bentham and John Stuart Mill. Deontology is derived mainly from the writings of Immanuel Kant. Elements of both theories persist in modern ethical approaches to clinical problems, usually in somewhat modified form. Most physicians will find themselves using utilitarian thinking on some occasions and deontological thinking on other occasions, or using some combination of both when it is necessary to resolve an ethical dilemma in clinical practice. A number of other ethical approaches have been developed more recently and also deserve consideration. As a general statement, probably no one theory or approach is optimal in every case in medical practice. A skillful physician will recognize which approach is best suited to the challenges of a specific ethical situation. Knowledge about these several ethical theories thus provides the physician with a kind of “ethical toolkit,” from which to select the approach that is most likely to be helpful in analyzing the specific issues present in a particular case.

UTILITARIANISM The essence of utilitarian theory is the idea that the morality of an action is determined mainly by its consequences: the morally right action is the one that produces the best result. Of course, the result of an action may be quite complex and challenging to identify. An action that helps one person may harm another person. Withdrawing support from a child in a vegetative state undoubtedly harms the child because it results in the child’s death, but the action may help the family grieve and may allow society to use limited medical resources to help other patients. The utility principle states that one should act to produce the best overall balance of positive and negative consequences of the act. This idea is embedded in the concept of balancing risks and benefits to achieve the best overall result. Utilitarian theory is often cited to justify actions that are most likely to increase happiness, but other desirable results

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are also possible. Individuals may wish to act in such a way as to increase personal quality of life, enjoyment of and satisfaction with life, success in a preferred career, and general knowledge and understanding, or to strengthen personal relationships. Lawyers and policymakers use the utility principle to produce the best overall balance of justice and fairness for society. Utilitarian thinking is almost intuitive in many aspects of ordinary life. Understanding this form of thinking is important because it may help avoid the potential pitfalls that can result from uncritical application of the theory. Perhaps the most familiar situation is the use of utilitarian theory to justify the killing of defective newborns. Although theoretically logical, such arguments are morally repugnant to persons who apply a different moral standard based on some other approach to ethics. Another problem with utilitarian theory is its failure to protect minorities, which results from its emphasis on producing the greatest good for the majority. The needs of children with rare neurologic disorders can be overlooked if utilitarian thinking allocates scarce medical resources primarily to children with more common and less debilitating disorders.

DEONTOLOGY The term deontology is derived from the root deon, meaning “duty,” and deontological theory is based on the importance of duty. Duty is based more on the intentions that lead a person to act than on the outcomes or consequences of the action. Utilitarian thinking is mostly situational and depends on the specific aspects of a given situation; deontological thinking strives to be more universal and to emphasize decisions that would apply in all relevant situations. Thus Kant’s categorical imperative states that we should act only in a way that is consistent with a universal law or obligation. Using people as means to an end implies that different actions (or reactions) are needed, depending on the end or outcome that is desired; therefore, the actions are not universally applicable. For this reason, deontological thinking stipulates that we should treat all people as “ends” and not as means to an end. This could cause problems in thinking about the morality of organ transplantation if the organ donor is thought of only as a means to the end of survival for the recipient. Clearly, deontological thinking imposes a duty to respect the rights and value of the donor as much as those of the recipient because anyone could be either a donor or a recipient. Deontological thinking emphasizes duties and obligations, but these may conflict. For example, physicians may have different and competing obligations toward patients, families, hospitals, insurance companies, and society. The attempt to describe duties leads to formulation of general or universal rules for moral action, but these rules may also conflict. Rules may be too abstract and impractical to apply to real-life situations. Deontologically based rules do not take into account the messiness of human relationships, a point that it is essential to keep in mind when considering the ethics of care discussed later in this chapter.

Common Morality and Natural Law What are the universal rules that spring from deontological thinking? Most Western philosophers would argue that these rules can be derived from the application of reason—from rational, logical thinking about the nature of human existence. The general argument is that all rational persons would agree that these rules are essential to govern and guide the moral actions of individuals in a cohesive society. The common morality represents the socially approved norms of human

conduct that form the basis of ethical theory. This commonsense understanding of what is needed for individuals to behave in society is not derived from theory, but rather forms the basis for potentially competing theories. Natural law theory is an ancient approach to deriving universal rules through the application of reason. For Thomas Aquinas, natural law sprang from man’s participation in God’s eternal law and was brought into being by the application to action of human intelligence and reasoning. This application leads first to the principle that all things desire that which is good; therefore, good is to be pursued and evil is to be avoided. Good things are those to which man has a natural inclination, such as life (existence), social interaction, family life, and civil government. To pursue these good things, one should act fairly, love God, and love other persons. Secondary precepts or rules (such as the Ten Commandments) follow from these basic principles. Secular interpretations of natural law are as old as Aristotle and are still used in some forms of legal theory. Beauchamp and Childress do not define any specific rules as part of their concept of the common morality, but they do define four principles that are not absolute and that need to be specified based on actual circumstances (Beauchamp and Childress, 2012). These four principles may be seen to correlate with the precepts of natural law: 1. Do good (beneficence). 2. Avoid evil (nonmaleficence). 3. Act fairly (justice). 4. Love one another (autonomy). Whatever the source of the common morality, it is the basis for principlism, the ethical theory based on the application of principles to specific situations.

Principlism Principlism is an approach to ethical problems that is based on the application of the four principles of beneficence, nonmaleficence, justice, and autonomy. It is more of a practical guide than an abstract theory, and it has found widespread acceptance in a variety of settings. It was adopted explicitly in the Belmont Report, which forms the foundation for research ethics in the United States. Although principlism is perhaps the best-known approach to clinical ethical problems, it is by no means the only approach. Understanding principlism is necessary to consider these alternative systems. The principle of autonomy has become preeminent in Western society, although it may be less prominent in Eastern or religiously oriented societies that place a greater value on social harmony. Physicians need to keep this in mind when caring for patients from other cultures. An autonomous choice is one that is based on sufficient knowledge of the facts involved, the ability to understand the situation, and the independence to choose without undue influence of other people. Autonomous individuals can determine for themselves what they think is best, and this principle states that other people should respect these choices, even when they do not agree with or approve of them. Autonomy is the basis for the concept of informed consent, which requires that a patient has the capacity or competence to understand the issues, full disclosure of all of the information needed to make a decision, and freedom from any coercion that might influence the decision. In general, persons younger than 18 years of age are not considered to have the capacity to make fully autonomous choices, although their preferences should be considered and respected, if possible. American law recognizes that persons 18 years of age and older are fully competent, unless a judge



has determined otherwise. This recognition is critically important for young adults with neurologic disorders (such as intellectual disability) that may affect their capacity to make fully autonomous decisions. If capacity is in doubt, the family will need to initiate legal proceedings to obtain guardianship when the person becomes 18 years old. A young adult (over 18 years) with a neurologic disorder that results in limited competence is unable to give informed consent, but that individual’s parents cannot give consent for him or her unless they have obtained guardianship. Failure to obtain guardianship when it is necessary can interfere seriously with timely medical treatment. It should be noted that this age threshold is arbitrary and may differ in other countries. The principle of beneficence encourages physicians to do good or to act in the best interest of the patient whenever possible. This principle can also be interpreted to suggest that physicians should seek to promote an optimal quality of life or satisfaction with life. Considerable debate exists about how to define and measure quality of life. Objective measures are based on the judgments of others, whereas subjective measures are based on the opinions of the patient about what constitutes a satisfying life. In general, preference is given to subjective judgments when they can be known with reasonable certainty. The principle of nonmaleficence encourages physicians to avoid doing harm to patients and dates back to Hippocrates (“primum non nocere”). It is related logically to the principle of beneficence. Both principles are considered when physicians attempt to strike a balance between providing a benefit for the patient (doing good) and not imposing a burden (avoiding harm). This balance may become especially problematic when the same action could produce a good, or desired, effect, along with a bad, or undesired, effect. The classic example is prescription of sufficient medicine to reduce pain while knowing that it may also cause the patient to stop breathing. This problem is known as the situation of double effect. In Catholic moral theory (which contains the most explicit analysis of such situations), an action that causes double effects is morally justifiable only if it meets all of the following criteria: 1. The action itself is not morally wrong (such as killing would be). 2. The intent is to produce the good effect, even though the bad effect may be expected. 3. The good effect is not based on achieving the bad effect. 4. The benefit to be obtained is greater than the harm that might occur. This concept is admittedly difficult to apply in practice. Evaluation of each criterion may be arguable in a specific situation. Perhaps the best that can be expected is that physicians will make a good-faith effort to adhere to the principles involved and seek to obtain the optimal balance between benefit and harm for the patient and family. The principle of justice requires that equals be treated equally, but the basis for an equal distribution of resources may be arguable. Should resources be distributed according to need, effort, merit, contribution to society, or some other factor? Utilitarian, libertarian, communitarian, and egalitarian approaches have been proposed to answer this question. Rawls suggests that resources should be distributed to ameliorate the effects of life’s inherently unfair natural and social lotteries. It may be simply bad luck (“losing the lottery”) that a child is born with a disabling condition or is born into poverty. If the child is not responsible for this condition, then society should act to remedy the situation. According to this rule, unfair situations would presumably have priority over merely unfortunate situations. How many resources should be provided to those who have been unfairly deprived? The limits

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of this redistribution policy may be the extent to which it disables or impoverishes the rest of society. Jonsen et al. (2015) suggest that ethical issues can be analyzed by asking the following four questions (which are, in fact, practical applications of the four principles discussed previously): 1. What are the medical indications for treatment? (principle of beneficence) 2. What are the patient’s preferences? (principle of autonomy) 3. What effect on the patient’s quality of life can be reasonably anticipated? (principle of beneficence) 4. What are the burdens and benefits that may affect the family and society? (principles of justice and nonmaleficence) The questions may be somewhat hierarchic, in the sense that medical indications and patient preferences are usually more important than potential social burdens, but physicians should not be too rigid about this. In fact, asking (and answering) these four questions in a particular case is an excellent way to make sure that the relevant issues are identified and evaluated. These issues can then be considered by the caregiving team, patient, and family. Resolution of the issues may vary from case to case, but at least everyone involved will be able to see how the decision was determined.

Virtue or Character Ethics Virtue can be described as a trait that has positive moral or social value. According to Aristotle, virtuous behavior requires both the right motive and the right action. In other words, wanting (or intending) to do the right thing is not enough by itself. This idea is somewhat at variance with pure deontological thinking, as described previously. In virtue theory, following a presumably universal rule is not necessarily a moral or virtuous act if it produces a bad result. Similarly, doing right for the wrong reason is not necessarily a moral or virtuous act if the motive itself was not virtuous. The catalog of virtues not surprisingly varies from one writer to another. Pellegrino and Thomasma (1993) suggest eight virtues that are necessary for sound medical practice: 1. Fidelity to trust (trustworthiness) 2. Compassion (understanding the patient’s feelings) 3. Prudence (clinical judgment) 4. Justice (in the sense of love and altruism) 5. Fortitude (sustained courage in the face of difficulty or despair) 6. Temperance (balance in one’s life, perhaps also Osler’s sense of equanimity) 7. Integrity (personal honesty and wholeness) 8. Effacement of self-interest (putting the patient’s interests first) They argue that these eight virtues are necessary but not sufficient for physicians to practice ethically. Possessing these virtues provides evidence of good intent but they must be linked to ethical action. They suggest that principlism, although not specifically part of virtue theory, can provide a guide for virtue-based ethical action.

Ethics of Care Care-based ethical thinking is prominent in nursing practice but may be unfamiliar to physicians. It arose as somewhat of an alternative to deontological, rule-based thinking that depends on adherence to more or less rigid principles. It also arose from feminist research studies comparing male and female approaches to ethical dilemma. Gilligan (1982) found

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that males were more likely to look for rules to follow and to insist on adherence to these rules. Females were more likely to look for some situation-based way to resolve a dilemma, taking into consideration the person’s feelings and significant relationships. This “feminine” way is not exclusively reserved for women (or for nurses), of course. Rather, it provides an alternative and perhaps more subjective way to evaluate an ethical problem that is especially relevant when a rule-based approach seems to be inappropriate or unhelpful. Somewhat obviously, care-based ethics does not have any fixed rules. In fact, this perspective challenges the idea that impartial or universal rules should guide ethical action. Instead, it looks at the particularity of the patient and the specific clinical situation and seeks to find answers that fit this unique case. Care-based ethics accepts the fact that emotions have important moral value and must be considered carefully. It also emphasizes the patient’s human relationships and the mutual interdependence of the patient, family, and all members of the caregiving team. A care-based approach to an ethical dilemma would say something like, “That can’t be the only possible ethical solution. There must be another way to resolve this problem that is acceptable to everyone here. We all want to do what’s best for the patient, so let’s think about what that means. Maybe we could start by understanding what the patient is feeling and by talking to the family. We should also talk about how we feel about all of this. Let’s brainstorm some ideas and think about what they would involve. Maybe we need to talk to some more people and get more information. If we keep working at it, we’ll find a way.” This approach will sound familiar to anyone who has been involved in difficult cases in the intensive care unit, which emphasizes the ubiquity and usefulness of this way of thinking in clinical practice. Perhaps an awareness of the sound ethical foundation of care-based ethics will also help clinicians give this way of thinking attention and consideration.

Casuistry Casuistry, or case-based ethics, is another alternative to utilitarian or rule-based ethical approaches. It rejects the very idea of a “moral calculus” that can be analyzed impartially, based on abstract concepts. Instead of a “top-down” approach, based on pure theory, it takes a “bottom-up” approach, based on the particularity of specific cases. Casuistry looks at specific cases and emphasizes points of agreement about those cases. It recognizes that moral intuition may be more important than adherence to principles. It is common knowledge that members of hospital ethics committees often agree on what needs to be done but cannot always say with clarity why they feel that way (or what ethical theory they relied on to make a particular judgment) or whether they share some degree of social commonality. This moral intuition may also reflect the influence of the “common morality” described previously. By looking at the particularities of a specific case, casuistry is also sensitive to contextual influences and individual differences. The method of casuistry is somewhat analogous to the method of case law used in the United States. One first identifies several key cases about which there is a consensus regarding the proper ethical approach. These are cases that have had careful scrutiny in the past and are still believed to be instructive. New cases are then compared with these key cases, selecting those past cases that have the greatest similarity to the current case. One then seeks to develop a consensus about how to resolve the current case, based on how these past cases were resolved. Each new case that is resolved in this way goes into the body of case experience, so that the consensus is revised and modified incrementally in the light of evolving and accruing clinical experience.

One can see that casuistry is very similar to what an experienced clinician does naturally, drawing on his or her experience in past cases to sort out the issues in a new case. One has to be careful about which past cases to consider and to what extent the decisions made in those cases apply to the current case. Experience in past cases may also be conflicting, and it may be difficult to sort out the similarities and differences compared with the current case. One also has to be careful about how much weight should be given to one past case compared with another past case. In a very real sense, every new case is different (as every clinician knows), but there is still much to be learned from past experience. Casuistry provides a sound ethical foundation for using this clinical experience in resolving ethical dilemmas.

Spirituality Spirituality is variously defined, but it can be understood as a belief system that focuses on intangible elements that impart vitality and meaning to one’s life. Because it is based on beliefs, or faith statements, it is not provable through logical argument. Spirituality in medicine is often based on religious beliefs but it need not be. As an expression of ultimate concern, it reflects the elements of our lives that are the most important and make life worth living. Most people have some spiritual beliefs that become prominent when their health is threatened; yet these beliefs are often not considered by physicians and other health-care providers. Physicians may anticipate that patients would have certain beliefs based on knowledge of their religious background, but individual differences exist, even within a religious tradition. A more direct understanding of the patient’s spirituality would be preferable. One approach to understanding the patient’s spirituality is the “three ways of looking.” The first look is to see the person subjectively as an individual human being. Compassion requires distance and objectivity, but this first look requires closeness and subjectivity. It is an attempt to understand the patient’s spiritual beliefs. The second look is to recognize in the other person that which we know to be central to our own existence. With the second look, we can value in the patient that which we most value in ourselves. These values include living, freedom, tolerance, respect, happiness, and satisfaction with life. Physicians would then seek to protect for their patients the values that they would protect for themselves. The third look is more elusive and is an attempt to grasp, through our relationship with another person, the transcendence or divinity that is the basis of our spiritual existence. This third look comes when it is least expected, often in the vulnerability of a frustrating or challenging ethical situation. When we are open to it, it can provide insight, enrichment, and ethical guidance. The three ways of looking can be the basis for a spiritual approach to medical ethics. Three precepts can be identified: 1. Respect in others what I value in myself. This precept is similar to the principle of autonomy but is based on the mutuality of spiritual sharing between physician and patient. 2. Do the most loving thing possible. When we love in the patient what we love in ourselves, we will strive to do that which is best for all. Love—not just duty, convention, rules, or cost containment—is the basis for action. 3. Seek guidance from the source of my own and the other person’s being, through deep reflection, prayer, advice, or sharing. Thoughtful physicians often do this in difficult ethical situations but may not recognize the spiritual nature of these reflections.



These precepts do not appear to depend on any specific religious tradition and should be applicable in all cultures and religions. One need not be religious to apply them to one’s practice. They avoid the relativity of accepting cultural practices at face value by providing a general structure for applying differing cultural beliefs to specific clinical situations. Spirituality cannot and must not be coerced or imposed on others, but physicians who are open to the role of spirituality in the lives of their patients may find these precepts useful in considering difficult ethical challenges.

ETHICAL RESPONSIBILITIES Child neurologists have duties as physicians, as pediatricians, and as neurologists. These categories overlap to some extent. Physicians in general have duties that are reflected in the Hippocratic Oath and the Code of Ethics of the American Medical Association (AMA). Pediatricians have duties as primary care physicians and as caregivers for minor children in a family context. Neurologists have duties as specialists to provide consultation and to maintain expertise in the field.

Duties as a Physician The AMA Code of Ethics is but one example of ethical codes that professional societies and organizations in many countries espouse. It is a document that has been revised over the years and includes opinions and statements on a variety of current issues. It is a good starting point for considering a physician’s duties. Additional guidance may be found in descriptions of the virtues needed for medical practice. These include the need for trustworthiness, compassion, empathy, prudent clinical judgment, altruism, fortitude, temperance, integrity, and primacy of the patient’s interest. Indeed, many of these virtues are implicit in the principles delineated by the AMA. Many professional societies have developed ethical codes or guidelines that are specific for their field. The websites of the American Academy of Pediatrics (www.aap.org), the American Academy of Neurology (www.aan.com), and the Child Neurology Society (www.childneurologysociety.org) may be consulted for the most up-to-date statements about the ethical responsibilities of members of these societies. Conflicts may arise in applying these principles during ordinary practice. For example, physicians should generally tell the truth, but what if truth-telling would appear to be harmful to the patient? There are no easy answers. The application of a care-based ethical approach may be useful in such situations. A carefully considered amount of information may be provided in such a way and in a particular context, taking into account the physician–patient relationship, so that all involved will understand the information being conveyed and be able to use it to benefit the patient. Consider this example. A 5-week-old infant had severe neonatal hypoxic-ischemic encephalopathy and remains on a ventilator. The magnetic resonance image shows extensive brain damage. To maintain optimal care and plan for the future, the clinical team has recommended a tracheostomy and gastrostomy. The neurologist is asked to provide an estimate of the child’s developmental potential, knowing that the family is also looking into withdrawal of life support and organ donation after cardiac death. The neurologist realizes the great difficulty in predicting outcomes in this context but also is aware of the literature that predicts severe neurologic disability in this case. How should the neurologist present this information? Emphasizing the small but real possibility of an outcome that might be better than expected could help the family choose to maintain support and plan

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for rehabilitation. Emphasizing the greater possibility of a poor outcome will likely result in the child’s death. Ultimately, it is the family’s decision to make, but the neurologist’s role in telling the truth, and how it is told, about the prognosis will have a significant influence on the family’s decision and on the child’s life. Physicians are often called upon to write letters for patients. These letters may be used to secure benefits for the patient in school, work, or other settings. Letters may also be requested to assist the patient or family in obtaining insurance coverage for tests or treatments, or in obtaining help with housing and utilities (heat, electricity, or telephone services). In general, physicians would seem to be required to do what is best for the patient, but what if this seems to conflict with a duty to respect the law and to do what is best for the community? Consider this example. A 10-year-old boy had Lyme meningoencephalitis 5 years ago and now is experiencing problems in school. The neurologist has recommended neuropsychological testing to help define the child’s school-related needs, but the family’s insurance company has stated that it will not cover testing for educational purposes. The neurologist is asked to write a letter to support the request for insurance authorization for the testing. Should the neurologist request the testing to define the cognitive implications of possible chronic Lyme encephalopathy (because the insurance company will cover neuropsychological testing for medical indications), even though the neurologist does not believe that the child has this condition? In a more general sense, is it ever ethical to lie to an insurance company for the benefit of the patient? The question puts so many ethical principles in conflict that no single answer can be given that would apply in every case. One way to approach the question is through virtue ethics. Compassion and effacement of self-interest might support lying for the benefit of the patient, but following the virtues of integrity and fidelity to trust might indicate otherwise. In this context, each physician would have to develop a balancing of these virtues that he or she can live with in good conscience. Physicians are often requested by insurance companies to prescribe older, cheaper drugs or to use generic products instead of new brand-name products. Indeed, in some insurance arrangements (such as full capitation), physicians may receive a financial benefit by limiting the cost of the patient’s care. Should a physician order expensive tests or prescribe expensive treatments anyway, if they are believed to be in the patient’s best interest? How much is a physician responsible for the overall cost of health care in society, and how should this responsibility be balanced against the responsibility to do what is best for the patient? Consider this example. A 14-year-old girl with epilepsy had a breakthrough seizure after having been well controlled for several years. She had been taking brand-name oxcarbazepine but was recently switched to the generic equivalent. The neurologist checks the blood level and finds that it has dropped from 20 to 10 mg/dl. Should the neurologist rewrite the prescription to specify brand name only (which increases the cost of health care in general), or just increase the dose of the generic product? Physicians are members of their community, and ethical questions can arise in the course of fairly ordinary activities. For example, suppose a physician is in church and observes a young child who is being presented for baptism. The physician suspects the child may be showing signs of autism, which the child’s parents do not seem to recognize. Knowing the importance of early diagnosis and treatment of autism, should the physician say something to the family or to the minister? This may be a situation where spiritual ethics might help guide the physician toward an answer.

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Clearly, application of general principles of medical ethics to complicated clinical situations is anything but straightforward. Nonetheless, physicians should make a genuine effort to do the best they can. The requirement to make the patient’s interests paramount would appear to be the defining standard in most cases. In doubtful or difficult situations, consultation or discussion with one’s colleagues (either formally or informally) is probably a good idea.

Duties as a Pediatrician Many (but not all) child neurologists have trained as pediatricians and have some experience with the roles and responsibilities of a pediatrician. Most also have frequent contact with referring pediatricians who provide primary care for the patients seen in neurologic practice. The role of a pediatrician often involves primary care in the United States, but in other countries and other settings the pediatrician is a specialist who manages diseases involving other parts of the body. Child neurologists interact regularly with pediatric specialists involved in the care of children with complex disorders. Thus there is an overlap between the duties of the child neurologist and the pediatrician that warrants some exploration. Primary care involves the longitudinal management of all of the health issues of the child and family and requires a commitment to being accessible, available, and capable. Effective primary care is compassionate, culturally competent and sensitive, and comprehensive, and includes coordination and oversight of all of the child’s health problems. Most child neurologists do not provide this type of primary care. Many do, however, provide many of the same elements of care for children whose neurologic problems constitute the main health issues. These include older children and adolescents who are otherwise healthy but have ongoing neurologic problems and patients with complex neurologic problems whose general health problems are fairly straightforward. Child neurologists have no obligation to take on this role and may confine their role to that of a consultant. Those who do take on this role would seem to have the same duties as those of a primary care physician, as listed earlier, except that their duties are limited to management of the child’s neurologic problems. All physicians who care for children (including pediatricians and child neurologists) have a duty to understand and respect the child’s status as a minor. This duty has two elements: one involves promoting the child’s emerging development into an adult, and the other involves protecting the child from harm. Promoting the child’s development involves an understanding of normal child development and helping the child succeed as much as possible. Child neurologists ordinarily monitor the child’s progress in school and provide whatever assistance is possible to secure special education and therapeutic resources needed to promote the child’s development. Although the primary responsibility rests with the parents and the school, the child neurologist should be available and capable of providing help when needed. Because children are not capable of making sound judgments about their own best interests, others must judge for them what is in their best interests. Social convention and the law generally recognize that parents are the best judge of what is in the child’s best interest, but this recognition is not absolute. A substantial body of law and regulation governs when and in what circumstances a parent’s rights may be superseded. Consideration of these laws and regulations is beyond the scope of this chapter. Child neurologists may be called upon to give an opinion about what medical care is in the child’s best interest. They may also be asked about whether they believe the child is capable of independent judgment. Persons

who are 18 years old are usually assumed to be fully autonomous adults who are capable of giving informed consent for medical treatment. Many neurologic patients with significant intellectual disabilities are not capable, however; therefore, others must be designated as guardians for them. The child neurologist should be aware of what is involved in determining the need for guardianship and assist the patient and family in whatever way is appropriate. The United Nations has formulated a declaration on the rights of children, the Convention on the Rights of the Child, which contains 54 articles that stipulate the rights of the child to life, safety, health, education, and a decent standard of living. Article 23 states that a mentally or physically disabled child should enjoy a full and decent life in conditions that ensure dignity, promote self-reliance, and facilitate the child’s active participation in the community. It further recognizes the rights of the disabled child to special care. Article 24 states that the child should have access to quality health services, including primary care, preventive health care, and treatment of health conditions. Although the Convention’s declaration is not legally binding, it provides a strong moral statement about the internationally accepted obligations of states to protect the best interests of all children. Awareness of this international consensus may be helpful to physicians who are advocating for children under their care.

Duties as a Neurologist Child neurologists are specialists or subspecialists and have duties that correspond to this role. They provide longitudinal care for children and adolescents with chronic neurologic disorders, and this includes corresponding duties that resemble those of primary care, as described previously. They also provide consultative opinions about diagnosis and treatment, both in outpatient and inpatient settings. As a consultant, the child neurologist has a duty to provide a fair, impartial, accurate, and (as much as possible) evidence-based statement about the facts of the case. The child neurologist’s principal role in evaluating ethical dilemmas is to clarify the facts. This is a critical role because accurate data are essential for making sound ethical decisions. Indeed, poor or questionable ethical decisions often are attributable to inadequate specialized medical information regarding the diagnosis, treatment, and/ or prognosis of a case. This problem is illustrated well in cases when the patient is in a vegetative state. Some may consider such a state permanent and hopeless after only a few weeks and seek to withdraw life-sustaining treatment. The child neurologist, acting as a consultant in such a case, would inform the family and caregivers about the published data indicating that the vegetative state is not considered permanent until 3 months after an anoxic injury and 12 months after a traumatic brain injury. The family may be given some slim hope for possible recovery of consciousness before these time periods, which may call for continued treatment and rehabilitation. The role of an expert consultant has certain limitations. For the most part, child neurologists are experts in child neurology and not in ethics. The child neurologist should distinguish between opinions regarding the neurologic data and opinions regarding the ethical issues involved in cases that present ethical dilemmas. The child neurologist’s opinion about the ethical issues is one voice among many and is not necessarily the most important or determining opinion. Normally, the family’s opinion about the ethical issues is the most important. The views of the extended family and the family’s religious or faith or cultural community are often important. In many cases, the views of individuals who have had long-term, close, and personal relationships with the patient (e.g., friends,



personal attendants, or group home staff) also deserve consideration. Child neurologists, in addition to other physicians and nurses involved in such cases, should be careful not to impose their own ethical opinions or attempt to override the expressed opinions of the patient’s family and friends. The child neurologist also has a duty to maintain expertise in the field. This is a duty that is shared with all medical specialists. Expertise is maintained through continuing education, which may involve reading journals, attending conferences, and discussing issues or cases with colleagues who may have more knowledge or experience regarding the issues in question.

Research Many child neurologists are involved in research, which carries additional ethical duties. One of the challenges for child neurologists involved in clinical research is to separate their ethical obligations as investigators from their ethical obligations as physicians responsible for treating patients who may be enrolled as subjects in the neurologist’s research study. This challenge is harder than it may seem. In the United States research ethics is based on the Belmont Report, which adopted the principles of autonomy, nonmaleficence, beneficence, and justice (see earlier discussion) as the basis of research ethics. In general, the researcher’s principal ethical obligation is to protect the rights and welfare of the research subject. Poorly designed research studies are inherently unethical because they are not likely to produce sound scientific results, and thus they place the patient subject at risk for harm without the prospect of benefit. The researcher’s ethical obligation as an investigator to pursue well-designed scientific studies is secondary to his or her obligation to protect the subject involved in the research. When the research subject is also a patient, this means that the child neurologist investigator’s clinical duties to the patient are ordinarily stronger than his or her duties to enroll subjects in the research study. In the United States federally sponsored research is governed by the Code of Federal Regulations, which stipulates the roles and responsibilities of researchers and institutions involved in clinical research. Researchers are required to obtain review and approval of the research study by a properly constituted Institutional Review Board for the Protection of Human Subjects in Research (IRB). Child neurologists involved in clinical research have legal and ethical obligations to follow these rules and regulations. In general, ethical issues in research should be considered when the study is being designed, not just at the end of the process when IRB review and approval are formally requested. The researcher should be knowledgeable about ethical issues in research. If the researcher has questions about ethical aspects of study design or protocol development, most IRBs will provide assistance. Building ethics into the study from the beginning will usually prevent problems later during the process of IRB approval and during continuing review and oversight of the study.

SYNTHESIS The child neurologist striving to do the right thing and to avoid doing the wrong thing will listen to many voices

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conveying a variety of messages. Some of these voices are internal and reflect the several theoretical approaches that provide a “best fit” for the patient’s problem. The neurologist’s mind will hear different ways of conceptualizing the problem, perhaps from an ethics of care or a utilitarian perspective, or some other approach. Experience teaches that clinical ethics is not procrustean, that no theory or approach will fit every clinical situation. Every case is unique and provides lessons that can be stored away in memory and called upon another day. Drawing upon his or her knowledge about ethics derived from careful study and the knowledge that can only come from having been at the bedside of many sick children over the years, the neurologist will struggle to derive a sense of harmony that will be helpful when a decision must be made. The child neurologist also listens to the external voices of others who are involved in the clinical situation. Foremost among them is the voice of the family. When love is present, families usually find a way to deal with whatever life hands them. It may not be the “right” way (the way others want them to take), but it is a way that works for them and deserves respect. At any given point in time, most people are doing the best they can, given their skills and abilities and the pressures and limitations they face. When physicians seek to understand the situation from the family’s point of view, they may be able to help them do the best they can for themselves and for their child. The neurologist will also hear the voices of other patients and families he or she has treated and followed over the years, who were in a similar situation in the past and whose subsequent history speaks to the wisdom of decisions that were made. The child neurologist also will hear the voices of other caregivers involved in a particular case, especially those of the nurses who have a more intimate relationship with the patient and family. In some cases, the voices of long-time friends, pastoral ministers, and staff who have cared for the patient before the present situation arose will need to be heard and considered carefully. The soft but insistent voices of insurance administrators and utilization reviewers may also be softly or stridently audible. Synthesizing all of these arguments and perspectives is never easy and perhaps benefits most from a deep sense of humility. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Beauchamp, T.L., Childress, J.F., 2012. Principles of Biomedical Ethics, 7th ed. Oxford University Press, New York. Bernat, J.L., 2008. Ethical Issues in Neurology, third ed. Lippincott, Williams & Wilkins, Philadelphia. Gilligan, C., 1982. In a Different Voice. Harvard University Press, Cambridge, MA. Jonsen, A.R., Siegler, M., Winslade, W.J., 2015. Clinical Ethics: a Practical Approach to Ethical Decisions in Clinical Medicine, 8th ed. McGraw-Hill (LANGE), New York. Pellegrino, E., Thomasma, D., 1993. The Virtues in Medical Practice. Oxford University Press, New York.

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165  Transitional Care for Children with Neurologic Disorders Carol S. Camfield, Peter R. Camfield, and Lawrence W. Brown

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION Neurologic disorders of childhood often persist into adulthood. Although many have a good medical and social outcome, 20% to 30% are complex with physical, psychiatric, or developmental problems complicated by societal stigma. The problem is compounded as more children with chronic neurologic diseases now survive into adulthood with advances in diagnosis, treatment, technology and management that continue to create a new “natural history.” Child neurologists need to facilitate the transition of all youth with neurologic disorders as they enter to adult healthcare (Brown and Roach, 2013). The distinction between transfer and transition is important (Camfield and Camfield, 2011). Transfer is the formal handing over of care from a pediatric to an adult healthcare system. The relationship with the child neurologist ends with a detailed referral letter to an adult care provider and responsibility for care is transferred. Transition is a long-term, purposeful, planned process beginning in childhood to prepare youth and their families for the adult healthcare system. Over a period of years the adolescent becomes knowledgeable about his or her medical condition and as independent as possible. Ideally, they become able to evaluate the adequacy of their care. The child neurologist actively participates in the transition process and develops and maintains a relationship with the adult healthcare team to prepare for the eventual transfer. Pediatric care includes intensive involvement with the family. Adult medical care is focused firmly on the individual, not their caregiver(s). Adolescents and young adults move from family-centered pediatric care dominated by their parents, a change that they may find difficult after years of a well-established relationship. Many of these young people have never developed full knowledge about their neurologic disorder, may not even know their diagnosis or treatment plan, and are unprepared to cope with the adult healthcare system. In 2014 the Child Neurology Society convened a panel to identify common principles underlying the process of transition to adult care that could help to clarify the process for neurologists and caregivers. The panel outlined eight critical points that are shown in Box 165-1. This chapter attempts to outline: 1) barriers to transfer; 2) the natural history of several disorders that evolve during or after adolescence; and 3) models that have been used for “transition.”

BARRIERS TO CARE The family, patient, pediatric neurologist, and adult neurologist have an underlying inertia to initiate the process of transition. Legal issues of confidentiality and age of consent are encountered. Electronic interchange of patient information currently is often awkward with differences in computing technology. Changes in insurance coverage in some countries (especially the United States) are of grave concern.

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Many worries cause barriers to transition (Box 165-2). Families may fear the unknown and the passing of their own responsibility to their child and new adult healthcare team. They are attached and comfortable with the pediatric service (often described as holistic, attentive, understanding, and knowledgeable). Parents of an adolescent with significant physical or intellectual disability understand that normal independence is precluded (he or she remains a “child”). They may fear that this reality will not be respected by the adult healthcare team. Interestingly, parents are typically more anxious about transition than the adolescent. For the child neurologist, transition/transfer means a loss of the long-term attachment associated with years of working with these families. There is often a nagging feeling of not having done everything possible to “cure” the child during the pediatric years. Adult service may be viewed as less holistic, particularly for management of comorbidities. Discussion of transition takes time and reimbursement may be inadequate for “nonmedical” counseling. There may be difficulty finding appropriate expert adult primary or subspecialty care. The adult neurologist faces other challenges. No professional wants to convince reluctant youths and families of their “credentials” or justify their model of care. It may be difficult for them because many child neurologists have not dealt with issues from sexuality and relationships to vocational challenges, from potential of death from the neurologic illness to end-of-life issues. Some patients have disorders that are rarely seen in adulthood; a whole new set of information is needed. The expectations for psychosocial care may be very difficult to meet, especially in a setting with little help from other professionals such as social workers. These issues cannot be easily addressed in a short visit. An American study documented barriers to transition by a Delphi survey (Peter et al., 2009). Internal medicine providers (n = 241) rated highest concerns about lack of training in congenital and childhood-onset conditions, lack of family involvement, difficulty meeting patients’ psychosocial needs, needing access to a super specialist, lack of training in the care of adolescents, facing disability and end-of-life issues during youth, financial pressures limiting visit time, and families’ high expectations. Other issues in adult care relate to the setting. The office is rarely set up for youth who are intellectually disabled or disruptive, and consultation rooms are often inadequate for parents or a power wheel chair. Young people with intellectual disability present a special problem for the adult healthcare system, even if the adult provider is comfortable with their limitations in providing a clear history or cooperating with the examination. Unless there is guardianship, does the patient or parent decide what is best? Office visits may need to be longer than usual for good cooperation. The pediatric model of care emphasizes a “medical home” that is optimal especially for those with rare, complex, difficult to treat medical problems involving multiple specialties. This is less common for adults who may suffer if there is no designated individual with overall responsibility for care. In



Transitional Care for Children with Neurologic Disorders

BOX 165-1  Principles for Transition for Child Neurologists (from the Child Neurology Society ref 16) 1. The pediatric neurology team should start to discuss the expectation of future transition to the adult care system beginning at an early age, no later than early adolescence. 2. This discussion should be continued annually and documented in the medical record and communicated to other healthcare providers. Reassessment of selfmanagement skills can help to gradually allow the adolescent to assume more responsibility for his or her own care. 3. This phased transition planning should occur at scheduled visits rather than acute care visits and allow for sufficient time to deal with emerging issues such as sexuality, driving, and graduation from secondary education. 4. For those with intellectual disability, the child neurology team should begin the discussion of the youth’s expected legal competency by age 14, support interventions to maximize this decision-making ability, and support caregivers who must address the legal implications of the assessment. This might include guardianship and power of attorney. 5. The child neurology team should collaborate with the youth and family, primary healthcare provider, and others on an annual basis to address comprehensive needs. Although the child neurologist is not responsible for healthcare finances and legal concerns, education, employment, and communitybased adult services, he/she is obligated to make sure that a comprehensive transition plan is developed and updated. 6. The child neurology team is responsible for the neurologic component of the transition plan and should update it yearly. 7. Appropriate adult providers, whether neurologists or others, should be identified in collaboration with the youth and family before the anticipated time of transfer. The child neurology team coordinates the transfer, preferably utilizing a transition packet that documents the diagnosis, supportive testing, previous drug trials and past procedures, current management, and any protocols for emergency care. 8. The child neurology team should directly communicate with the identified adult providers to ensure successful transfer and document the youth’s transfer (i.e., completion of transition) into the medical record.

addition, multidisciplinary clinics are common in pediatrics but rare in adult medicine, which may lead to fragmented, incomplete care. In the next section, we provide examples of transition/ transfer issues for a variety of childhood neurologic disorders.

Disorders that May be Dangerous to   Society if Untreated Attention deficit with or without hyperactivity (ADHD or ADD) is important because it is so common and persists into adulthood in approximately 30% of individuals. It may exist as a single diagnosis or as a comorbidity of other disorders. For example, 20% of children with epilepsy also have ADHD, as do more than 50% with Tourette Disorder, possibly 20% with cerebral palsy, and 40% of survivors of some brain tumors. The symptoms have a profound effect on adult functioning, including accidents, substance abuse, and suicide. In 2012 Montano noted, “The current literature reveals a number of barriers to continuity of care of ADHD, including disparities and inadequacies in ADHD education in primary care and internal medicine residencies, prohibitive prescribing practices with respect to stimulants, inadequate clinic staffing, lack

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BOX 165-2  Barriers to Care 1. Family • Fear of the unknown • Comfort and attachment to pediatric service • Personal negative past personal experiences with adult care • Behavioral/psychiatric difficulties within family • Cultural and racial barriers attached to the family’s financial and socioeducational background • Child with intellectual handicap or severe disabilities perceived always as a “child” 2. Child neurologist • Loss of long-term professional “friendship” and sharing relationship with family members • Adolescent and family resistance to transfer • Nagging feeling that care was not as complete as possible • Difficulty identifying appropriate adult healthcare providers perceived as excellent and compassionate • Long wait lists for entrance into the adult system • Financial reimbursement, institutional support for transition/ transfer services • Reminder of personal mortality 3. Adult Neurologist • Reluctance of family and adolescent to change • Insufficient time and reimbursement for complex care • The challenge of dealing with “taboo” subjects such as sexuality, potential of death, and longevity • Possible insufficient of knowledge of the natural history and management of rare, chronic neurologic diseases of childhood • Unease with youth with intellectual disability and the complexity of deciding who is the decision maker • Lack of multidisciplinary clinics

of support by college health services, inadequate health insurance coverage, and failure to conduct transitional planning. Without improved continuity of care and adherence to medication, adolescents and young adults with ADHD are at greater risk of academic, social, and vocational difficulties, as well as behavioral problems, including substance abuse, unsafe driving, and criminal activity.” (Montanto et al., 2012.) Barkley compared 149 children with ADHD who were followed into young adulthood to a matched cohort of “community” controls. Only two thirds with ADHD completed high school compared with all of the controls. ADHD subjects were more likely to have been involved with a pregnancy (38% versus 4%) and have a driver’s license suspension (41% versus 26%). Automobile accident rates in those with ADHD are alarming, and the effect of ADHD is similar to moderate alcohol intoxication according to studies using driving simulators. The combination of mild alcohol intoxication and ADHD is even more striking. Adults with ADHD are more competent drivers if they take stimulant medication. Effective management of ADHD in young adults can dramatically reduce the rate of substance abuse. Therefore sophisticated adult care is needed to continue to optimize treatment for ADHD.

Disorders that are Potentially Lethal in Childhood and Young Adulthood and Have Emerging Treatments Leading to Increased Survival Well into Adulthood Treatment advances have allowed improved function and prolonged survival in some conditions such as boys with

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Duchenne muscular dystrophy. Affected boys can now walk well into their teenage years and 85% survive to age 35 years or longer since the addition of positive pressure ventilation. However, the burden of disease increases with longevity and is further complicated if there is significant learning and/or intellectual disability. Sleep-related breathing disorders, cardiomyopathy, and progressive restrictive lung disease from scoliosis are among the challenging issues. Adult neurology, rehabilitation, pulmonary medicine, and cardiology all need to be involved along with many allied health professionals and social workers. These services are typically well coordinated in a pediatric hospital, but it is rare to find comparable adult comprehensive programs. As more youths are surviving with formally fatal disorders, “taboo” issues such as sexuality management, life-threatening cardiopulmonary complications, and end-of-life care need to be discussed more fully (Barkley et al., 2006). Goals for young adult life require innovative solutions as do satisfying daily activities, acceptance by peers, coping with difficulties, and establishing optimism.

Disorders that Are Problematic and “Static” in Childhood but Progress in Adulthood The brain lesions causing cerebral palsy (CP) are not progressive. They are permanent and associated with evolving movement disorders that limit activities (Backman and Conaway, 2014). Comorbidities are frequent: 50% of patients have intellectual disability and/or epilepsy. Over 90% live beyond 18 years of age, and many are able to successfully adapt to adult life; however, others face monumental challenges. Learning or behavioral problems often become troublesome as the child reaches school age and may persist into adulthood, resulting in low educational attainment, decreased employment, limited finances, living with family, reduced social opportunities, and overall poor quality of life. Limitations in coordination, strength, and mobility gradually lead to curbing activities with peers. Associated epilepsy may be intractable. Unfortunately, there is increasing evidence that mobility for children with cerebral palsy worsens in adulthood. An initial survey of 226 adults with cerebral palsy was repeated after an interval of 7 years. Depending on the type of CP, one-third to three-fourths of patients reported increased walking difficulties that included pain, fatigue, and decreased balance. Others have noted a variety of progressive orthopedic problems in adults with cerebral palsy frequently complicated by musculoskeletal pain. Young adults with cerebral palsy between ages 20 to 22 years were twice as likely to rate their health as poor (21%) compared with those who were 15 to 16 years old (9%). Some studies have been more optimistic. A cohort of patients who underwent dorsal rhizotomy in early childhood seemed to have stable gaits 20 years later. Nonetheless, a comprehensive program that includes adult neurology would appear to be necessary to optimize management of a myriad of needed services, including orthopedic surgery, gastroenterology, pulmonary medicine, pain management, physical, occupational and speech therapy, and social services.

Disorders Diagnosed in Childhood with Their Most Serious Manifestations in Adulthood Neurofibromatosis 1(NF1) is a complex disorder for transition/ transfer. Most patients are diagnosed in childhood and followed by child neurologists without progressive problems unless they have an optic pathway glioma; however, the effect of NF1 in adulthood may be profound. A recent meta-analysis

of eight studies relating NF1 with adult health-related quality of life found that NF1 decreases all aspects of quality of life compared with the general population. Medical complications and visible cosmetic effects were strong predictors of quality of life. During the school years, learning/behavior problems, sometimes autistic spectrum disorder, headache, and epilepsy are the focus of clinicians. Schwannomas become increasingly prominent with age, but many of the really serious complications begin in adulthood with sarcomas, renal failure and cerebrovascular disease. In our experience, referral is infrequent between the pediatric and adult neurology services. Primary care physicians are left to provide overall medical care but may not have the detailed knowledge to coordinate comprehensive care. Most guidelines for NF1 management have focused on children and have not been recently updated nor have they recognized that life expectancy now approaches the seventh decade. Different issues exist for children with tuberous sclerosis complex (TSC) (De Waele et al., 2015). Recent improved understanding of the pathophysiology has lead to new therapies. One of the most promising is mTOR inhibitors which have potential for treatment of subependymal giant cell astrocytoma as well as renal angiomyolipoma, lymphangioleiomyomatosis, and facial angiofibromas, all problems that span the ages between childhood and adulthood. Renal disease is the most common cause of mortality after the age of 30 with renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors causing chronic renal disease. These problems become nearly universal in adulthood. Epilepsy is typically a persistent problem. In infancy, TSC may present with infantile spasms. During childhood and adulthood seizures are focal or secondarily generalized. Autism, learning disorders, intellectual disabilities, ADHD, or other psychiatric disorders ordinarily present in childhood but persist. There are few “birth-to-death” programs for neurocutaneous disorders that ensure optimal long-term care, and such multidisciplinary clinics are unusual. The need for TSC patient advocacy along with an awareness and knowledge of the upcoming treatment advances underlies the requirement for continued lifelong surveillance. There are presently no clinical guidelines for patient management of TSC; however, a recent consensus statement by international experts describes a standardized, routine “surveillance” program for life.

Disorders that Are Cured in Childhood but Have Neurologic Sequelae that Persist   into Adulthood An increasing number of children survive brain cancers due to improvements in early diagnosis, surgery, radiotherapy and chemotherapy. Oncologists may continue to follow these patients for problems related to the late effects of chemotherapy and second malignancies, but many continue to have significant neurologic problems. It is critical to have neurologic involvement in their care. Ongoing surveillance by adult neurologists is increasingly important now that so many children with brain tumors survive into adulthood. Unfortunately, long-term survival does not necessarily equate to optimal outcome; a large cohort of childhood brain tumor survivors was compared with their siblings. Over 1800 cases were followed for a median of 19 years; survivors were much less likely to graduate from college, more likely to be unemployed, and much less likely to be married than their siblings. Of those with medulloblastoma, more than 40% of survivors had neuropsychiatric problems. One other study from a single center



suggested that about 50% of survivors of childhood brain tumors were “disabled.” The long-term neurologic issues may be complex and include intractable epilepsy or remote vasculitis from radiation. Clearly, adult neurologic expertise is required.

Disorders that May/May Not Remit in Childhood but Have Persistent Effects   on Adult Social Function As a group, children with epilepsy have very high rates of poor social outcome in adulthood, rates that are higher than other pediatric chronic disease comparisons and population controls (Borlot et al., 2014; Geerlings et al., 2015). Adult consequences of pediatric epilepsy are reviewed in Chapter 62. A critical observation is that social outcome appears to be independent of seizure remission, although those with persistent seizures may have even greater problems. Although the main focus is always seizure control, optimizing quality of life is critical if children with epilepsy are expected to live fulfilling lives. Identifying and treating comorbidities must begin in childhood but is a lifelong concern.

Disorders that May Be Uncomfortable for   Adult Care Youth with intellectual disability are at particular risk for care discontinuity as they approach adulthood. Lack of communication skills, disruptive behavior, and inadequate medical insurance are particularly challenging for adult neurologists. As these young people become adults, their parents age, and siblings move away. When placed in an institution or a group home with high rates of staff turnover, many intellectually handicapped adults soon become “well known by no one.” The link with their medical records may be broken, and the original diagnosis and management become unfamiliar or unknown to their caretakers and physicians. Caretakers may not be aware of new approaches to diagnosis or treatment. For example, profoundly handicapped adults with untreated phenylketonuria may still benefit from a low phenylalanine diet with improved quality of life. Organizing transition and transfer for this type of patient is a major challenge. A strong case can be made for a birth-to-death clinic, although institutional barriers are to be expected.

Disorders in Childhood Treated in a   Way that is Difficult to Replicate   in Adult Medicine Adult care rarely uses the “medical home” model that brings together specialists working together with families and community resources. Such care is ideally suited to the many children now surviving with neurologic disorders who would have died 20 to 30 years ago. Without major efforts at coordination, their complex care easily becomes fragmented and suboptimal. For example, gastrostomy tubes are well accepted in pediatrics and have been a major contributor to longevity. Dietary/nutrition support for tube feeding may not be available in adult care settings nor is there often familiarity with the ketogenic diet or other special diets for metabolic disorders. There are many young people with disorders in this category; examples include progeria, craniosynostosis syndromes, Ondine’s curse, Down syndrome, serious head injury, and neural tube defects.

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POOR OR LITTLE DEVELOPMENT OF THE TRANSITION PROCESS YIELDS POOR OUTCOME There is very little literature about the unsatisfactory transition for youth with neurologic disorders. Examples from other chronic diseases suggest that the effect may be devastating. For example, youths with type 1 diabetes dropped attendance rates within 2 years of transfer to adult clinics from 94% to 57%; 21% were lost to follow up. Only 40% of those with asymptomatic ulcerative colitis adhered to their medication regime after transfer to the adult setting. Renal transplant patients are another example. One study tracked 20 young adult kidney transplant recipients and found that medical outcomes sharply deteriorated in the 36 months after transfer. One third lost their transplant; nonadherence to immunosuppressant medications was suspected as the primary cause.

Models of Care for Transition An optimal model of transitional care has not been identified in general or specifically for neurologic patients. The Kaiser Permanente Patient Risk Stratification Pyramid is a method to stratify patients with long-term health conditions and defines the appropriate level of required care. This approach divides the population of patients with chronic conditions into three groups based on their level of risk and degree of need. For those with relatively low healthcare needs (Level 1), adult care might be provided by a family physician with sufficient knowledge, skills, and confidence; this may encompass 70% to 80% of youths with chronic neurologic conditions. A multidisciplinary team, including a nurse practitioner, might be optimal. Level 2 indicates a need for more structured assisted care or care management for a single or multiple conditions. These youths have increased risk because their condition is unstable or is likely to deteriorate unless they receive specialist disease management. Transfer from the pediatric neurologist to adult specialist care is appropriate. For the most complex conditions (Level 3), management of multiple, high intensity conditions through case managers, nurse practitioners, and super specialists should be provided along with care from an array of professionals to plan and coordinate services. As suggested in the Child Neurology Foundation report, this does not have to be an adult neurologist, but it is essential to have a designated “captain.” Beyond medical needs, additional issues to be addressed over time include the individual’s cognitive function and level of competence, personal and family psychosocial issues, the degree of support from family and friends, community resources, capacity to navigate and engage with the medical system, ethnicity and language that may create barriers/challenges, and end-of-life care, power of attorney, and creation of wills and trusts. A variety of transition/transfer models has been described in Box 165-3 (Carrizosa et al., 2014).

1.  Abandonment of Specialized Care or “Fend for Yourself” This approach places the burden for ongoing care entirely on the youth’s pediatrician or family physician. Unfortunately, this physician may have had limited involvement in the child’s chronic disorder and is unlikely to have full, current knowledge of the disease. The youth and family may not be particularly attached to the provider or may doubt his or her competence. An alternative is a group of family physicians who might develop a special interest in chronic neurologic disorders (preferably with an able nurse practitioner as a case manager)

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BOX 165-3  Models for Transitional Care 1. Abandonment of specialized care or “fend for yourself” 2. Referral to adult rehabilitation program 3. Referral to adult neurologist or internist 4. Referral to an internal medicine/pediatric subspecialist 5. Referral to a nurse-run transition clinic 6. A formal transition clinic with pediatric and adult neurologists and other professionals 7. Referral to a professionally moderated Internet support group (From: Carrizosa, J., An, I., Appleton, R., Camfield, P., Von Moers, A., 2014. Models for transition clinics. Epilepsia 55(Suppl 3), 46–51.)

and, as a group, follow transferred youth with neurologic problems. To be successful, multidisciplinary consultation would need to be available with financial compensation adequate for the additional time needed.

2.  Referral to an Adult Rehabilitation Program These programs are typically oriented toward a single consultation or short-term intervention. Examples would be management for gait difficulties, repetitive strain injury, or wheel chair assessment. Care in this setting is generally multidisciplinary, but long-term follow up is unusual. “Botox” treatment for spasticity may be an exception. Rehabilitation programs are found in large tertiary centers and cities more often than in smaller hospitals or communities.

3.  Referral to an Adult Neurologist or Internist This is generally a consultation model with follow-up visits. It begins with a request for consultation to an adult specialist. Although follow-up visits may be scheduled with the specialist, they may require a new referral from the primary care physician. There are limitations to this approach. Few adult internists or neurologists are trained or interested in the long-term care of developmental brain disorders. Financial pressures limiting visit time and high expectations of the family are particularly problematic. Many adult neurologists and internists are uncomfortable treating patients with intellectual disability and worry about not having easy access to appropriate subspecialists.

4.  Referral to an Internal Medicine/Pediatric Subspecialist We are unaware of published literature about the effectiveness of a neurology transition program that uses the United States model of a fully accredited Internal Medicine/Pediatrics residency program. The concept is that during a “med/peds” residency, training is offered in comprehensive care for children, adolescents, and adults with chronic health disorders. This model allows for 2 to 4 years before transfer to an adult specialist or return to the family physician. During this period, the youth has time to mature, gain skills to manage medical care, and recognize when and where to seek additional help for health issues. Families have time to establish estate planning and learn to relinquish their responsibility for their child, allowing the young adult to “grow up.”

5.  Referral to a Nurse-Run Transition Clinic This model was described in Edmonton, Alberta. A pediatric epileptologist completes a referral to the adult care team. The

patient and family meet jointly with the pediatric and adult epilepsy nurses for several visits to prepare for their initial and long-term visits with the adult epilepsy team.

6.  A Joint Pediatric/Adult Transition Clinic We favor this approach (Camfield et al., 2012). Careful initial review in such a transition clinic may revise the original diagnosis, reconsider medications, investigate surgical options, and address comorbidities. Adherence can be addressed along with potential side effects to medications and potential lifestyle alterations. Counseling may include sexuality, life expectancy, newer treatments, and ways to improve quality of life with the opportunity for increased maturity and self-esteem in addition to realistic long-term goals. In 1997 Appleton first described such a program for youth with epilepsy in the United Kingdom. There were 120 “transitioned” patients— 37% with intellectual disability. Patients were seen several times by the clinic staff of a pediatric and adult neurologist, as well as a nurse practitioner. During these visits a new diagnosis emerged for 10%, and medication was changed 22% of patients. After an average of two visits, the pediatric neurologist bowed out leaving the youth to be followed in the adult care system. The pediatric neurologist continued to be available for consultation to the adult staff.

7.  Internet-Based Support Groups Encouragement for youth and families to align with a professionally moderated, disease-specific online support group or organization will hopefully permit very long-term access to new developments in treatment. Such a connection is not a replacement for a transition process.

CONCLUSIONS More information is needed about the long-term outcome of neurologic diseases in children and the best way to manage transition and transfer. The optimal age to begin the transition process is not known, but starting in early adolescence seems appropriate. The best time for transfer may vary from high school graduation to completion of college or when the young adult is fully emancipated. The success of any transition program will surely be strongly related to the enthusiasm and commitment of the physicians and other healthcare professionals who are involved. Personal contact between providers in the pediatric and adult settings is likely the most important ingredient to success. Given the intensity of treatment for children with chronic neurologic disorders, it is essential to transition satisfactorily to adult medicine. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Backman, J.A., Conaway, M., 2014. Adolescents with cerebral palsy: transitions to adult healthcare services. Clin. Pediatr. (Phila) 53 (4), 356–363. Barkley, R.A., Fischer, M., Smallish, L., et al., 2006. Young adult outcome of hyperactive children: adaptive functioning in major life activities. J. Am. Acad. Child Adolesc. Psychiatry 45, 192–202. Borlot, F., Tellez-Zenteno, J.F., Allen, A., et al., 2014. Epilepsy transition: challenges of caring for adults with childhood-onset seizures. Epilepsia 55 (10), 1659–1666. Brown, L.W., Roach, E.S., 2013. Outgrowing the child neurologist: facing the challenges of transition. JAMA Neurol. 70, 496– 497.

Camfield, P., Camfield, C., Pohlmann-Eden, B., 2012. Transition from pediatric to adult epilepsy care: a difficult process marked by medical and social crisis. Epilepsy Curr. 12 (Suppl. 3), 13–21. Camfield, P.R., Camfield, C.S., 2011. Transition to adult care for children with chronic neurologic problems. Ann. Neurol. 69 (3), 437–444. Carrizosa, J., An, I., Appleton, R., et al., 2014. Models for transition clinics. Epilepsia 55 (Suppl. 3), 46–51. doi:10.1111/epi.12716. De Waele, L., Lagae, L., Mekahli, D., 2015. Tuberous sclerosis complex: the past and the future. Pediatr. Nephrol. 30 (10), 1771–1780. doi:10.1007/s00467-014-3027-9.

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Geerlings, R.P.I., Aldenkamp, A.P., de With, P.H.N., et al., 2015. Transition in adolescents with epilepsy. Epilepsy Behav. 51, 182–190. Montano, C.B., Young, J., 2012. Discontinuity in the transition from pediatric to adult healthcare for patients with attention deficit hyperactivity disorder. Postgrad. Med. 124, 23–32. Peter, N.G., Forke, C.M., Ginsburg, K.R., et al., 2009. Transition from pediatric to adult care: internists’ perspectives. Pediatrics 123 (2), 417–423.

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166  Practice Guidelines in Pediatric Neurology David J. Michelson, Gary Gronseth, and Stephen Ashwal

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION

DEVELOPMENT PROCESS

Clinical practice guidelines (CPGs), practice parameters, and practice advisories are documents developed to address the need of practitioners for guidance in making medical decisions. High-quality CPGs are written by panels of authors, including topic experts, using a formalized process to reach consensus recommendations based on a systematic review (SR) of available clinical evidence regarding the benefits and harms of different treatment options. The last half century has seen CPGs evolve along with the field of evidence-based medicine and come to play an increasingly important and highly scrutinized role in medical practice and health care policy.

Over the years, guidelines have come to play a more prominent role in healthcare practice, administration, and law. Private and government insurers are supporting guidelines for their potential to reduce practice variations, improve the quality of care, and reduce healthcare costs by discouraging ineffective or harmful practices. Hospitals are using guidelines as the basis for quality assessments and computer-based decision support tools. Lawyers working both sides of malpractice suits are attempting to introduce guidelines into evidence as the accepted standards of appropriate care. Many previously published guidelines fall short because of limitations in the scientific evidence upon which they are based. Even when developers can overcome the difficulty and expense involved in reviewing all available studies, there may still be a lack of sufficiently rigorous, unbiased, consistent, and generalizable evidence to support more than vague recommendations. CPG development groups may only be able to produce specific recommendations by relying on expert opinion. The process of guideline development may also suffer from a lack of transparency, inclusiveness, or consistency, diminishing the actual or apparent reliability of the result. Perception that one or more authors of a guideline are biased by selfinterest can diminish the acceptance of a guideline by both practitioners and the public. Conflicts of interest (COIs) can be academic, intellectual, and financial. The American Thoracic Society defined COI as “a divergence between an individual’s private interests and his or her professional obligations such that an independent observer might reasonably question whether the individual’s professional actions or decisions are motivated by personal gain, such as financial, academic advancement, clinical revenue streams, or community standing” (Schünemann et al., 2009). The evidence available to guideline developers may also suffer from COIs. Many published clinical trials are industry sponsored and conducted to obtain U.S. Food and Drug Administration (FDA) approval for a new medication or clinical indication. Although these studies tend to be of high quality, they are more likely to show favorable results than independently done studies and to use socioeconomically homogenous populations, exclude patients with important medical comorbidities, utilize relatively brief follow-up periods that may underestimate risks, and rely on surrogate endpoints that may overestimate benefits (Avorn, 2005). These shortcomings have reduced the generalizability of even very recent guidelines. With evidence lacking, imperfect, or disputed, and guideline developers making recommendations based on some estimation of expert consensus, multiple guidelines on a subject have been published with conflicting recommendations. Concerns about CPG quality prompted the U.S. Congress to direct the Secretary of Health and Human Services to contract with AHRQ and the Institute of Medicine (IOM) of the

HISTORY The first SRs were efforts to analyze the combined data from multiple small clinical trials. Concurrently, authors began to use SRs of evidence as the basis for practice recommendations. Evidence-based medicine (EBM) emerged from work done in the 1970s that uncovered wide geographic variations in care received by seemingly similar groups of patients. An EBM Working Group report in 1992 advocated for a greater emphasis on rigorous and systematic evaluation of high-quality scientific medical evidence for understanding causation, prognosis, diagnostic accuracy, and treatment effects (Eddy, 2005). Within a few years, dozens of medical specialty societies and disease-specific societies began publishing practice guidelines. However, these guidelines continued to rely more heavily on the beliefs of the authors, or on expert consensus, than on empirical evidence. Governmental agencies and insurance providers, acting on their interest in improving patient outcomes and slowing the rising cost of healthcare, began to take an active role in the guideline development process. In 1989 the U.S. Congress established the Agency for Health Care Policy and Research (AHCPR), later renamed the Agency for Healthcare Research and Quality (AHRQ), which currently provides support for a network of centers that produce systematic reviews for public and private groups and maintains the National Guideline Clearinghouse (http://www.guideline.gov), a searchable online CPG database. Private and international organizations have also been significant contributors to the field in EBM development. The Cochrane Collaboration produces systematic reviews following protocols that emphasize transparency and scientific rigor. The Scotland-based Guidelines International Network (GIN) library has collected more than 6000 guidelines from around the world (http://www.G-I-N.net). Several dozen guidelines with particular relevance to child neurologists have been developed in the last 20 years, mostly through the work of what is now called the Guideline Development, Dissemination, and Implementation (GDDI) subcommittee of the American Academy of Neurology (AAN), often with involvement and endorsement by the Child Neurology Society (CNS) (Table 166-1) (Hurwitz et al., 2015).

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TABLE 166-1  Selected Practice Guidelines Related to Child Neurology Year

Type

Topic

Developer

References

1995

E

Persistent vegetative state

AAN

[62]

1996

E

Simple febrile seizures

AAP

[63]

1996

T

Seizure-free patients

AAN

[64]

1999

T

Simple febrile seizures

AAP

[65]

1999

T

Closed head injury

AAP, AAFP

[66]

1999

E

Tuberous sclerosis

NTSA

[67]

2000

E

Autism

AAN, CNS

[68]

2000

E

Attention deficit disorder

AAP

[69]

2000

E

First nonfebrile seizure

AAN, CNS, AES

[70]

2000

T

Status epilepticus

SEWP

[71]

2001

T

Attention deficit disorder

AAP

[72]

2002

E

Neuroimaging neonates

AAN, CNS

[73]

2002

E

Recurrent headaches

AAN, CNS

[74]

2003

E

Hypertonia

TFCMD

[75]

2003

T

Severe TBI

AAN

[76]

2003

E

Global developmental delay

AAN, CNS

[41]

2003

T

Severe TBI

CNS, others

[77]

2003

T

Guillain-Barré syndrome

AAN

[78]

2003

T

First unprovoked seizure

AAN, CNS

[79]

2004

E

Cerebral palsy

AAN, CNS

[42]

2004

T

Epilepsy

AAN, AES

[80, 81]

2004

E/T

Migraine headaches

SFEMC

[82]

2004

T

Migraine headaches

AAN, CNS

[83]

2004

T

Infantile spasms

AAN, CNS

[84]

2005

T

Duchenne muscular dystrophy

AAN, CNS

[85]

2006

T

Epilepsy

ILAE

[86]

2006

E

Status epilepticus

AAN, CNS

[87]

2007

E/T

Spinal muscular atrophy

ICSMASC

[88]

2008

T

Stroke

AHA

[45]

2008

E

Antiepileptic drug levels

ILAE

[89]

2009

E

Microcephaly

AAN, CNS

[90]

2010

T

Cerebral palsy

AAN, CNS

[91]

2010

T

Cerebral palsy

CPI

[92, 93]

2010

T

Congenital muscular dystrophy

ISCCCMD

[94]

2011

E

Simple febrile seizure

AAP

[95]

2011

E

Brain death

AAP, CNS, SCCM

[47]

2012

E/T

Traumatic brain injury

CNS, AAP, others

[48]

2012

T

CVST

FSPN, EPNS

[96]

2012

E/T

Epilepsy

NICE

[97]

2012

T

Infantile spasms

AAN, CNS

[98]

2012

E/T

Insomnia in autism

ATN

[99]

2013

T

VNS for epilepsy

AAN

[100]

2013

T

Prolonged seizures

NLAE, BSEDM

[101]

2014

T

Status epilepticus

MGMSECI

[102]

2013

E/T

Sports concussion

AAN

[40]

2015

E/T

Congenital muscular dystrophy

AAN, AANEM

[103]

2015

T

Infantile spasms

ILAE

[104]

AAFP, American Academy of Family Physicians; AAN, American Academy of Neurology; AAP, American Academy of Pediatrics; AES, American Epilepsy Society; ATN, Autism Treatment Network; BSEDM, Belgian Society for Emergency and Disaster Medicine; CNS, Child Neurology Society; CPI, Cerebral Palsy Institute; CVST, cerebral venous sinus thrombosis; E, evaluation; EPNS, European Pediatric Neurology Society; FSPN, French Society of Pediatric Neurology; ICSMASC, International Conference on Spinal Muscular Atrophy Standard of Care; ISCCCMD, International Standard of Care Committee for Congenital Muscular Dystrophy; ILAE, International League Against Epilepsy; MGMSECI, Multidisciplinary Group on Management of Status Epilepticus in Children in India; NICE, National Institute for Health and Clinical Excellence; NTSA, National Tuberous Sclerosis Association; SCCM, Society of Critical Care Medicine; SFEMC, French Society for the Study of Migraine Headache; SMA, spinal muscular atrophy; T, treatment; TFCMD, Task Force on Childhood Motor Disorders; VNS, vagus nerve stimulator.

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PART XIX  Care of the Child with Neurologic Disorders

BOX 166-2  Institute of Medicine (IOM) Standards for Developing “Trustworthy” Guidelines 1. Transparency a. Details regarding clinical practice guideline (CPG) development and funding should be explicit and public. 2. Conflict of Interest (COI) a. Potential guideline development group (GDG) members should declare all potential COIs. b. COIs should be reported and discussed by the GDG before any member joins the group. c. Each member should explain how COIs could influence their work. d. Members should take steps to minimize their current and future COIs. e. Ideally, members should not have COIs, but when necessary, those who do should be a minority of the group and should not serve as the chair or cochairs of the group. f. Funders should have no role in CPG development. 3. GDG Composition a. GDGs should be multidisciplinary and balanced. b. Patient and public involvement should be facilitated. c. GDGs should adopt strategies for increasing effective participation of patient and consumer representatives. 4. CPG–Systematic Review (SR) Intersection a. CPG developers should use SRs that meet standards set by the IOM. b. When SRs are conducted specifically for a CPG, the GDG and SR team should interact regarding the scope, approach, and output of both processes. 5. Establishing Evidence Foundations for and Rating Strength of Recommendations a. Each recommendation should be accompanied by: i. the reasoning underlying the recommendation, including 1. a clear description of potential benefits and harms; 2. a summary of relevant available evidence (and evidentiary gaps), a description of the quality (including applicability), quantity (including completeness), and consistency of the aggregate available evidence; and 3. an explanation of the part played by values, opinion, theory, and clinical experience in deriving the recommendation.

ii. a rating of the level of confidence in (certainty regarding) the evidence underpinning the recommendation; iii. a rating of the strength of the recommendation in light of the preceding bullets; and iv. a description and explanation of any differences of opinion regarding the recommendation. 6. Articulation of Recommendations a. Recommendations should be articulated in a standardized form that makes clear what actions are recommended and under what circumstances. b. Strong recommendations should be worded to facilitate evaluation of compliance. 7. External Review a. External reviewers should include scientific and clinical experts, interested organizations (e.g., healthcare, specialty societies) and agencies (e.g., federal government), patients, and representatives of the public. b. The confidentiality of authorship of external reviews by individuals and/or organizations should be maintained unless waived. c. The GDG should record its responses to all reviewers’ comments. d. A draft of the CPG should be made available to the general public for comment and reasonable notice of impending publication should be provided to interested public stakeholders. 8. Updating a. The CPG publication date, date of pertinent SR, and proposed date for future CPG review should be documented in the CPG. b. Literature should be monitored regularly to evaluate the continued validity of the CPG. c. CPGs should be updated when new evidence suggests the need for modification of clinically important recommendations.

(Adapted from Institute of Medicine (IOM). Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press; 2011.)

National Academy of Sciences to research the most objective, scientifically valid, and consistent methods for producing SRs and CPGs. The IOM’s report “Clinical Practice Guidelines We Can Trust,” published in 2011, outlined eight recommendations for improving the transparency and validity of the guideline development process (Box 166-2) (IOM, 2011).

THE AMERICAN ACADEMY OF   NEUROLOGY PROCESS The AAN GDDI subcommittee produces guidelines according to a process manual that has incorporated each of the IOM report’s recommendations (AAN, 2011).

Choosing Topics and Panelists AAN guidelines may be written to address any number of the decision points facing practitioners in the management of patients with neurologic disorders, including how diagnostic tests should be used, how to choose the most appropriate medical and surgical treatments, and how to apply test results to counseling about prognosis.

Topics for AAN guidelines can be suggested by anyone, but typically come from physicians interested in serving as guideline authors, physician or patient interest groups and organizations, and members of the AAN GDDI and Practice committees. These nominations are rated by a topic expert designated by the GDDI based on relevance, prevalence, degree of practice variation or controversy, financial implications, feasibility of the project, and the potential for changes in treatment to improve patient care and outcomes. Once a topic is selected, the GDDI then uses the same factors to decide whether the topic and its time-sensitivity warrant the production of a full SR, a more focused SR, a full CPG that uses a full SR, or a practice advisory focused on one or two clinical questions, based on a focused SR. Next, a writing panel made up of volunteer subject experts and GDDI members serving as process experts is assembled, with careful attention to minimizing and balancing COIs. For full systematic reviews and guidelines, the panel includes at least one patient or patient representative. The writing panel formulates a protocol with an introduction to the topic, the clinical questions the panel will try to answer, and the search strategy the researchers will use for collecting scientific



Practice Guidelines in Pediatric Neurology

evidence. Clinical questions are written in PICO format, specifying the population (P) or type of patient involved, the intervention (I) experienced by the patient (e.g., treatment, risk factor, or positive test result), the co-intervention (C) that serves as a comparator to the intervention (e.g., no-treatment or different treatment, lack of the risk factor, or negative test result), and the outcome (O) by which the effect of the intervention is being assessed. For fully IOM-compliant products, the panel protocol is posted for public review and the framework and PICO questions are revised based on the comments received.

Collecting and Grading Evidence The search strategy for fully IOM-compliant products must query more than one database, including the so-called “gray literature,” which refers to results of clinical studies and literature reviews that are never published as articles in medical journals, but are nonetheless available (www.graylit.org/ about). Including data from unpublished studies may help to counter some of the bias that leads to studies showing less benefit and more harm from treatments or tests being more likely either to be rejected for publication or to never be submitted in the first place. Most clinical trials performed in academic centers are now registered with the National Institutes of Health (NIH), and their protocols are published and maintained on an online site (www.clinicaltrials.gov) so that the investigators can be asked for study data even when the study is never completed or never published. The AAN process calls for an explicit search strategy to be laid out, for the abstracts of all papers identified by that search to be reviewed by at least two people for relevance, and then for the full text of all remaining papers to be reviewed by at least two people for relevance and stratification of the evidence into one of four classes based on characteristics of the study design that are relevant to bias. Different criteria are applied to studies addressing different clinical questions. For randomized, controlled clinical trials (RCTs) pertaining to the effectiveness of a treatment, studies can receive the highest rating (lowest risk of bias), class I, only when they are done in a sample of patients representative of the population, use masked or objective outcome assessments, exclude or adjust

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for substantial differences between treatment groups in relevant baseline characteristics, use appropriate concealment allocation, prospectively define no more than two primary outcome measures, have clearly defined exclusion and inclusion criteria, and follow at least 80% of enrolled subjects to completion of the study, adequately accounting for dropouts. Studies that fail to meet one or more of these criteria will be downgraded to class II (moderate risk of bias) or class III (high risk of bias). Uncontrolled case series are given the lowest rating (very high risk of bias), class IV (Table 166-4). The rationale for classifying evidence relates to the likelihood that given methods will affect the internal and external validity of the study’s results and conclusions. When there are multiple studies pertaining to a question, particularly when they reach conflicting conclusions, greater weight should be given to studies providing stronger evidence (i.e., ones that because of their methodology are more likely to accurately reflect reality). For treatment trials, biases affecting internal validity lead to an underestimation or overestimation of the effectiveness of interventions. These biases frequently involve improper use of control groups, blinding, and randomization. External validity is lower when a study’s results cannot easily be generalized to real-world patients and clinical settings, as a result of such factors as the exclusion of representative patients, high costs, and onerous burdens on patients and caregivers.

Drawing Conclusions Each study is then abstracted for a measure of the strength of the association between the intervention and outcome pair. For treatment trials, such association measures might be relative or absolute risk or odds differences between the treatment and control groups, with the precision in measurement shown by 95% confidence intervals (CIs) or by p-values (from which the 95% CI can usually be estimated). For relative risks or odds, a 95% CI that does not cross the value 1 is statistically equivalent to a p-value of less than 0.05. A study may or may not show a statistically significant association between interventions and outcomes, but the width of the CI should also be considered. A study may have great precision (narrow CI) and show significance (p < 0.5) but still lack clinical relevance

TABLE 166-4  American Academy of Neurology Process CONFIDENCE IN EVIDENCE Confidence

Evidence

High Moderate Low Very Low or Unknown

At least 2 consistent class I studies 1 class I or at least 2 class II studies 1 class II or at least 2 class III studies Insufficient for a higher rating

LEVELS OF RECOMMENDATIONS Recommendation Level

Level U

Level C

Level B

Level A

Wording Adherence expected to affect Variation in patient preferences Cost Availability Value of benefit relative to risk Confidence in evidence Strength of principle-based inferences

None Few Large Prohibitive Limited Too close to call Very low Not plausible

May Some

Should Most

Small Low Plausible

Moderate Moderate Convincing

Must Nearly all Minimal Minimal Universal Large High Compelling

The recommendation level is anchored by the lowest of the confidence in evidence and the strength of principle-based inferences. The recommendation level can be decreased for any factor. The recommendation level can be increased only for a value of the benefit relative to risk that is moderate or large and can only increase by one level. With the exception of the unusual circumstance of recommendations derived solely from first principles, the level of recommendation can never attain level A without high confidence in evidence. (Adapted from AAN. Clinical Practice Guideline Process Manual. 2011 Ed. St. Paul: The American Academy of Neurology; 2011.)

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because of actually small or clinically irrelevant differences in outcome. A study lacking both precision (wide CI) and statistical significance (p > 0.5) may be inconclusive, rather than negative, suggesting that an intervention could be clinically important if measured more precisely. If a great deal of the identified evidence suffers from lack of precision, a metaanalysis to combine the results of comparably performed studies may be appropriate. The AAN uses the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process for determining the confidence in the evidence, modified by using the class of the supporting evidence as an anchor point. First, interventions are assigned an initial level of confidence based on the class of evidence supporting their association with an outcome. This serves as an anchor limiting how much a recommendation can be upgraded or downgraded based on other factors that are then considered. The confidence can be downgraded by one level if the panel feels that there are additional factors limiting confidence in the evidence, including biological implausibility, the number and consistency of studies, their statistical precision, their generalizability, and their potential for being skewed by reporting bias. Similarly, the panel members may decide to raise their confidence in the evidence by one level if supporting factors are present, such as a large effect size, a dose–response relationship, and a bias that tends to minimize effect size. To complete an evidence report or systematic review, the writing panel must summarize the collected evidence for each PICO question into conclusions that account for the class of evidence found, the strength and precision of the measures of association, the populations to which the findings apply, and the consistency, or lack thereof, between studies. The AAN uses language in writing its conclusions that is directly tied to the confidence in the evidence. For example, if there are multiple, consistent class I studies showing a clinically meaningful association between a treatment and improved clinical outcomes supporting high confidence, the panel is prompted to conclude that it is “highly likely” that the treatment is effective. If there is a single class I study or there are multiple class II studies showing a similar association supporting moderate confidence, the panel will conclude that it is “likely” that the treatment is effective, and so on. The panel may exclude negative studies lacking the precision to exclude a meaningful association (high risk of random error) when drawing conclusions, even if those studies were rated highly for class of evidence (low risk of systematic error).

Writing Recommendations If the writing panel had intended to draft a clinical practice guideline or advisory, and the evidence review was able to identify evidence of good quality and consistency, the writing panel then begins the process of formulating recommendations. Each recommendation is rated according to the level of the panel’s confidence in making it. The levels imply the obligation of practitioners to follow the recommendations. High-level (level A) recommendations direct practitioners toward things that they “must” or “must not” do. Moderatelevel (level B) recommendations suggest to practitioners things that they “should” or “should not” do. Low-level (level C) recommendations imply that practitioners “may” or “may choose not to” decide to follow them. The lowest-level recommendation (level U) is assigned when there is insufficient evidence and rationale for choosing between available options (Table 166-4). The author panel then drafts a set of recommendations, starting with the clinical questions and considering the available evidence in a realistic context. Each recommendation is

rated for the strength of deductive inference behind it, based on how well it can be related to accepted principles of medicine, related clinical evidence, and deductive reasoning. Recommendations considered at this stage can be based on this deductive process alone, rather than on conclusions from the evidence review. Each recommendation is assigned an overall rating based on the lower of the two ratings, the level of confidence (high, medium, low, very low) and the level of plausibility (compelling, convincing, plausible, or not plausible). The panel then systematically considers additional factors affecting the relative value of an intervention (the benefits [effect size], risks [tolerability and safety], availability, cost, and presence [or lack] of alternatives) and the variation expected in patient preferences. Only a large relative value can raise the level of confidence in a recommendation, and even then it can do so by only one level and cannot raise a recommendation up to level A. Interventions that might otherwise be worthy of a level U recommendation may also be designated level R (research-only) if concerns about costs or risks are such that the panel feels that patients should only receive the intervention in the context of ongoing research. Often, the AAN uses a modified Delphi technique to reach consensus between the guideline development group (GDG) members regarding the wording and rating of the level of recommendations. The Delphi process involves GDG members anonymously answering a series of questions intended to determine the soundness of the recommendation and the relative importance of the factors that might influence the strength of the recommendation. The GDG responses are summarized and then presented to each member again, along with any commentary, and another round of rating is carried out. This rating and summarization process is repeated until consensus is obtained (>80% agreement), up to a maximum of three voting rounds. Because the process maintains participant anonymity, it reduces some negative group dynamics, including the tendency for opinion to be strongly influenced by participants with greater authority, reputation, or personality, and the tendency for participants to avoid changing their opinions out of fear of appearing inconsistent. Some important clinical questions cannot be answered with current data, and some studies, even if conceivable, are unlikely to ever be financially or ethically feasible. Clinical context sections in some recent AAN guidelines have provided discussions by the authors of what is common in clinical practice without making specific recommendations. In the absence of sufficient evidence to support strong recommendations, the AAN has typically opted to lay out the limitations of the evidence and leave decisions regarding the best course of action to individual neurologists, who are those with the best understanding of their patients’ values and circumstances. Once the author panel has finalized the wording and grading for its recommendations, the guideline is vetted by the AAN staff working with the GDDI subcommittee, including the staff EBM methodologist; reviewed by other members of GDDI committee; posted online with invitations for public comments; reviewed by the AAN Practice committee; and finally submitted for publication to the AAN’s official academic journal, Neurology. At each step, the feedback received and the reasoning behind any modifications made or not made in response are documented. Finally, the manuscript is submitted to the AAN Board of Directors and to any cooperating professional and patient-centered organizations for endorsement. Dissemination efforts beyond publication in Neurology include press releases and official AAN written and electronic announcements directed at AAN members and the public. An archive of prior guidelines and educational materials for



patients and practitioners, including summary pages and slide sets, are freely available for download on the AAN website (http://www.aan.com/Guidelines). The GDDI considers whether or not to update previously published AAN guidelines every 2 years, based on whether sufficient and compelling new evidence is identified by an interim literature search that would significantly change prior recommendations. If a guideline appears to still be valid, the panel may vote to reaffirm it. If a guideline no longer appears to be valid, the panel may decide to either retire it or nominate it for revision.

LAW AND ETHICS Many clinicians have a reflexive objection to the idea of being obligated by a clinical practice guideline to take specific actions in the care of their patients, feeling that rote application of “cookbook” standards of care cannot adequately substitute for their use of their own clinical judgment, incorporating their experience, their knowledge of disease pathophysiology, and their understanding of the nuances in their patients’ characteristics and individual values and preferences. There has been little demonstrable effect of guidelines on the frequency with which defensive medicine is practiced. It has been suggested that CPGs would be more widely accepted, and that greater improvements in the cost-effectiveness of care could be realized, if it was clear that CPG recommendations could serve as an effective defense against malpractice claims. However, most malpractice trials take place in state courts, which tend to look to customary local practices, rather than to recommendations from a CPG, for the standards of care to which they will compare the actions of physician defendants (Avraham and Schanzenbach, 2010). Courts in most states will not hold practitioners liable for care that is judged customary, even if it is not optimal or evidence-based. However, the U.S. federal legal system has allowed the submission of CPGs as expert testimony even if not as evidence. CPGs have been introduced into court proceedings both to defend a practitioner’s actions and to suggest negligence. In one case, a court ruled a physician’s care negligent for following a guideline without consideration of his patient’s specific circumstances (Recupero, 2008). Because of ongoing concerns about their legal implications, all guidelines produced by the AAN carry a general disclaimer that their recommendations, even when worded as strongly as possible, should be considered suggestions rather than explicit directives. Nevertheless, some specific AAN guidelines anticipated to be controversial or upsetting to particular interest groups have been submitted to the AAN’s legal team before their publication to be vetted for wording that might be unnecessarily provocative.

GUIDELINE UTILIZATION There have been several studies done regarding awareness and acceptance of guidelines; these studies suggest that practitioners value them, but do not follow their advice (Davis and Taylor-Vaisez, 1997). A general obstacle to guideline utilization is the consideration of how decisions for real patients must usually account for far greater complexity, nuance, and specificity than clinical trials, meta-analyses, or guidelines can cover. Financial incentives to order unnecessary tests and treatments probably play a smaller role in the overutilization of services than do inclinations to perform defensive medicine out of concern for potential lawsuits. Guidelines may adversely affect their own adoption by lacking clearly actionable language or simply because they rely on a weak base of evidence.

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It is clear that the most successful strategies for changing practitioner behavior use financial incentives, such as those that can be directed by hospitals and insurers (Rosenthal and Dudley, 2007). The pay-for-performance incentives and penalties incorporated into the 2008 Affordable Care Health Care law are driving sweeping systematic changes in physician participation in electronic health record (EHR) systems, registries, and quality improvement (QI) measurement efforts. Guidelines can suggest improvements in standards for practice when based on evidence of benefit verus harm that is clear, strong, and generalizable. For example, studies have shown that patients treated in accordance with CPG recommendations for asthma (Licska, Sands, and Ong, 2012) tend to have better health, shorter hospital stays, lower short-term costs, and lower rates of early rehospitalization. Ongoing research in measuring the impact of guidelines will involve the use of electronic medical records (EMRs) to assess implementation and outcomes. Additional research will address the most effective ways for hospitals and practice groups to integrate guideline recommendations into the care of patients, such as through prompts generated in EMRs and assignment (especially of noncontroversial and strongly supported recommendations) to physician extenders such as nurse practitioners.

CONCLUSION When developed using methodologically sound processes, clinical practice guidelines can provide clinicians, researchers, and administrators with a clear picture of the state of the art in the evaluation, diagnosis, and management of a disease. In addition, systematic reviews and guidelines, by providing a clear accounting of the quality of the existing evidence, can suggest where the need for additional information is greatest. Because recommendations can only be as strong as the evidence will support, the growing interest in evidence-based guidelines is naturally stoking interest in creating a stronger evidence base. In 2010 the U.S. Congress established the nonprofit Patient-Centered Outcomes Research Institute (PCORI), which has already provided more than $1 billion to fund comparative effectiveness research projects to “provide information about which approaches to care might work best, given [patients’] particular concerns, circumstances, and preferences” (http://www.pcori.org). The methods used for disseminating and implementing CPGs are undergoing rapid changes, with some trends having unintended consequences. Healthcare providers share the interest of consumers and payers in identifying and minimizing practices that are questionable or outright harmful. However, institutions must take care to ensure that practitioners do not end up feeling overburdened with levels of regulation of unproven value. The coming years, with additional insights from studies assessing the impact of CPGs on outcomes, will see these competing interests brought into better balance. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. REFERENCES American Academy of Neurology (AAN), 2011. Clinical Practice Guideline Process Manual, 2011 Ed. The American Academy of Neurology, St. Paul, MN. Avorn, J., 2005. FDA standards – good enough for government work? NEJM 353 (10), 969–972.

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Avraham R., Schanzenbach M., 2010. The Impact of Tort Reform on Private Health Insurance Coverage. Am Law Econ Rev. 12 (2), 263–4. Davis, D.A., Taylor-Vaisez, A., 1997. Translating guidelines into practice: A systematic review of theoretic concepts, practical experience and research evidence in the adoption of clinical practice guidelines. CMAJ 157, 408–416. Eddy, D.M., 2005. Evidence-based medicine: A unified approach. Health Aff. 24 (1), 9–17. Hurwitz B.A., Hurwitz K.B., Ashwal S., 2015. Child neurology practice guidelines: past, present, and future. Pediatr. Neurol. 52 (3), 290–301. Institute of Medicine (IOM), 2011. Clinical Practice Guidelines We Can Trust. The National Academies Press, Washington, DC. Licska, C., Sands, T., Ong, M., 2012. Using a knowledge translation framework to implement asthma clinical practice guidelines in primary care. Int. J. Qual. Health Care 24, 538–546. Recupero, P.R., 2008. Clinical practice guidelines as learned treatises: understanding their use as evidence in the courtroom. J. Am. Acad. Psychiatry Law 36 (3), 290–301. Rosenthal, M.B., Dudley, R.A., 2007. Pay-for-performance: will the latest payment trend improve care? JAMA 297 (7), 740–744. Schünemann, H.J., Osborne, M., Moss, J., et al., 2009. An official American Thoracic Society Policy statement: managing conflict of interest in professional societies. Am. J. Respir. Crit. Care Med. 180 (6), 564–580.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Box 166-1 Current Evidence-Based Practice Centers Funded by the Agency for Healthcare Research and Quality Table 166-2 Classification of Therapeutic Trials Table 166-3 Sources of Bias in Clinical Trials Table 166-5 American Heart Association Level-of-Evidence Algorithm Table 166-6 National Comprehensive Cancer Network Clinical Guidelines Framework Table 166-7 GRADE Rating System

Education Law as it Relates to Children with 167  Special Neurologic Disorders Kathleen A. Hurwitz

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

HISTORY Special education case law carried out by individual states and the federal legislation for the education of children with disabilities has its roots in the Fourteenth Amendment of the U.S. Constitution. This post-Civil War proposal insured that no state could deprive a person to life, liberty, or property without due process of law. Defining educational laws for children with special needs took its next big leap during the civil rights movement in the 1950s and 1960s. The equal rights amendments and the desegregation laws opened the door for children with disabilities to fall under the umbrella of antidiscrimination legislation. Educators, families, physicians, and disabled children have lobbied for education provisions that provide the best possible learning environment for special needs children. Physicians and allied healthcare providers who deliver diagnostic and prognostic information to patients and families are compelled to understand current special education laws. In 1992 the American Academy of Pediatrics put forward a policy statement that called upon all pediatricians and pediatric subspecialists to provide a “medical home” for their patients. The medical home concept is particularly relevant for children with special needs. The statement advocates that physicians develop a “coordinated, comprehensive plan” for each child and involve community resources, including schools and educators in that plan. The physician needs to “claim responsibility” and oversee the implementation of the child’s care plan. Expansion and inclusion of healthcare services during school hours is increasingly falling under the jurisdiction of public education. Children with complex medical needs who frequently are sustained on technological devices require physician input for their care during school hours. In anticipation of the clinician’s changing role, a working knowledge of the evolution of the legislative process as it pertains to special needs education is presented in this chapter.

SPECIAL EDUCATION CASE LAW Special education law developed in state courts. A chronologic review is presented to give a historical perspective. These changing state rulings are precursors to federal legislation (Table 167-1). Brown v the Board of Education (1954) was a class action suit that was a plea for racial desegregation. African American parents who had attempted to enroll their children in neighborhood schools with Anglo American students had been refused. They were required to attend segregated schools. Previously, “separate but equal” facilities were acceptable as long as they were equivalent. The Supreme Court ruled that in “the field of education separate but equal has no place. Separate educational facilities are inherently unequal.”

In Hobson v Hanson (1969), the first objection to the use of standardized testing as part of tracking students was challenged. Ninety percent of students in Washington, DC, were African American. However, they were given Intelligent Quotient (IQ) testing benchmarked to Anglo American standards. Children were placed based on socioeconomics and race as opposed to their learning aptitude. The legal decision abolished Washington, DC’s tracking system. IQ testing in a child’s native language was first tested in Diana v State Board of Education (1970) (Reynolds, 2007). Civil rights groups brought suit on behalf of a bilingual student who was placed in a classroom for the mentally retarded. The child, Diana, had been tested in English and not in her native language, Spanish. The case never was heard because a decree was issued that IQ testing must be performed in the child’s primary language. Lau v Nichols (1974) was a case involving Chinese-speaking students who claimed that they could not take advantage of certain educational opportunities because instruction was only in English. The court ruled that supplemental English be provided or instruction be carried out in the native language. In 1979, Larry P. v Riles clarified testing of African American children. Larry P., one of six African American children, brought suit against the California Superintendent of Schools, claiming overrepresentation of African American children in classes for the mentally retarded. The children were placed in these classes solely on IQ testing. The court’s ruling favored the plaintiffs and restricted IQ testing for African American children. It was ruled that testing could only be performed if: 1) the court had received a request; 2) the test was validated for identifying cognitive delays; 3) the test was not racially or culturally biased; 4) the test was administered in a nonbiased environment; and 5) an open public hearing was held regarding the test. Stanford Binet and WISC-R testing procedures were evaluated in the Illinois case, PASE v. Hannon (1980). Cultural bias was on trial for each test question. Very few biased questions were found. The case never became historically significant because the state of Illinois banned the IQ testing of African American children as part of a settlement in a desegregation case. High school competency testing as a requirement for graduation has been challenged in Florida. Debra P. v Turlington (1984) challenged the fact that a disproportionate number of African American children were failing their exit examinations. Because students taking the test started school when Florida was still segregating students, the court found for the plaintiffs. The courts also placed an injunction and the test was not required for graduation. Mills v Board of Education of the District of Columbia (1972) is a landmark case for special needs children. Seven children brought suit against the schools because they were excluded

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TABLE 167-1  Summary of Case Laws Case

Complaint

Ruling

Brown v Board of Education (1954)

Unable to enroll African American students in neighborhood school

Separate schools are inherently unequal

Hobson v Hanson (1969)

Objection to using Intelligent Quotient (IQ) testing for tracking students

Abolished tracking system

Diana v Board of Education (1970)

IQ testing in nonnative language

IQ testing must be in native language

Lau v Nicholas (1974)

Instruction not in native language

Supplemental English or instruction in native languages required

Larry P. v Riles (1979)

Overrepresentation of African Americans in EMR classes

Courts severely restructured IQ testing

PASE v. Hannon (1980)

Cultural bias in IQ tests

Very few culturally biased questions

Debra P. v Turlington (1984)

High school competency testing for graduation

Requires adequate notification to student before enforced

Mills v Board of Education (1972)

Excluded from school based on behavior, hyperactivity, and mental retardation

Free and appropriate education to all children regardless of disability type

Pennsylvania Association for Retarded Children v Pennsylvania (1972)

Excluded from classroom

Must include all children in education process and attempt to educate alongside nonhandicapped children if possible

Pennsylvania v Battle (1980)

Related service terminated at end of school year

Must be continued year round if a negative or regressive effect would result from termination

Board of Education of the Hendrick Hudson Central School District, Westchester County, et al. v Rowley (1982)

Deaf student requested an interpreter even though meeting IEP goals

No; the program in place was adequate

Timothy v Rochester (1989)

Severely handicapped and thought to be uneducable

Free and appropriate education upheld

N.B. v Warwick School (2004)

Parents wanted a different education program for autistic child and not the school-offered program

School providing program with a reasonable prediction of success was adequate

from public education based on their disabilities. These were issues of behavior, hyperactivity, and mental retardation. Many of the students excluded had not received a fair hearing. The court found in favor of the children; thus began “a free and appropriate education” for all children regardless of the disability. The case predated but greatly influenced the federal 1965 legislation called the “Education for all Handicapped Children Act” of 1975. Defining a free and public education in the least restrictive environment became clearer from the case, Pennsylvania Association for Retarded Children v Pennsylvania. Thirteen mentally retarded children on behalf of all such children sued for a free and appropriate education under the equal protection clause. The court developed the concept of a least restrictive environment. A regular public classroom was a better choice for educational training than a special education classroom, which in turn, was preferable to a separate educational facility. Battle v Pennsylvania (1980) extended benefits and services to disabled children beyond the traditional 180-day school year. The court supported the claim that discontinuing special education and programs, particularly self-help skills during recesses, could have a negative, regressive effect on children. This legal precedent protects interruption of much needed services. The Board of Education of the Hendrick Hudson Central School District, Westchester County, et al. v Rowley (1982) was ultimately heard by the Supreme Court and interpreted the legal language of a “free and appropriate education” more clearly. Amy Rowley, a deaf student with two deaf parents, was enrolled in a regular classroom with an Individual Education Plan

(IEP) in place. She thrived in her environment, yet her parents requested an interpreter. The lower courts supported her parents because of a discrepancy between her performance and potential. However, the Supreme Court felt the program in place was “benefitting” her and fell under the definition of a free and appropriate education. Accessibility of education for children with disabilities was tested in the courts in 1989. In Timothy W. v Rochester, it was ruled that the severity of a disability was not at the interpretation of the state. Timothy was severely mentally retarded, a spastic quadriplegic, cortically blind, and thought to be uneducable. Timothy’s right to a free and appropriate education was upheld (Murdick et al., 2007). N.B. v Warwick School Committee (2004) has important ramifications for child advocates. The parents of an autistic child brought suit against a school district. The child in question had an IEP that supported a program called Treatment and Education of Autistic and Related Communicatively Handicapped Children (TEACH). The parents preferred a program that promoted “discrete trials” and enrolled their child at their own expense into such a program and were requesting reimbursement. The court found in favor of the school. The school was not required to provide the requested program but rather any program as long as it had a “reasonable prediction” of success.

Federal Legislation Federal legislation for children with disabilities emerged from a combination of social, political, and legal pressures. In the late 1960s and early 1970s, over 8 million disabled children



Special Education Law as it Relates to Children with Neurologic Disorders

attended U.S. public schools (Wright et al., 2007). However, the special education needs of each child were not being provided in any consistent manner. Some states had exclusionary practices whereas others were struggling to meet the demands without appropriate classification procedures in place. Parental advocacy groups, education leaders, and lawmakers realized the need for federal legislation. The first program of federal assistance to local school districts was defined in the Elementary and Secondary Education Act of 1965 (P.L. 89-10). Title 1 of this statute provided federal funding for schools based upon the number of students living at or below the poverty level. The No Child Left Behind Act of 2002 replaced this legislation. The Handicapped Children’s Early Education Assistance Act of 1968 (P.L. 95-538) provided for educational programs for disabled young children. Demonstration projects or educational models were to be funded, established, and measured for their success in providing educational services. This act also funded research institutes to study behavioral, cognitive, and emotional functioning of children. In 1982 funding was also provided for the evaluation of children with autism. The Vocational Rehabilitation Act of 1973 (P.L. 93-112) provided services for the educationally handicapped (physical or mental) to promote independent functioning or employability. Section 504 of this act protected against discrimination of services. It ensured that children who may not meet “special education” definitions can have appropriate classroom modifications. This is important for children with medical conditions who cannot meet the full demands of a classroom. Children with attention deficit disorder or attention deficit hyperactivity disorder are an example of those needing a “504” in place. This “504” can provide extra time for testing, frequent breaks, etc. (Osborne and Russo, 2006). Access to a minor’s academic records is defined in the Family Education Rights and Privacy Act (1974). Parents of minors or 18-year-old students must provide a written request to review their records. If they believe the record to be incorrect they can request that the record be amended. A hearing can be called if the school disputes the amendment. Law enforcement records must be maintained separately and are not included in a student’s file (Family Education Rights and Privacy Act, 1974, Pub. L No. 93-380). In the early 1970s, Congress recognized that over 1.5 million children were excluded from school based on their disabilities. Therefore P.L. 142, known as The Education of All Handicapped Children Act (1975), was passed. This act included the all-important inclusion of an Individual Education Plan (IEP) for every child in special education. It was mandated that the child’s education be carried out in the least restrictive environment and that parents be given informed consent regarding testing and evaluation results. Testing and reports were to be conducted and discussed in the child’s native language. Due process must be provided for conflict and disagreement, and placement in special education must be nondiscriminatory. The concept of “zero reject” was established in P.L. 142. No child regardless of the disability could be excluded (Murdick et al. 2007). This act was expanded as P.L. 101 to 476, as the Individuals with Disabilities Education Act of 1990 (IDEA). Just before this, the Americans with Disability Act of 1990 (P.L. 101-336) was passed. The Americans with Disability Act mandated the elimination of discriminations for individuals with disabilities. It prevented the disabled from being discriminated against in employment and required that public school services (e.g., field trips, after school activities, and school facilities) be physically accessible to all disabled students. Passage of this act also required private entities to provide public services to all disabled individuals. Effective telecommunications and

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BOX 167-1  Summary of Individuals with Disabilities Education Act 1. Age 3 to 21 that are disabled 2. Free and appropriate education 3. Least restrictive environment 4. Related services 5. Public school must search and find children who qualify 6. Nondiscriminatory testing 7. Individual Education Plan (IEP) for every qualified child 8. IEP’s are transferable 9. Transition program from infant to preschool 10. Personnel development 11. Transition programs for after high school graduation 12. Confidentiality

closed-captioning services were also mandated for the speech and hearing impaired.

Individuals with Disabilities   Education Act (IDEA) The seminal legislation in protecting disabled children’s educational rights is embodied in federal statutes 101 to 426, 102 to 119, 105 to 17 and 108 to 445, the Individuals with Disabilities Acts of 1990, 1991, 1997, and 2004. This act is divided into four sections. The first, Part A, is composed of definitions. Part B houses the important laws and bulk of the legislation. Part C refers to infants and toddlers, and Part D refers to the national activities that exist to improve special education. The essence of this act, Part B, contains the legislative components important to physicians. Any state that receives federal funding must include these essential components (Box 167-1). The act states who qualifies for special education in Section B. Any child between the ages of 3 to 21 who has been evaluated under this act’s standards who is mentally retarded, speech or hearing impaired, deaf, a victim of traumatic brain injury, visually impaired, orthopedically impaired, autistic, possesses another health impairment, or is learning disabled qualifies for special education if the preexisting impairment influences the learning potential of the child. Children with disabilities are entitled to a free and appropriate education. Free literally means “no charge.” The child and his parents cannot be refused a service or billed for a service if it is covered under this act or if it is part of the child’s IEP. The school can provide the least expensive form of the service. Medicaid or MediCal or private insurance can be billed for services covered under this act as long as it does not financially injure the family. Schools cannot charge for transportation to public or private facilities if the service is part of an agreed IEP. Appropriate education has been tested at the court level. In Board of Education of the Hendrick Hudson Central School District, Westchester County, et  al. v Rowley (1982), an appropriate education must have “a reasonably calculated benefit to the child’s education.” A child’s “educability” and prognosis does not exclude him from the process as seen in Timothy v N.H. (1987). Section 504 of the Rehabilitation Act of 1973 included modification and support for children with “other health impairments.” Children with allergies, asthma, diabetes, attention deficient and hyperactivity disorder, etc., who do not qualify for an IEP are entitled to accommodations to protect their right to a free and appropriate education. The term “least restrictive environment” is the general education classroom. A classroom with an aide for the child is less

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restrictive than a special education classroom, followed by a special school. The most restrictive setting would be a home environment. The Individuals with Disabilities Education Act includes “related services” and covers a child’s need for services as long as the child qualifies for special education and the services are necessary to meet the education goals set forth in the IEP. The services covered are transportation, counseling, physical, occupational and speech therapy, recreation and enrichment programs, and school nurse services. Transportation includes “door to bus” assistance but not transportation from school to after-care programs unless it is a part of the IEP. Counseling services do not include psychiatric services because these services fall under medical need unless they are required for the achievement of educational goals. Equal opportunity to participate in extracurricular activities must be provided, if appropriate. Health or nursing services such as intermittent catheterization, suctioning, etc., are included. Medical services that must be performed by a licensed physician are not provided. Drug abuse programs are not considered related services. Various classroom modifications, for example an air conditioner, are covered if maintaining body temperature in a brain-injured child is required for that individual to meet their IEP goals. Public schools and educational agencies must search, find, and identify children with special educational needs as per the Individuals with Disabilities Education Act. Children in private schools and homeless children are included. Nondiscriminatory testing and assessment is guaranteed by this act. The testing process must be free of cultural or language barriers and be administered by a person who is trained and speaks the student’s native language. Importantly, no single testing modality can be used solely to qualify a child for special education. Multiple evaluations and inputs must be performed before a child qualifies for special education. An IEP must exist for every child that qualifies for special education. The IEP is a legal document that must be followed or the local public agency (school) can be cited for noncompliance. The IEP is reviewed every year and evaluated every 3 years. All confidential material must be made available to parents. The IEP team includes the child’s parents, the child if appropriate, one regular education teacher (only if the child will be participating at some level in a regular classroom), a special education teacher, an individual from the school who is responsible for overseeing the performance of the others, an individual (usually a school psychologist) who can interpret the testing tools and their instructional implications, and, lastly, persons who also may contribute to the IEP process. Current (2004) amendments to the IEP do not require, for example, the presence of a physical therapist, an occupational therapist, etc., unless that particular service is being provided. The IEP, as an education plan for the disabled child, needs to include the following: a general statement regarding the child’s current capabilities, annual goals, a statement regarding “related services,” the approximate time spent out of a “regular” classroom, modifications needed for mandated assessments, the projected date of commencement of the plan, how progress will be measured, and a method to keep parents regularly informed. An IEP is transferable. It travels with the child between schools and between states. This continues until a new plan is adopted or the current one is accepted. Provided services can be continued through summer recesses. The summer IEP is separate from the school year and may be completely different. The student must be at risk for “substantial regression” if recess services are to be provided. Children with disabilities, at the age of 14, need an IEP that includes transition planning. By age 16, the transition process

must be in action. Transition IEPs include vocational planning, assessment of activities of daily living, employment plans, and access to community services. Credentials and diplomas should be offered to special education students. An IEP diploma, the minimum requirement for armed services vocational training, can be earned. The diploma also can be used for seeking employment. Part C of this act addresses infants and toddlers (up to 2 years) with disabilities. The Individualized Family Service Plan (IFSP) must be adopted, planned, and implemented by the local public agency and carefully mirrors an IEP. Federal grants are available for developing interagency systems in individual states for these services. The IFSP is a legal document specifying: the current status of the child’s abilities; a statement of a family’s resources and concerns; a plan for measurable treatment outcomes; a specific early intervention service plan based on research evidence; the location of the services; dates of commencement; and the name of the “service coordinator” who will oversee the IEP. Part D of this act includes national activities to improve education of disabled children. Parent training, personnel improvement, and preparation and grants for research fall under this portion of the act.

HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT OF 1996 (HIPAA) The Health Insurance Portability and Accountability Act (HIPAA) was enacted to protect health-insured individuals from preexisting penalties and privacy violations when changing jobs and hence health insurance carriers. Schools that provide health services that are federally funded (catheterization, tracheostomy care, suctioning, and medication administration) are under HIPAA law guidelines.

No Child Left Behind Act (NCLB) The No Child Left Behind Act was signed into law in 2002 (No Child Left Behind Act 2002, Pub. L No. 107 to 110). The Individuals with Disabilities Education Act of 2004 aligns itself with this act. The No Child Left Behind Act replaced the Elementary and Secondary Education Act of 1965 and is a huge paradigm shift from previous legislation. Federal funding to schools, based on the Education Act of 1965, was preferentially given to schools with the greatest number of children whose family incomes were near or lower than the poverty level. The No Child Left Behind Act distributes federal funding to schools that are in need of improvement based on student performance. Children with disabilities were expected to be included in this annual progress assessment of academic proficiency. Adequate progress must be made, and if a school fails for two consecutive years, the students and their parents may transfer to a nonfailing school. The sending school district must provide transportation until it is no longer a failing school for two consecutive years. This applies to all children in the school, regardless of disabilities.

INTERNATIONAL SPECIAL EDUCATION Educational programs for children with disabilities vary widely internationally and approaches in several different countries are described in this section.

Canada The Constitution Act is the legal document that gives the provinces of Canada the control of educational policies and



Special Education Law as it Relates to Children with Neurologic Disorders

their funding. Within the act, the Canadian Charter of Rights and Freedoms is the highest law of the country. So, the laws of any province regarding special education cannot be in violation of these fundamental rights outlined in the Charter of Rights and Freedoms. Passage by a province of their Education Act outlines the powers, responsibilities, and specific education laws for that province, and the minister of education enforces these laws. In the Education Act, special education, suspension, and expulsion resolutions are defined. Special needs schools are available for children with physical, mental, behavior, and communication disorders, as well as for gifted children.

China The United States special education laws have been adopted by China in many ways (Kritzer, 2012). The 1975 Education for All Handicapped Children Act and IDEA Act have served as models for China. Interestingly, despite the large number of children with disabilities in China, the percentage of children receiving services in China is much lower than in the United States (Worrell et al., 2009). China excludes children who have learning disabilities, emotional behavioral disorders, language impairments, and other health impairments from receiving special education services. A lack of experienced professionals, of diagnostic technology, and of delivery systems decreases the number of children who are properly identified and who ultimately receive services. China’s law, The Compulsory Education Law (CEL) issued in 1986, demands that all children attend school at the age of 6. However, in remote areas of China, the CEL-2006 requires only children from the age of 7 to attend. The length of mandated education in China is 9 years. Children with disabilities are entitled to the same number of years of education (Worrell, 2009). Unfortunately, China’s legislation does not guarantee financial support for schools or for the agencies that provide services for disabled children. Class size can reach 70 to 90 students per class, preventing special education children from having their needs met (Worrell, 2009). Infants and toddlers are excluded from special education services unlike in the United States. Some large cities in China, however, do have programs to teach parents with challenged infants and toddlers on how to provide services. China’s beliefs and ideology are contradictory to an IEP so that the unique needs of a child are not readily defined and addressed.

India Special education has moved from segregation to integration through government laws and policies. India’s Integration and Education of Disabled Children (IEDC) law was written in 1974. In 1991 there were 1200 special schools for disabled children that included children with visual impairments, intellectual disabilities, and orthopedic problems. In 1992 a new IEDC program was approved, and financing was provided to integrate disabled students into regular classrooms. Teacher training began and intensive teacher education was undertaken. Selected teachers at a given school were given a 1-year training program. They were then designated as resource teachers. In 1996 the government of India enacted the Persons with Disabilities Act, ensuring opportunities for, protecting the rights of, and allowing for full participation for all citizens. Education, employment, and rehabilitative services were covered for the blind, those with cured leprosy, and those with hearing impairment, motor disability, intellectually disability, and mental illness. Free and appropriate education until the age of 18 was included (National Policy for Persons with Disabilities, 2006).

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Challenges occurred with attempts to integrate students and implement education. Because of poverty, access, and religious beliefs, many children did not receive services. The prevailing belief among many Hindus in India is that the disabilities a child or individual possessed were the result of past deeds in a former life and assisting the disabled could interfere with “karma.” Therefore many disabled students did not receive education and inclusion.

Israel Israel has very comprehensive special education programs for its citizens. The Special Education Law (SEL) of 1988 provided landmark legislation. A child with special needs is defined as “a person aged 3 to 21 whose capacity for adapted behavior is limited due to faulty physical, mental, psychological, or behavioral development and is in need of special education.” A special education placement committee decides a child’s educational needs. The committee includes a social worker, pediatrician, psychologist, minister of education services, and a representative of the National Special Education Parents Organization. A parent has no legal right to attend the meeting, but if the parent does not agree with the placement committee’s decision, he or she has 21 days to request an appeal. Individual Educational Programs are developed for each child (Gumpel, 1996).

Italy Since 1977, children with special education needs in Italy have an opportunity for inclusion with an Individual Educational Program. Special needs schools, separate from the parent school, have essentially been discontinued. All students, since 1987, are entitled to secondary education. In 1992 the Italian Parliament approved the Disabled Persons Bill (L.104/92), which allows inclusion education from preschool to university. A functional dynamic profile is developed utilizing public health doctors. Infants and children with disabilities are involved in education from birth to 19 years of age. Classrooms are composed of 20 students, and no more than 25 students are allowed in a classroom that contains a disabled student.

Japan Japanese laws for special education began after World War II. The School Education Law of 1947 stated that special needs children should receive education with similar expected goals of ordinary children. Ultimately, the School Education Law made school attendance for all disabled children mandatory. In 1994 the law extended compulsory education to all students between the ages of 6 to 15 years. Multiple school arrangements are available in Japan. The severely disabled attend special education schools, and students are given individual education plans. The National Institution for Special Education (NISE) was founded in 1991 and oversees the education of special needs children. Furthermore, special classes exist as well as resource learning classes for students with milder disabilities. Schools exist for children with vision, hearing, or orthopedic impairment as well as for those who are intellectually disabled and children who fall under the category of being “sickly” (Ministry of Education, Culture, Sports, Science and Technology, 2015). REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details.

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SELECTED REFERENCES Family Education Rights and Privacy Act of 1974, Pub. L No. 93-380. 1974. Gumpel, T., 1996. Special Education education law in Israel. J. Spec. Educ. 29, 457–468. Kritzer, J.B., 2012. Comparing Special Education in the United States and China. Int. J. Spec. Educ. 27 (2), 52–56. Ministry of Education, Culture, Sports, Science and Technology. Special support education in Japan: education for children with special needs. ; Retrieved 1 March 1 2015. Murdick, N.L., Gartin, B.C., Crabtree, T., 2007. A free appropriate education. In: Special Education Education Lawlaw, second ed. MerrilMerrill Prentice Hall, New Jersey, pp. 56–57. National Policy for Persons with Disabilities. Ministry of Social Justice and Empowerment. Government of India, 2006.

No Child Left Behind Act of 2002, Pub. L No. 107-110. Osborne, A.G., Russo, C.T., 2006. Section 501 of the Rehabilitation Act of 1973. In: Special Education Education and the lLaw. Corwin Press, CAThousand Oaks, CA, pp. 10–16. Reynolds, C.R., 2007. Diana v State Board of Education. In: Reynolds, C.R., Fletcher-Janzen, E. (Eds.), Encyclopedia of Special Special Educationeducation, third ed. Wiley, New York, pp. 724–725. The Education for All Handicapped Children Act of 1975, Pub. L No. 94-142. Vocational Rehabilitation Act of 1973. Section 504, Pub. L No. 93-112. Worrell, J., Taber, M., 2009. Special Education practice in China and the United States: what is to come next? Int. J. Spec. Educ. 24 (3), 132–142. Wright, P., 2007. History of special education law. In: Special Education Law, second ed. Virginia: Harbor House Law Press, Virginia, pp. 11–16.

of Health Outcomes in Pediatric 168  Measurement Neurologic Disorders Annette Majnemer and F. Virginia Wright

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. This chapter focuses on outcome measurement from the perspective of rehabilitation specialists such as occupational therapists, physical therapists, speech language pathologists, and psychologists. The general principles described apply to all outcome measures; however, specific examples and considerations for specialized areas such as educational or psychiatric assessment are not provided. Most standardized measures require either formal training according to the tool’s guidelines and certification protocols or expertise in child development, in addition to clinical experience in the components that are being assessed.

OUTCOME MEASURES: PURPOSE,   PROPERTIES, PRIORITIZING An outcome is something that follows as a consequence or result of a process, which may be a disease, treatment, or service. An outcome measure is a tool that evaluates or determines the result of a disease, activity, or program. Outcome assessment using the appropriate tool(s) enables objective determination of changes in a neurologic condition over time or changes related to an intervention or program. Identifying the purpose of outcome measurement in a given situation is essential because this will guide the selection of the most appropriate outcome measure(s). Whether in clinical practice or research, the evaluator must first consider what areas (domains) are most important to measure. These considerations always need to be accompanied by the question “why” to ensure that the outcome results will have direct relevance. Once what needs to be measured has been determined, the assessment tools that best align with the concepts (constructs) of interest within the targeted domains can be chosen. It also is essential when selecting an outcome measure to know the intended purpose of the tool itself. With the recognition of the strong importance of being able to measure outcomes, tools have been created to measure particular outcomes and are typically identified as such in the corresponding validation literature that pertain to them. Examples include the Gross Motor Function Measure (observational measure) and Pediatric Evaluation of Disability Inventory (parent-report questionnaire). For an outcome measure to be used for change detection, the tool must contain items that have potential for change in the clinical group being measured and also have a response-option format that will permit change detection. Dichotomous (yes/no) response scales are not sufficiently sensitive to change, whereas response sets with five to seven options, although more difficult to score, enhance detection of small but potentially meaningful changes (Streiner, Norman, and Cairney, 2014). There are two other categories of measures that users need to be aware of. Discriminative measures differentiate children as

having or not having a particular characteristic or skill level (e.g., delayed or not delayed). Most of these measures have normative values for comparison. Although these can be useful at the initial assessment (e.g., Bruininks-Oseretsky Test of Motor Proficiency, Battelle Developmental Inventory), their application to outcome measurement needs to be approached with caution because they may lack item and response characteristics needed to detect change. Predictive tools are meant to classify children into categories with respect to their future status (Streiner et al., 2014). For example, the Alberta Infant Motor Scales and the General Movement Assessment are used to predict future motor ability in young infants. These measures are typically not well suited to evaluate change. As part of this selection process, the properties of candidate measures need to be considered. They need to be age appropriate and applicable to the child’s condition, appropriately scaled, and psychometrically sound and feasible. Measures must produce consistent and reproducible results (reliable), whether tested by independent evaluators (interrater reliability) or repeatedly by the same evaluator (test-retest reliability). The tester’s experience or training or the child’s level of attention or lack of engagement can contribute to measurement error. Subscales items should aggregate well together to represent particular attributes of interest (internal consistency). It is imperative that assessment tools are actually measuring what they are intending to measure (valid). Content may be verified by experts to ensure it has the attributes of interest (face validity), and results may be compared with other goldstandard measures of a similar construct (concurrent validity) or a gold standard in the future (predictive validity). Goldstandard measures often do not exist for children, and therefore the potential correlations will be less than perfect. Validity also can be estimated by determining that the measurement tool behaves as expected. It may differentiate between children with low and high performance levels (discriminant validity). Finally, if an outcome measure is to be used to evaluate change over time, it must have evidence of being sensitive to change (responsiveness). This is important to verify when clinicians want to use the tool to evaluate treatment effectiveness; it is also important for researchers who are conducting an intervention trial (Streiner et al., 2014). The clinical or research priorities for outcome measurement should also influence the selection of measures. In clinical practice, the functions of the clinician will guide the choice of the best-fitting outcome tools. In acute hospital-based care, providers focus on diagnosis and need to consider the healthrelated attributes they must identify. In a rehabilitation center, specialists provide intensive interventions and need to focus on the child- and family-related attributes they expect to change. In the home or community setting, the focus is on integration and child/family adaptation to the real-life context, and therefore assessment will focus on the activities/areas in which the clinician can make a difference.

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Assessment results should inform clinical decisions and promote greater accountability and a reflective practice approach. The outcome measures selected by providers should inform their goals for intervention plans that are unique and specific to the child and family and their needs and priorities. After treatment or following a period of evolution of the neurologic condition, reassessment is helpful in determining whether there are clinically meaningful changes and whether treatment goals should continue in the same direction or need to be realigned. For the family, the findings on their child’s assessment offer objective quantitative information regarding abilities (strengths), areas of challenge, and changes documented over time. In research endeavors, investigators need to select valid outcome measures to address their hypotheses. In pediatric neurology, these questions could relate to the underlying biologic mechanisms of disability, determinants of brain recovery or brain organization, validation of new diagnostic tools, treatment efficacy, quality and benefit of services, or knowledgetranslation efforts (Majnemer and Limperopoulos, 2002). Researchers need to be specific in formulating their questions, and may use a patient intervention comparison outcome (PICO) format for question formulation (Thebane, Thomas, and Paul, 2009). For example, if the researcher wanted to evaluate the efficacy of botulinum toxin, the PICO question might be: Will there be a significant improvement (the comparison) in range of motion, gross motor function, participation, and quality of life (the outcomes) in preschoolers with spastic diplegia (the patients) 3 months after treatment with botulinum toxin (the intervention)? The researcher may want to determine which children benefit most, and may evaluate how specific attributes of the child (e.g., age, baseline motor/ cognitive function) or environment (e.g., family support, access to interventions) affect the outcomes. These attributes would also need to be specifically measured. One other priority is that the outcome measurement process and the actual measures selected need to reflect and support a child- and family-centered philosophy of practice. This means using tools that elicit information directly from participants themselves about what they experience and do (performance) in their daily lives in addition to using observational measures that show what the child can do (capability) in the clinical setting. With respect to parent or child report questionnaires, it is important to ensure the measures will be acceptable as far as content, format, and wording. For example, a validated measure of family stress created 30 years ago, developed for a context that is very different from today’s extended-family and multicultural environment, may no longer be optimal from the standpoint of response comfort or relevance. Being family centered requires that the clinician think carefully about the relative burden of assessment to ensure that the measurement that is done is worth the time and effort expended and also fits with the information needs of the child and/or parent. It is important to explain to families the rationale for measurement and to discuss the measurement approach(es). This information sharing helps to optimize family engagement in the outcomes process at the outset of a new intervention block. Sufficient time needs to be provided to allow for discussion of results as they occur. This ongoing dialogue helps families develop realistic expectations regarding their child’s progress, outcome, and goals. The welltargeted intervention planning that results from this collaborative and systematic process is expected to result in a more efficient intervention-delivery process and potentially better outcomes. It is important to recognize that standard items within measures “typically focus on selected aspects of health and

frequently do not include items that directly reflect a client’s unique needs and goals” (McDougall and Wright, 2009, p. 1363), even though they may be valuable in providing an overall picture of the child’s abilities and be sensitive to change. Integration of standard item measurement tools and individualized measures such as the Canadian Occupational Performance Measure (COPM) and/or Goal Attainment Scaling (GAS) (Cusick et al., 2006) is a powerful way of bringing child and family outcome priorities into a comprehensive and collaborative measurement approach. For these two goal measures, the child or caregiver (for younger children) selects the specific activities that he or she feels are problematic and important to improve. The child’s present abilities are rated preintervention using the measure’s specific scoring approach, and re-evaluated using the same goal-specific rating scale is done at targeted follow-up periods.

ICF AS A FRAMEWORK FOR OUTCOME MEASUREMENT Given the breadth of areas and domains that can be measured, the number of measures available, and the growth in the number of new measures being developed, it can be daunting to determine which areas to measure and to examine how the measures interrelate in terms of a child’s health and functioning. These relationships are critical in understanding how a child and family are doing and will influence goal setting and planning of interventions. The International Classification of Functioning, Disability and Health (ICF) framework developed by the World Health Organization (2007) serves well as a template for conceptualizing the priority outcome areas to measure for a given child and family. The ICF language offers a way of moving beyond the notion of disability (formerly thought of as the absence of health) and reframing it as functioning (in terms of body functions/structure, activity and participation) and the relationship to health (Table 168-1). The ICF framework looks at the child’s abilities and the effects of the social and physical environment on a child’s functioning and health. Use of an ICF diagram (as illustrated in the following scenario describing a 3-year-old with cerebral palsy) to plan the measures used by a clinician/team for a child provides awareness of the current emphasis (and relative balance) of a measurement/goal/intervention focus and added clarity on how one might adjust the focus and balance at times of re-evaluation. As an illustration of the use of an ICF-based outcome measurement approach, consider the scenario of a child who is age 3 and has monoplegic cerebral palsy (right leg) with spasticity in her right calf muscles resulting in mildly impaired walking and running (consistent with a definition of mobility in Gross Motor Function Classification Level I [GMFC I]). The parents describe an increasing tightness in her ankle when they put her socks and shoes on, a tendency to toe walk that has become more pronounced, tripping and occasionally falling, and a reluctance to try new physical activities. It is this last observation that worries the parents most because they fear she is starting to be excluded from activities in her preschool class and neighborhood. Physical examination by her pediatric neurologist revealed that she is an ideal candidate for botulinum toxin injections. Although the area of outcome measurement pertaining to this intervention relates directly to changes (gains) in body function/structure (spasticity, range of motion) (Fig. 168-1), the parents’ observations make it clear that evaluating changes in gross motor skills (activities such as running, going down hills, ascending/descending stairs) and doing new activities/keeping up with peers (participation



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TABLE 168-1  Components of the ICF–Children and Youth Version (ICF-CY) Components of the ICF

Abnormalities

Examples

1.  FUNCTIONING AND HEALTH Body structure Anatomic parts of the body

Impairments

Body function

Physiologic functions of the body or psychological functions Activity (A)—execution of a task/action Participation (P)—involvement in life situation or role

Impairments

Periventricular leukomalacia, spinal muscular atrophy Spasticity, decreased attention span, poor short-term memory Walking (A), mobility in all environments (P); reading (A), education (P); brushing teeth (A), self-care (P)

Internal influences on functioning and health External influences on functioning and health

Can be facilitator or obstacle

Lifestyle preferences, age, gender

Can be facilitator or obstacle

Family functioning, peer support, health-care services, policies, resources,

Activities and participation

2.  CONTEXTUAL FACTORS Personal factors Environmental factors

Description

Activity limitations and participation restrictions

Health condition: Monoplegic CP

Body functions/structures: Spasticity – modified Tardieu scale44

Activities: Gross motor skills – GMFM-6645 Functional gait – 6 minute walk test46 PEDI-CAT – Mobility4

Environment: YC-PEM47 COPM ties in with GAS

Participation: YC-PEM47 GAS COPM15 tied in with GAS (same goals)

Personal factors: Dimensions of Mastery Questionnaire48,49 (child’s motivation/comfort to try new)

Figure 168-1.  An example of the application of the ICF framework to a child with cerebral palsy. (Based on the WHO International classification of functioning, disability and health. Geneva, Switzerland: World Health Organization; 2001.)

or mobility in the playground and in gym activities) is also critical as evidence that the intervention is working. Two well-validated measures that physical or occupational therapists can administer are the Gross Motor Function Measure-66 (GMFM-66) and the Pediatric Evaluation of Disability Inventory’s (PEDI-CAT’s) Mobility Domain, parentreport questionnaire that directly address gross motor skills and functional abilities in young children with cerebral palsy. Collectively these provide measurement of what the child can do (GMFM-66: ICF Activity) and how the child is able to integrate those skills into daily life (PEDI-CAT: ICF Activities and Participation). There is also a recently published parent report measure that delves more deeply into a young child’s participation in the environment, the Young Children’s Participation and Environment Measure (YC-PEM), which was adapted from the Participation and Environment Measure for Children and Youth (PEM-CY). This measure was incorporated into the assessment because

it considers the role of the environment as a facilitator or barrier to participation. Finally, GAS could be used with these measures to highlight two or three well-operationalized individualized goals focused on important everyday activities, with outcome specifications tailored directly to the parent’s hopes and expectations. A word of caution in using the ICF framework for the linking of outcome measures is that there is a lack of incorporation of the overarching concept of quality of life (QOL) in the model (McDougall et al., 2010). Although enhancement of a child’s QOL is at the core of the care clinicians provide, there will be times when changes in QOL will be seen as a direct goal of an intervention, whereas in other scenarios, higher QOL/life satisfaction may be an outcome of a series of interventions over a longer time frame. Tables 168-2–168-6 provide examples of measures that can be used to assess children with physical disabilities (Table 168-2), intellectual disabilities (Table 168-3), and global

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developmental delays (Table 168-4), and generic measures of activities and participation (Table 168-5) and health and quality of life (Table 168-6). These tables are available in the online version of this chapter.

CHILD’S AGE AND STAGE AS A DETERMINANT OF MEASUREMENT FOCUS Child development is a dynamic process marked by ongoing change. When evaluating a child, it is essential that relevant activities and life roles are evaluated based on the stage of the child’s development (i.e., chronologic age), not the level of functioning or mental age. A second important principle is that evaluation of the outcomes of children with neurologic disorders requires periodic assessment at key transition points because their development, functioning, and health are continuously changing and evolving, even if their health condition is static. Difficulties at each stage of development may be identified, with the expectation of periodic utilization of additional services to enhance outcomes (Majnemer and Mazer, 2004). Finally, evaluators should seek to identify strengths within the child at a particular developmental stage because capitalizing on these strengths can enhance motivation, takes advantage of the child’s abilities and competencies, and is more solutions-focused. This would include strengths within the family as well. In rehabilitation interventions, there is increasing interest in applying a strengths-based approach to promote positive youth development, meaningful participation, and resilience. The following websites offer additional information on these concepts: http://www.acywr.org/2011/09/the-strength-based -approaches-backgrounder/ http://humanservices.ucdavis.edu/academy/pdf/strength_ based.pdf In practice, a uniform template of specific measures is not applied to all children of all ages. Rather, the child’s stage of development will influence the scope and focus of assessment, and the neurologic disorder and its associated impairments that manifest at each stage of development will guide selection of the most important measures. For example, in a 3-year-old with Down syndrome, it would be appropriate to ask the child to build a block tower to examine fine motor control (e.g., grasp, release, eye–hand coordination, proximal control, motor planning); however, at 13 years of age this activity would not be age appropriate. Rather, observations carried out during assessment of everyday tasks such as dressing, writing, and eating would be helpful in evaluating fine motor control, and use of standardized measures such as the Purdue Pegboard Test can provide objective and age-appropriate measurement of unilateral and bilateral manual dexterity. For newborns, the primary focus is sensorimotor, such as the neonate’s response to auditory and visual stimuli; the quality and symmetry of the infant’s movements in prone, supine, and supported sitting; muscle tone; primitive reflex patterns; and behavioral state (e.g., lethargy, irritability). Many standardized neonatal neurobehavioral assessments (see review in Majnemer and Snider, 2005) are available and can be used in the neonatal intensive care unit. Feeding efficiency, an emerging life skill with important consequences for growth and development, may also be assessed. In infancy, standardized evaluation tools such as the Bayley Scales of Infant and Toddler Development (BayleyIII, 3rd edition) are meant to assess the developmental abilities of infants and toddlers (up to 42 months), focusing predominantly on gross motor and fine motor skill development and cognitive abilities but also expressive and receptive

language skills, social-emotional development, and adaptive behavior. At this stage, all domains of development begin to unfold, and delays in particular areas may gradually manifest themselves. Preschool age is marked by rapid changes in developmental abilities across all domains, and children also become independent in basic self-care activities such as eating, toileting, and dressing. Children are able to communicate their needs and participate in conversations. At this developmental stage, important preacademic skills are also achieved, such as listening to instructions and attending to task demands, basic writing and copying, interacting socially with other children, and separating from caregivers. Measurement must be holistic and cover the spectrum of developmental and functional expectations. At school age, there is increasing emphasis on functioning and health. Outcome measurement focuses on educational achievement, oral and written communication, independence in daily living skills to include domestic chores, mobility in all environments, socialization, and community engagement. By adolescence, personal identity formation, preferences and motivation, and life choices shape these areas, influencing functional potential. Environmental resources and supports, such as availability of aids and adaptations and accessibility of and participation in adaptive programs and activities, exert important influences on functioning and health. Therefore measurement at school age and adolescence is increasingly focused on activities and participation and personal and environmental factors, as framed by the ICF, and less on developmental impairments. Reflecting back on the scenario of the 3-year-old child receiving botulinum toxin injections, and thinking instead about a school-aged child (e.g., an 11-year-old) with the same diagnosis and similar body function/structures issues in her right leg, although the areas of priority for measurement are likely similar, the actual measures that are used will need to differ to ensure that the measurement focus and perspective are optimal. First, it would be of value to use activity and participation measures that allow self-report by the child herself (instead of or in addition to the parent). In this regard, although the PEDI-CAT would apply as far as content for evaluating the aspect of gross-motor-related functional abilities, at the time of writing this chapter, the child report version had not been validated, and therefore it would still be necessary to have the caregiver as the proxy reporter of the child’s abilities on the PEDI-CAT. An alternative might be use of the well-validated Activities Scale for Kids questionnaire. This outcome tool is a good content fit from the viewpoint of advanced motor skills and has a validated version that allows school-aged children to self-report on abilities. Second, although the GMFM-66 will serve well to capture the child’s stand and walk/run/jump abilities in the 3-year old child, the ceiling effect that is present with children in the category of GMFC I who are ages 7 and up is a key issue. Hence, to be able to measure this area, an outcome measure for advanced gross motor skills is necessary. At present, one of the few possibilities in this outcome-measure category is a new observational tool known as the Challenge. Third, a shift from the YC-PEM to the PEM-CY (which the YC-PEM was modeled after) would allow age-suitable measurement of the participation and environment outcome areas. Finally, it will be important to capture priority goals directly from the child using the COPM or GAS and then work with the child and parent together to allow these goals to guide the intervention offered. Irrespective of age or stage of development, a holistic view of the child’s functioning and health in the context of



Measurement of Health Outcomes in Pediatric Neurologic Disorders

the personal (e.g., lifestyle, intrinsic motivation, sociodemographic factors) and environmental (e.g., family functioning and well-being, peer support, resources in the community, societal attitudes) factors that can positively or negatively influence functioning is needed. This enables the clinician to capture a complete picture of the child’s abilities and disabilities, which will then inform the next steps in intervention and health promotion.

NEW DIRECTIONS IN OUTCOME MEASUREMENT One of the important considerations in using outcome measures that relates to the psychometric properties of the measures is the actual clinical meaning or interpretation of the changes that are observed. Change-score magnitude needs to be considered in light of the measure’s reliability and the estimated measurement error. As the awareness of the importance of this concept has grown, recent outcomemeasure validation studies have tended to place greater emphasis on reporting the minimum detectable change (MDC) or minimum detectable difference (MDD) estimates. For example, the MDC95 estimate for the GMFM-66 is 2.5 points, meaning that the user can have 95% confidence that a change of more than this will reflect true change and not measurement error. These estimates are still emerging for many of the commonly used pediatric outcome measures. A related concept pertains to the minimum clinically important difference (MCID) (Streiner et al., 2014). Although it is often confused with MDC (Stratford and Riddle, 2013), this concept relates to what children, parents, and clinicians deem to be a meaningful change. Thus although it is fully reliant on the strength of the measure as far as reliability and related MDC, it goes a step beyond and takes child/parent priorities into account. There have been attempts to establish the MCID within different diagnostic groups for measures such as the PEDI and GMFM, and when these values are available, they at least give users some benchmarks to consider. However, at this point, caution is advised when using these values to signify intervention success because these estimates are at best only an average value across a group of parents/ children and have been based upon statistical or consensus methods that are still in early conceptual stages (Copay et al., 2007). An important new direction in outcome measurement is the concept of patient-reported outcomes (PROs). PROs include any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by the clinician or anyone else. These are self-report measures that are completed by the youth or by a proxy, typically a parent. PROs allow patients (or their proxies, if they cannot report for themselves) to describe and assess a number of attributes, such as symptoms, functional status, participation in life roles, health perceptions and quality of life, environmental facilitators and barriers, and satisfaction with services. Numerous global initiatives promote the use of PROs as an emerging priority for clinical and research measurement. At the National Institutes of Health (NIH) in the United States, person-centered medicine and outcome research (PCOR) emphasizes the conduct of research that compares the benefits and harms of interventions to prevent, diagnose, and treat health conditions, and researchers are expected to apply PROs in the real-life context. NIH has funded research programs such as PROMIS, which is focused on PROs in health care and rehabilitation. In Canada, the strategy for patient-oriented

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research (SPOR) has been launched by the Canadian Institutes of Health Research; PROs are integral to SPOR programs. The United Kingdom has policies in place to promote the use of PROs and a focus on patient experience frameworks. In reality, PROs are not often used in clinical practice but can be instrumental to allow patient voices to be heard and to identify outcome status or factors influencing outcomes, and they can be influential in setting goals and making treatment decisions based on patient priorities and values. Finally, a challenge for selection of outcome measures is that this is a growing area in which new measures will continue to be developed to address identified measurement gaps or issues related to existing measures. The concept of a toolbox of measures (Koene et al., 2013) that can apply to a clinical group or intervention has been advocated across rehabilitation settings, providing a cohesive approach and common language to outcome measurement across the international community. The reader is referred to an earlier paper for an example of how this concept pertains to cerebral palsy (Wright and Majnemer, 2014). Within any outcomes toolbox, there will also need to be space for a few new emerging measures (e.g., the Focus on the Outcomes of Communication under Six and the YC-PEM) that may fill important measurement gaps and have foundational evidence of psychometric strength; current work on responsiveness and MCID may also be worth considering for the toolbox, either as a replacement for or addition to the measures for given clinical situations (e.g., the use of the Challenge mentioned earlier to replace the GMFM-66 for children with cerebral palsy at GMFC I). In summary, outcome measurement is essential to characterizing a child’s functioning and health. The ICF provides a universal framework to ensure that outcomes are viewed holistically, across the spectrum of the child’s functioning and in the context of personal and environmental factors that can influence outcomes. Outcome measurement provides essential individualized information to children and families regarding the child’s current status and how it evolves over time; it also provides clinicians objective feedback about the changes that can be documented in response to interventions. Managers also benefit from outcome measurement as part of quality improvement, and researchers use standardized measures to answer their research questions. Selecting the most appropriate measures can be a daunting task and is best achieved in collaboration with patients and families and team members across health disciplines. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Copay, A.G., Subach, B.R., Glassman, S.D., et al., 2007. Understanding the minimum clinically important difference: a review of concepts and methods. Spine J. 7, 541–546. Cusick, A., McIntyre, S., Novak, I., et al., 2006. A comparison of goal attainment scaling and the Canadian Occupational Performance Measure for paediatric rehabilitation research. Pediatr. Rehabil. 9 (2), 149–157. Koene, S., Jansen, M., Verhaak, C.M., et al., 2013. Towards the harmonization of outcome measures in children with mitochondrial disorders. Dev. Med. Child Neurol. 55, 698–706. Majnemer, A., Limperopoulos, C., 2002. Importance of outcome determination in pediatric rehabilitation. Dev. Med. Child Neurol. 44, 773–777.

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Majnemer, A., Mazer, B., 2004. New directions in the outcome evaluation of children with cerebral palsy. Semin. Pediatr. Neurol. 11 (1), 11–17. Majnemer, A., Snider, L., 2005. A comparison of developmental assessments of the newborn and young infant. Ment. Retard. Dev. Disabil. Res. Rev. 11, 68–73. McDougall, J., Wright, V., 2009. The ICF-CY and goal attainment scaling: benefits of their combined use for pediatric rehabilitation practice. Disabil. Rehabil. 31, 1362–1372. McDougall, J., Wright, V., Rosenbaum, P., 2010. The ICF Model of Functioning and Disability: Incorporating Quality of Life and Human Development. Dev. Neurorehabil. 13 (3), 204– 211. Streiner, D.L., Norman, G.R., Cairney, J., 2014. Health measurement scales: a practical guide to their development and use. fifth ed. Oxford University Press, London. Thebane, L., Thomas, T., Paul, J., 2009. Posing the research questions: not so simple. Can. J. Anaesth. 56, 71–79. World Health Organization, 2007. International classification of functioning, disability and health-child and youth version. World Health Organization, Geneva, Switzerland. Wright, F.V., Majnemer, A., 2014. The concept of a toolbox of outcome measures for children with cerebral palsy: why, what, and how to use? J. Child Neurol. 29, 1055–1065.

E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Table 168-2 Measures Commonly Used for Children with Physical Disabilities Table 168-3 Measures Commonly Used for Children and Youth with Intellectual Disabilities Table 168-4 Measures Commonly Used for Young Children with Global Developmental Delays Table 168-5 Generic Measures of Activities and Participation That May Be Relevant for Children with Neurologic Disorders Table 168-6 Generic Measures of Health and Quality of Life That May Be Relevant for Children with Neurologic Disorders

169  The Influence of Computer Resources on Child Neurology Michael M. Segal and Steven M. Leber

An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. As computer technology becomes more integrated into our lives, much of the information that we use now, including summarization of knowledge in textbooks, will be accessed primarily electronically. This chapter examines how such changes are unfolding in the ways we communicate and discuss information, in the ways we marshal information to diagnose and treat patients, and in the ways we educate newcomers to the field and keep experienced clinicians up to date. Table 169-1 in the online version of the chapter lists websites of interest to child neurologists.

CLINICAL DISCUSSIONS AND GROUPS Throughout medical history, doctors have talked to one another, patients have talked to one another, and doctors and patients have talked to each other. With the advances in information technology, such communications have become faster, cheaper, and, in some situations, more anonymous. For over a century, doctors have used conferences, journals, and textbooks to exchange information. Recent innovations in technology have moved such discussions to the Internet and made them more instantaneous. These have used listservs (discussions sent by e-mail to groups of subscribers) and web-based forums that are organized by topic, in which people post questions, answers, and news. Speeding up communication is no small thing. It can take one or two decades for therapeutic advances to become part of routine clinical practice (http://archive.ahrq.gov/ research/findings/factsheets/translating/tripfac/trip2fac .html). The ability to learn of such advances and hear con­ sidered responses from leaders in the field within days, results not only in an increased speed of learning of new advances but also in attention directed to potential problems in published interpretations of research. Web forums and listservs are also popular, in part, because they have created an environment that encourages spontaneity and sharing of hypotheses. The specifics of the technology of listservs versus forums seem not to matter much. What matters most is the community. The Child-Neuro listserv (http://www-personal.umich .edu/~leber/c-n/e-mailUM.html) was established in 1993, using what is now antiquated technology—using text-format messages distributed individually or in daily digests. Nevertheless, the Child-Neuro listserv continues to be the core Internet discussion group in the field, whereas more technologically sophisticated web-based discussion services, such as Sermo (http://www.sermo.com/), have less influence because they do not have the same presence of experts. It is too early to be able to assess the utility of the Child Neurology Society’s new “Open Forum” web-based service. The technology for discussions among patients is often newer, since the communities are newer, the numbers are greater, and the needs for privacy are lower. In the past, patients had much less contact with one another due to difficulty finding each other and the reluctance to disclose illness to people they knew personally. As a result of the anonymity of the Internet and the ability to find others with similar problems through search engines, patient-to–patient discussions have proliferated. Since these discussions are new, they have tended

to use newer Web-based forum technologies. Communities such as PatientsLikeMe (http://www.patientslikeme.com/) and Brain Talk (http://braintalkcommunities.org/) have become meta-sites for people with neurologic diseases. Some forums offer advanced community capabilities. For example, PatientsLikeMe allows users to search for others with similar symptoms, an ability that can be used for identifying hypotheses to test in controlled studies. In addition to these meta-sites, there are communities for individual disorders, such as attention deficit disorder (http://www.addforums .com/forums/index.php) and periodic paralysis (http://www .periodicparalysis.org/). Another innovation enabled by the Internet is medical blogging. Blogs, the shorthand term for “weblogs,” are websites on which articles, commentary, and other forms of textual, graphic, or multimedia content are posted. Blogs are often run by a single individual, providing a personal perspective and a top-down structure. As the costs associated with blogging have fallen essentially to the cost of the time involved, blogs have proliferated. In medicine, blogs have tended to cover medical practice and common diseases; blogs covering rare diseases would have very small audiences, and online communities make more sense as forums for such communication. However, there is quite a continuum. Blogs are sometimes a group effort and typically include some discussion in each thread, and discussion groups often have several regulars who sustain the discussion. So, in actuality, there are hybrids between pure blogs and pure discussions that have evolved to meet the needs of individual communities. One of the important innovations in online discussions is the breaking down of the separateness of doctor-to-doctor and patient-to-patient discussions to create doctor-to-patient discussions. Doctor-to-patient discussions are of course the core of medical practice, but sharing such discussions among wider communities has value. An advantage of the Internet is the ability to have doctor-to-patient discussions with anonymity that one cannot achieve by group visits to doctors. The main barriers to doctor-to-patient discussions on the Internet are the absence of physical examination and medical records from other doctors, making the doctor less confident about giving advice, as well as the lack of incentives for physicians to provide such assistance with commitment and consistency. However, this may be merely an issue of creating the proper incentives and structures. One of the authors of this chapter has spent a significant amount of time in recent years interacting with patients on a variety of sites as part of an effort to uncover the molecular mechanism of attention deficit disorder (Segal, 2014). The patients would make little progress by themselves because they lack the deep expertise of the doctors in understanding the biology of disease. The doctors would stagnate without the patients’ descriptions of their clinical symptoms. The combination is much more effective. In the past, progress could be made by studying the patients in a large clinical practice and hearing their observations personally, but such a process is difficult to arrange for less common diseases. Now, the ability to have such interactions is much accelerated. A doctor can post a query and get responses from many patients within days and, furthermore, can get a sense

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of how many of the regular participants respond in a particular way. Such interactions allow patients to partner with doctors, not only in decisions on treatment, but also in advances in understanding pathophysiology. A patient-centered movement that calls itself “Health 2.0” has touted patient-to-patient discussions as a replacement for many types of doctor-to-patient interactions and replacing top-down “information therapy.” Health 2.0 is the exchange of information in Internet forums “that get richer as more people use them” by “harnessing collective intelligence” (http://patients.aan.com/news/?event = read&article_id = 5277), whereas information therapy involves more traditional instructional materials provided by doctors. However, drawing a distinction between Health 2.0 and information therapy may be more theoretical than real. For example, the patients in the listserv of a prototypical Health 2.0 group, the Periodic Paralysis Association, asked the doctors associated with the listserv to write an “owner’s manual” for hypokalemic periodic paralysis (http://simulconsult.com/resources/ hypopp.html), a prototypical information therapy type of resource. The patients used the listserv to collect questions for which they wanted answers, both for their own education and to educate physicians caring for them. Yet the patients made very clear that they wanted the responses—that is, the content—to be written by people whom they and their physicians trust as experts. Far from guarding their realm as a patient-to-patient self-empowerment organization, the patients encouraged two doctors to participate in the listserv, one motivated by a research interest in the area and the other motivated by having one of the diseases himself. This ability to add doctor-to-patient interactions and mix Health 2.0 and information therapy shows how some of the rigid conceptions of the types of medical information on the Internet are evolving into more flexible approaches that are better at meeting the needs of patients. There is an important need to institutionalize resources valued by patients such as “owner’s manuals” into a meta-site covering many diseases and thus known widely and trusted in the field. The discussion groups described previously involve groups of patients, groups of doctors, and sometimes a few doctors and many patients. Yet in medical practice, a different type of exchange predominates: discussions about one patient in a clinical chart. With only a bit of exaggeration, one could characterize an electronic health record (EHR) as a privacyprotected blog about one patient. Despite the simplicity of blogs, they have the ability to incorporate a wide variety of types of external content. Currently, however, EHRs have a lot of standardized, nonpertinent material that distracts the reader from the main points. However, one should expect improvements in the EHRs of the future; as discussed later in “Diagnostic Decision Support,” it is possible to use computerized tools to reintroduce pertinence to EHRs and do so in ways that leverage large amounts of information. There is much discussion about automating some types of doctor-to-patient interactions using e-mail and telemedicine. This is most extensively implemented so far in radiology, in which the subtleties of patient interaction are largely absent and reimbursement issues are most clearly defined. It is widely expected that such techniques will expand. Using telemedicine in radiology and psychiatry, however, is more practical than in in some areas of neurology in which physical examination plays a much large role. In other areas, however, such as epilepsy and movement disorders, the history and observation of the patient is more important than hands-on examination, and telemedicine may be boon for patient-centered health care (Joshi, 2014). Over the years, it is expected that telemedicine will increase, driven by provisions for reimbursement, technology and services for physical examination and patient monitoring, and secure options for such online interactions.

On a more basic level, many patients already are using e-mail to communicate with their physicians. Electronic communication between patients and healthcare providers is advantageous, in that the communications can be thought out carefully in advance, posted and read at convenient times, and saved for future reference and for the medical record. Supplemental information (e.g., medication instructions and handouts going from doctors to patients, or videos of patients’ events going from patients to doctors) can be attached or linked. “Asynchronous communication” also avoids “phone tag,” long telephone queues and holds, and long distance phone charges, a difficulty for many patients. However, the use of e-mail to convey sensitive information raises numerous security and privacy concerns, particularly given the legal right of employers to access their employees’ e-mail. A potential solution to many of the problems posed by e-mail lies in the development of comprehensive, password-protected patient portals for doctor-to-patient interaction. Most commercial EHRs have built-in portals with secure messaging; having at least 5% of a provider’s patients use the portal is now a requirement of the Centers for Medicare and Medicaid Services (CMS) Meaningful Use Stage 2 requirements (http:// www.cms.gov/Regulations-and-Guidance/Legislation/ EHRIncentivePrograms/downloads/Stage2_EPCore_17_ UseSecureElectronicMessaging.pdf).

WIKIS Wikis are a type of web content with no real analog in the precomputer age. A wiki is a document that can be edited independently by many people using a simple set of web page formatting tags. The prototypical and dominant wiki is the collection called Wikipedia. The advantage of Wikipedia is that the wide participation has resulted in millions of pages of content, with many popular articles having material contributed by many different authors, none of whom is paid. The disadvantage of Wikipedia is that battles can erupt over controversial issues and editing of pages can be banned by editors with a particular perspective despite the existing information being false or misleading. In medicine, a key concern about Wikipedia is that articles are often written by people who are not medical professionals, sometimes resulting in content that is dubious or very incomplete. Although Wikipedia has articles on thousands of diseases, many physicians will prefer wikis with authorship restricted to doctors, but there is not much content of this sort for child neurology. As with traditional narrative content, a promising future direction for wikis is finding some way of getting doctors and patients “on the same page.” One such example is having a doctor who has a particular disease write material that combines both the doctor’s and patient’s perspectives, resulting in a full understanding that comes from living with the disease from both perspectives. As with Internet forums, the chief difficulty in achieving the desired doctor-to-patient collaboration is creating financial and professional models for inducing the doctor to write patient-directed material. Due to the value of such material, it seems likely that this will be achieved, but it remains to be seen what incentives will get doctors involved in such patient-directed materials. Such helpful but hard-to-monetize resources are an example of the benefit of large, integrated health organizations (Christensen et al., 2008).

DIAGNOSTIC DECISION SUPPORT The basic difficulty with diagnosis is that medical information is typically organized by disease, yet the process of diagnosis begins with a collection of findings and considers which diseases best fit with these findings. Some of the resources for



diagnostic decision support, such as flow charts and diagnosis confirmation protocols, existed long before computers. These approaches are very useful in situations in which a particularly salient finding is present or a particular diagnosis is being considered. However, for the more general case, we now have access to novel approaches to decision support that did not exist in the precomputer age and can improve both diagnostic accuracy and cost-effectiveness of workups. These new approaches include automated search and diagnostic software. Although in the past people argued about whether such resources were useful, with the proliferation of newly recognized genetic disorders and the advent of inexpensive genome sequencing, little doubt remains that such computerized approaches are needed. The advantage of automated search is the ability to process huge amounts of information collected in an inexpensive, automated process of searching accessible web pages (e.g., Google; http://www.google.com/) or adding some natural language processing (e.g., Isabel; http://www.isabelhealthcare .com/). The disadvantage of search is that many of the subtleties of the information are lost or jumbled, including information about timing and onset, absent findings, frequency of findings, and treatability. Such subtleties can be used in a diagnostic software approach, but a “curation” process of collecting information manually in a standardized format is needed to characterize diseases, and tradeoffs must be made as to level of granularity to characterize findings (e.g., SimulConsult: http://www.simulconsult.com/; and Phenomizer: http://compbio.charite.de/phenomizer/). Furthermore, there are many subtleties to how we think of patient findings such as how we group them (e.g., including orthostatic changes in blood pressure as part of the disease or considering it incidental) and with what level of granularity the clinician should describe findings (should weakness be described as proximal vs. distal, rapid vs. slow onset, and so forth). Another advantage of diagnostic software is the ability to offer advice prospectively on which findings or laboratory tests would be most useful and cost-effective to distinguish among likely diagnoses. This is important in getting doctors and insurers to focus on evidence relevant to decisions about whether a test should be covered by insurance. Software also offers the ability to link such recommendations about useful tests to resources such as the Genetic Testing Registry (http:// www.ncbi.nlm.nih.gov/gtr/) and the NextGxDx gene test shopping service (https://www.nextgxdx.com/). The ability to suggest useful findings is also important in promoting communication among medical specialties. For example, a radiologist can begin from a diagnostic software session begun by a neurologist, using a display of useful radiologic findings to ensure that the findings most useful to the neurologist are commented on explicitly. One area in which doctors need help is in interpreting genetic tests. Increasingly, we face situations in which a mutation is found in a gene or an abnormality is found on a chromosomal test, but it is not clear whether the result is pathogenic or incidental. Such information is a key proprietary resource of companies that have interpreted many genetic tests, but such information is being increasingly centralized in the ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/), which allows genome interpretation software to tap into such listings via automated queries. A basic philosophic issue is developing about interpretation of whole exome and whole genome testing. Is this similar to a single gene test, in which the laboratory returns an answer, or is it more similar to an MRI, in which the neurologist provides detailed information to the radiologist, and the ultimate diagnosis is made by the neurologist, not the radiologist? Clinical diagnostic decision support software that can also do genome analysis in a clinical context can be a crucial way of

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empowering the neurologist to interpret genome results with appropriate clinical correlation (Segal, 2015). Clinicians who know the patient can often check findings (such as crying without tears or a molar tooth sign on MRI) that were not recognized as useful to check until results became available from genomic analysis of the patient.

TREATMENT DECISION SUPPORT Treatment is a more straightforward software task than diagnosis because one already knows the diagnosis. If the disease is unfamiliar, software simplifies access to narrative text, calculators, and flow charts to help with treatment. Even when the disease is familiar, integration of computer programs into the workflow can enhance fine-tuned management and increase safety and improve outcomes. Examples of freestanding or integrated applications include calculators (such as automated anticoagulation calculators), drug information and interactions, flowcharts, look-up tables, nomograms, and automated guidelines and protocols (e.g., an online ordering system that might recommend deep vein thrombosis prophylaxis in an adult in bed for longer than 2 days, or a patient-controlled anesthesia pump that puts an upper limit on the amount of morphine infused). The difficulties in deciding about treatment typically arise from lack of data and from conflicts between data sources. Perhaps the most useful recent advance in treatment decision making has been the ability of groups of healthcare professionals to address specific treatment questions, review the medical literature, and make these systematic reviews widely and easily available via the Internet (http://en.wikipedia.org/wiki/ Systematic_review). The best known collection is the Cochrane Database of Systematic Reviews section of the Cochrane Library (http://www.cochranelibrary.com/). Yet even when clear recommendations have been formulated, they often are not used (McGlynn et al., 2003). Why is this the case? First, even when guidelines exist, it takes extra effort for the practitioner to look for them and remember to use them. However, “guideline execution engines” are being developed to address this issue; these are programs integrated into EHRs that translate clinical guidelines into recommendations (http://en.wikipedia.org/wiki/Guideline_execution_engine). Examples might include alerts about drug interactions and dosage errors, disease management pathways (e.g., reminders to obtain surveillance laboratory tests in patients on certain medications or renal ultrasounds in patients with tuberous sclerosis) and automatic retrieval of relevant systematic reviews. A meta-analysis of clinical decision support systems for treatment or screening revealed that 68% of these support systems improved clinical practice and that the only ones that did so were those in which decision support was automatically supplied to the clinicians as part of their normal workflow; none of the support systems in which clinicians were required to seek out the help of the support system improved clinical practice (Kawamoto et al., 2005). Other features associated with improvement in clinical practice for treatment and screening were: 1. Computerized systems compared with manual systems 2. Systems integrated into the charting or order system, rather than acting as standalone applications 3. Systems that prompted clinicians for reasons when they chose to override automated recommendations, rather than allowing bypass of recommendations without recording a reason 4. Systems that provided recommendations rather than those that simply assessed risk (e.g., “Patient is at high risk of coronary artery disease; recommend initiation of betablocker therapy” rather than simply “Patient is at high risk of coronary artery disease”)

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5. Systems that provided decision support at the location and time of decision making compared with those providing support away from the point of care Some 94% of clinical support systems that incorporated these key features were associated with improvement in clinical practice. Paper-based clinical guidelines do not have the influence of guidelines that are integrated into a clinical management system. The second reason why these clinical protocols are not used is that there are so few of them, and even the ones we have are based on limited information and often do not give definitive guidance. For example, the American Academy of Neurology and Child Neurology Society have a total of only 12 treatment guidelines for child neurology on their websites (https://www.aan.com/Guidelines/home/ ByTopic?topicId=14 and http://www.childneurologysociety .org/resources/practice-parameters; accessed 11 April 2016). Moreover, guidelines frequently do not exist for or apply to the individual patient in front of us and the specific clinical question being asked (Gronseth and French, 2008). The patient in front of us is not the “average patient” addressed in the study and may have secondary diagnoses that affect treatment. Establishing recommendations can be very difficult (e.g., Smeets et al., 1999; regarding initiation of anti-epileptic medications), particularly for rare diseases. We are hopeful that, as medical records are digitized, medical information will become more easily abstracted, coded, and shared, aiding generation of better information about diseases, treatments, and outcomes. However, the complexities of coding information at appropriate levels of granularity are far from trivial, particularly because medical knowledge is in a constant state of flux.

EDUCATION Education is an area likely to be transformed in major ways by computer technology. Many of the information resources discussed previously, from narrative resources to wikis to decision support, are already being used in education. The ability of the web to disseminate video is of huge importance to teaching areas of neurology that are very visual, such as movement disorders and epilepsy; even the ability to provide still images at low cost is very helpful for neurocutaneous diseases and neuroimaging. The ability of diagnostic decision support software to highlight useful findings and link to resources about them is crucial to enabling such just-in-time education. Several online educational resources relevant to child neurology are listed in the table accompanying the online version of this chapter. The web has also facilitated case-based education by allowing many training programs to share interesting clinical cases. The Child Neurology Society and the Professors of Child Neurology have been running such a program since 2008 (http:// www.childneurologysociety.org/resources/continuingeducation/cns-case-studies), making use of the web to include images and to hyperlink the cases directly to articles in the literature and to diagnostic software. Decision support software is also useful in teaching in a very concrete context how we approach differential diagnosis. Typically, medical students are taught to make diagnoses by collecting all relevant information, thinking about it, and constructing a differential diagnosis. In reality, the process is far more iterative (Bowen, 2006). One collects a bit of information, forms hypotheses, and then collects more information based on the hypotheses and continues in this manner, refining the differential diagnosis iteratively. Using diagnostic software, one can show this process in a very concrete way and illustrate other factors that are important in diagnostic thinking such as frequency of findings, treatability, and time information. Diagnosis turns out to be far more complex than the

way it is presented in medical schools, and the ability to demonstrate this in a very concrete fashion with diagnostic software makes it easier to convey these complexities to students.

PERSPECTIVES One of the big questions about computerization in medicine is whether the new medium will change the type of medical information used. For new tools, such as diagnostic software, the use of the tool at all is a real change. But the wider question is how traditional narrative material will be changed by the Internet. Will we move away from authoritative sources and toward a social networking approach in which information is amplified by the community of users? The examples discussed in this chapter suggest that both doctors and patients want some mix of certification and social networking approaches and that the successful resources will be those that merge these to combine the solidity of expertise with the nimbleness of a vigorous community. It seems clear that most of our information will be on the Internet, and new approaches to information will become common. We expect a rapid move toward interoperability among information resources, jumping not only from software to narrative resources but also from narrative resources to software to obtain advice tailored to an individual patient.

CONFLICT OF INTEREST Dr. Segal is the founder of SimulConsult. He acknowledges that his interest in promoting use of the software poses a potential conflict of interest. Dr. Leber has no conflicts of interest. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Bowen, J.L., 2006. Educational strategies to promote clinical diagnostic reasoning. N. Engl. J. Med. 355, 2217–2225. Christensen, C.M., Grossman, J.H., Hwang, J., 2008. The Innovator’s Prescription: A Disruptive Solution for Health Care. McGraw-Hill, New York. Gronseth, G., French, J., 2008. Practice parameters and technology assessments: what they are, what they are not, and why you should care. Neurology 71 (20), 1639–1643. Joshi, C., 2014. Telemedicine in pediatric neurology. Pediatr. Neurol. 51, 189–191. Kawamoto, K., Houlihan, C.A., Balas, E.A., et al., 2005. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ 330 (7494), 765. McGlynn, E.A., Asch, S.M., Adams, J., et al., 2003. The quality of healthcare delivered to adults in the United States. N. Engl. J. Med. 348, 2635–2645. Segal, M.M., 2014. We cannot say whether attention deficit hyperactivity disorder exists, but we can find its molecular mechanisms. Pediatr. Neurol. 51, 15–16. Segal M.M., 2015. Genome interpretation: Clinical correlation is recommended. Appl. Transl. Genom. 6, 26–27. Smeets, R., Talmon, J., Meinardi, H., et al., 1999. Validating a decision support system for anti-epileptic drug treatment. Part I: initiating anti-epileptic drug treatment. Int. J. Med. Inform. 55 (3), 189–198.

E-BOOK TABLE The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Table 169-1 Selected Websites of Interest to Pediatric Neurologists

and Training of Child Neurologists and 170  Education Workforce Issues David K. Urion An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details.

INTRODUCTION This chapter considers two interrelated issues: how should child neurologists ideally be educated and trained in terms of their early development and introduction to the field, and how do these issues of education and training have an influence upon the workforce for the first half of the current century? Consideration of the issues of education and training, as well as the workforce in child neurology, directly affects the very nature and identity of child neurology. How we educate and train those who will follow us, to whom we are accountable for the content and outcome of that education, and how we deploy the workforce we thus prepare define our very essence as child neurologists. The term most frequently used these days is “training,” but we must consider this in a broader sense. We are not limiting the notion of “training” to the acquisition of a set of skills and knowledge, a craft. Skills and knowledge are necessary but not sufficient. The training of child neurologists must also include the development of habits of mind, ethical and moral considerations, and the cultivation of certain virtues. Russell Gruen and his colleagues have argued quite persuasively that the evolution of the profession of medicine has been one of the constant extensions of domains of professional obligation into what had previously been domains of professional aspiration. Individual patient care was the sole domain of professional obligation for a long period of time. As time passed, he argues that access to care becomes a domain of professional obligation—whether or not all children have access to child neurology care becomes our professional obligation. Direct socioeconomic influences then became our professional obligation—do our patients have access to insurance coverage, and does their family’s socioeconomic status have an influence upon their health? Gruen then argues that broader socioeconomic influences and global health issues are still in the domain of professional aspiration, not currently normative for us, but that this will likely change as time goes on. This concept of “training” is more akin to the notion of “formation” that was prevalent in the 19th century among the so-called liberal professions—medicine, law, the clergy, and the military. In those days, “formation” meant taking individuals and engaging them in a process in which they obtained not only the knowledge and skills necessary for a profession, but also a world view, a set of attitudes and beliefs, a common set of reference values and virtues, which were all recognized as essential to the profession. Another central feature to this calculus was the independence of the profession: it determined its own standards for becoming a member of the profession, as well as that which was needed to remain a member of the profession. The profession argued that it was the guarantor of skills and proficiency, ethical behavior and practice, and the public could, and should, be reassured by that. Although the use of the term “formation” has fallen out of currency, the broadness of the concept it embraces is one we should still

continue—it allows us to consider historical approaches before formal programs in child neurology evolved and to contemplate a generation of our forebears that became child neurologists through pathways other than our current mode of education and training, the residency program. It also allows us to think more broadly about the nature of child neurologists and what skills, attributes, and virtues they need to be successful, competent, and compassionate practitioners of the art and science of child neurology for the 21st century. This chapter will use the framework of the development of child neurology training from the vantage point of how training evolved in the United States. It is but one example of the development of the field as a paradigm for consideration. Child neurology training has evolved differently across the globe based on how regional socioeconomic, cultural, and religious factors have influenced the development of different medical specialties.

HISTORICAL ASPECTS Unlike most other pediatric subspecialties, child neurology in the United States emerged from the evolution of certain adult neurology practitioners, who became particularly interested in the problems and disorders that were particular to children in the context of their discipline. This contrasts with most other pediatric subspecialties, whose history is one of pediatricians becoming increasingly interested in a specific set of disorders and a subspecialty organizing itself in that emergent fashion. This maintains itself today by the organization of the certifying bodies of pediatric subspecialties. Most derive their authority from the American Board of Pediatrics. Child neurologists are certified instead by the American Board of Psychiatry and Neurology. Even the preferred name for our discipline subtly demonstrates this. One is a pediatric cardiologist and is board certified as such. Our discipline is populated by people who usually refer to themselves as child neurologists and whose certification is in neurology with special competence in child neurology. The distinction is not merely semantic but is foundational in terms of identity. It is beyond the scope of this chapter to consider in detail the founders of child neurology; the reader is referred to the excellent text by that name for a biographic compendium (Ashwal, 1990). We can, however, note several pathways that emerged in the evolution of the discipline. The vast majority of the early practitioners of what became our discipline began as adult neurologists who developed abiding interests in the neurologic disorders of children. They, in turn, began to gather like-minded younger physicians around them and what we can consider the first era of child neurology formation ensued. Informal and centered around one or two charismatic teachers, these schools of child neurology emerged at some of the larger university teaching hospitals of the early 20th century. The disciples of these schools then moved out across the country, taking their traditions, interests, and approaches with

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them. The late Dr. David Clark likened this era of child neurology to tracing bloodlines in racehorses. One could trace many of these early leaders back to their original progenitor. Thus one could say that Charles Barlow, for example, personified the education he received from Douglas Buchanan, and the Boston Children’s Hospital child neurology program could have been considered in the mid-20th century as a branch of the University of Chicago tree. The American schools of child neurology emanated from individuals such as Philip Dodge in Boston and then St. Louis and Sidney Carter in New York. The argument could be made that during this period, individuals chose places in which to be formed in child neurology based upon the leadership and the school of child neurology that was represented there. Although this was undoubtedly fruitful for the development of career interests, it did not assure the public that formation in child neurology would be broad, inclusive, and comprehensive in all places in which it was being undertaken. As child neurology emerged as a distinctive discipline within neurology, it was argued that it represented a competence sufficiently separable to be distinguished from adult neurology. Thus whereas adult neurologists were being certified by the American Board of Psychiatry and Neurology (ABPN) by 1935, it was not until the late 1950s that a set of examinations were promulgated by the ABPN to determine the competence an applicant had in that field. In response to this, we can see that places in which child neurologists were being prepared began to respond to these early standards. The ABPN has argued since its inception that one of its chief fiduciary responsibilities is to the public; the standards for board certification create a body of persons in whom the public can trust in terms of competence, ethics, and professional behavior. The emergence of a separable competence in child neurology extended that approach. The ABPN was thus a public guarantor of the general competence of an individual to practice child neurology. Supported by efforts from the United States government, child neurology programs took on a sort of mixed selforganization—some in response to the mandates of the certification examination of the ABPN, some in response to the mandates inherent in various parts of federal funding, particularly training grants which incentivized research into large domains such as intellectual disability. The meeting of those standards, however, was left to the individual programs with great leeway. The disadvantages of this relatively unstructured approach became obvious, not just in child neurology but across almost all domains of medicine. Thus the last quarter of the 20th century saw increasing requirements of programs on the part of bodies such as the ABPN and the Accreditation Council for Graduate Medical Education (ACGME). Most of these requirements, however, were time-based; that is, the chief metric was so many months of a given type of rotation. One needed to do 1 year of adult neurology, for example, and rotations in psychiatry, to be eligible for the ABPN examination. Theorists of professional education refer to this as an industrial model of education. So much time on the assembly line assures the product.

CURRENT APPROACHES Among child neurology educators, this led to a general dissatisfaction with the variability in training that could still occur with this time-based, examination-referenced approach. In addition, there was a feeling that the public needed to be assured that there was sufficient consistency across child neurology programs that they could be confident that any child neurologist their child saw was well prepared and

broadly informed. Robert Rust edited an issue of Seminars in Neurology (Rust, 2011), which attempted to describe the corpus of knowledge that a child neurologist should have in a broad spectrum of domains of clinical practice. Each section was authored by a recognized expert in that domain. One could thus argue that the community of scholars was making a statement about what was essential to the practice of child neurology at the beginning of the new century. The Professors of Child Neurology subsequently formed a working group that undertook to convert this set of essays and outlines into a framework of the knowledge that was viewed as essential to the practice of child neurology, a so-called “Universal Curriculum.” The name cited the normative nature of the material—that is, an organization representing the academic training programs and departments, divisions and sections of child neurology across the country had endorsed this as the corpus of knowledge and skills required to practice child neurology in the new century. A similar process is also happening in Canada. The Royal College of Physicians and Surgeons has embraced this concept under the rubric “competency by design.” Competency is to be demonstrated in each of the CanMEDS roles: medical expert, communicator, collaborator, manager/leader, scholar, advocate, and professional. From a pedagogic viewpoint, this effort shifts the emphasis from time-based, rotation-based metrics of training to the achievement of mastery in a given domain, independent of the time spent on a rotation devoted to that area of expertise. This happened in parallel to the movement by the ACGME to create “Milestones,” a developmentally oriented approach to specific domains of performance for persons in training, which would chart their progress from absolute beginner to mastery of a given domain. Each recognized specialty represented in the ACGME was asked to convene a group that would work with the staff to draft a set of milestones relevant to that specialty. The child neurology milestones which were developed (Child Neurology Milestones, 2015) were very pragmatic and focused by and large on observable, verifiable behaviors. Other specialties, such as pediatrics, created Milestones frameworks that were oriented toward pedagogic theory such as Bloom’s taxonomy of adult learning (Pediatrics Milestones, 2015). The authors of the Universal Curriculum subsequently demonstrated how it could project onto the child neurology milestones. This allows the more granular Universal Curriculum to be used for the mandated reporting of resident progress through the milestones, which all programs must report to the ACGME on an annual basis (Urion et al., submitted). Child neurology therefore has two interrelated metrics to assess the progress of individuals through the course of their formation toward the established goal of being capable of the independent practice of child neurology. For those programs that find using the milestones themselves convenient, this can be done directly. For those who find that they think along the lines of the Universal Curriculum, this can be used and then translated into milestones. Table 170-1 demonstrates some examples of the child neurology milestones; it should be noted that the levels do not correspond to years in training, but rather steps along a road toward basic competence to practice independently (level 4 in any given milestone) or the further step of contributing to the scholarly literature in a given domain (level 5). It is anticipated that graduates of child neurology training programs will achieve level 5 competences in perhaps one or two domains, likely to be the focus of their careers. One of the further implications of the milestones system would be a gradual move toward more individualized models of formation. In the past, residency has been viewed as a time-based



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TABLE 170-1  Two Examples of Child Neurology Milestones Example 1: Patient Care—Obtaining History in a Neonate With a Neurologic Disorder Level 1

Level 2

• Obtains a perinatal and developmentally appropriate neurologic and behavioral history

• Obtains a complete and • Obtains a complete, relevant perinatal and relevant, and organized developmentally perinatal and appropriate neurologic developmentally and behavioral history appropriate neurologic • Elicits patient contribution and behavioral history in addition to family as • Integrates patient and appropriate based on parent/caregiver cognitive level and cultural contribution into history norms • Incorporates information from readily available sources external to the encounter (e.g., medical records

Level 3

Level 4

Level 5

• Efficiently obtains a complete, relevant, and organized perinatal and developmentally appropriate neurologic and behavioral history • Synthesizes patient, parent/caregiver, and external source contribution into history

• Incorporates information from sources difficult to access external to the encounter (e.g., teachers, social workers)

Example 2: Patient Care—Evaluation of a Pediatric Patient With a Neuroimmunologic and White Matter Disorder Level 1

Level 2

Level 3

Level 4

Level 5

• Recognizes when a patient may have a neuroimmunologic or white matter disorder

• Diagnoses and manages patients with common neuroimmunologic and white matter disorders

• Recognizes patients with uncommon neuroimmunologic and white matter disorders • Manages acute presentations of neuroimmunologic and white matter disorders

• Diagnoses patients with uncommon neuroimmunologic and white matter disorders

• Manages patients with uncommon neuroimmunologic and white matter disorders • Engages in scholarly activity in neuroimmunologic or white matter disorders (e.g., teaching, research)

(With permission from the Child Neurology Milestone Project, a joint initiative of the Accreditation Council for Graduate Medical Education and the American Board of Psychiatry and Neurology, 2015.)

progression: so many months of ward or consult services, so many months of elective rotations in allied disciplines, and the like, with everyone spending equal amounts of time on all rotations. The milestones would allow individuals to progress at rates commensurate with their own achievement of expertise and would ideally spend time in various areas of clinical work commensurate with their need for the development of expertise in that area. The implications of this for organizing clinical services with a workforce within a hospital thus not automatically placed on a given service for a set length of time are profound and potentially disruptive to long established modes of health service delivery in teaching hospitals. Table 170-2 demonstrates examples of goals established within the Universal Curriculum. These are perhaps more familiar in appearance to most child neurologists and represent identifiable goals of instruction and mastery of various parts of clinical child neurology practice. They are, in a sense, agnostic to means of instruction and learning, as well as the organization of that learning. Thus although they can be associated with the milestones, they might also readily map onto another structure being discussed by medical educators and certifying bodies, the Entrustable Professional Activities (EPA) (ten Cate, 2005). In the EPA model, one considers an activity such as performing a lumbar puncture. The activity, from its start to finish, includes many elements. The resident must know that the lumbar puncture results are essential to the diagnosis of the patient at hand (medical knowledge and a sound differential diagnosis). The resident must be able to explain the rationale for this test to the family (communication skills and professionalism in conduct). The resident must assemble the needed personnel (working in multidisciplinary team), and then be able to execute the procedure skillfully (technical skills). It has been argued that an EPA model of education

TABLE 170-2  Two Examples of the Universal Curriculum Example 1: Demyelinating Disorders 1. Recognition of patterns of lesion localization identified on brain, optic nerve or spinal cord MRI characteristic of multiple sclerosis (MS), neuromyelitis optica (NMO), CNS vasculitis, other inflammatory CNS disorders (e.g., infection, sarcoidosis), and disorders of cerebral white matter that are metabolic or malignant in origin 2. Identification of clinical “red flags,” including persistent headache and raised intracranial pressure that should prompt consideration of central nervous system (CNS) vasculitis 3. Appropriate use of diagnostic tests including brain, optic nerve, and/or spinal MRI, CSF examination, and multimodal evoked potentials 4. Familiarity with intravenous corticosteroid use and appreciation of second-line therapies including IVIG, plasma exchange, and other immunosuppressant or immunomodulatory therapies 5. Referral for rehabilitation services as appropriate Example 2: Relapsing CNS Inflammatory Diseases 1. Knowledge of current diagnostic criteria for multiple sclerosis (MS), neuromyelitis optica (NMO), and CNS vasculitis 2. Familiarity with established MS treatments including interferon beta 1a, interferon beta 1b, and glatiramer acetate 3. Recognition of new and emerging MS therapies including natalizumab, fingolimod, teriflunamide, and dimethyl fumarate 4. Knowledge of treatment algorithms for MS, NMO, and CNS vasculitis 6. Appreciation of key genetic and environmental risk factors for pediatric MS (e.g., HLA-DRB1 haplotype, vitamin D deficiency, and viral exposures) 7. Recognition of emerging biomarkers (e.g., anti-MOG antibodies) and neuroimaging advances (e.g., DTI and OCT) in CNS inflammatory diseases 5. Appropriate involvement of a multidisciplinary care team

170

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PART XIX  Care of the Child with Neurologic Disorders

more closely captures what goes on for a child neurologist in actual practice, given the synthetic nature of multiple separate skills and attributes which must come into play,and thus is a more proximate and direct measure of an individual’s readiness for clinical practice. Recent investigations have supported this assertion (Johnston, 2003). Regardless of the measures used to determine a resident’s progress through formation, the previously-noted Universal Curriculum and Milestones represent the current state of the conversation in the profession about what constitutes the body of knowledge, skills, and professional attributes that are considered necessary for the effective, compassionate, and ethical practice of child neurology.

EDUCATION AND TRAINING PRECEDING   CHILD NEUROLOGY It is worth considering, for a moment, the current dialogue regarding the necessary formation that precedes child neurology formation. At present, the ABPN requires 2 years of formation before child neurology formation itself can begin. The most common pathway is 2 years of general pediatrics, organized in such a fashion that the person will be eligible for board certification in general pediatrics (that is, certain critical rotations must be accomplished in those 24 months). A less frequently used path is 1 year of general pediatrics and 1 year of internal medicine, the latter in a program that leads to board eligibility in internal medicine (that is, rotations must be supervised by board certified internists and not by family medicine specialists, for example). A so-called third path, with 1 year of general pediatrics and 1 year of neuroscience research, approved at the discretion of the local child neurology residency program director, requires approval at the ABPN as well. This latter pathway was designed to both assist individuals with significant research interests and also to help address a perceived lack of child neurologists with basic, clinical, or translational science expertise.

CURRENT WORKFORCE ISSUES This leads us into the consideration of workforce issues. After a period of substantial growth in the last quarter of the last century, child neurology approached and then reached what we might consider “zero population growth”—as many people were leaving the field annually through retirement or death as were entering. This steady state, however, is a bit deceptive. Numbers of persons in practice or board certified is a less important measure from the standpoint of the families served by a child neurologist; access to child neurology care is more closely determined by the amount of time a given person spends seeing patients. This is the “full-time equivalent” measure of which organizations are so fond. Despite its provenance as a term, we might consider what the implications of this are for child neurology. Recent surveys have shown that the mean clinical FTE (that is, the average amount of time spent seeing patients) of a retiring child neurologist was just lower than 0.7; that is, most people leaving the practice were spending more than twothirds of their time seeing patients. The average clinical FTE of persons joining child neurology is slightly over 0.4. (Child Neurology Society/American Academy of Pediatrics survey on Child Neurology, 2015) This means that in order to keep the same amount of clinical time available across the country, we would need to add nearly two child neurologists to the roster for every one that dies or retires. Thus our “zero population growth” actually represents a likely progressive decline in the

number of available clinical child neurologists expressed as clinical FTE across the country. Given the nature of the disorders that child neurologists see, the increasing acuity reported on most hospital services, and the increasing number of treatment options available for previously untreatable diseases, our current staffing and training models would seem to be on a collision course with access to care. A separate issue is that of the distribution of child neurologists. Child neurologists are generally unequally distributed across the country, tending to center in urban/exurban/suburban areas, often close to the children’s hospitals in which they trained. This geographic distribution creates huge challenges for access to child neurology care, with families from rural areas of the country having to travel great distances in order to see a child neurologist. In addition, urban populations often have very poor access to specialty pediatric care, including child neurology, despite geographic proximity. Given the observation that urban and rural populations bear a greater burden of conditions that predispose to neurologic disorders (higher rates of premature births and lower birth weights of full term infants), this makes this lack of access all the more problematic. United States programs that provide incentives to primary care physicians to practice in medically underserved areas (primarily through loan forgiveness) do not apply directly to child neurologists. The federal calculation of medically underserved is based upon all physicians in a region, weighted toward primary care providers. The calculation is not made in a specialty-specific fashion. Thus one could be in an area that is adequately staffed by primary care providers but be the only child neurologist serving that jurisdiction, and still not be considered in a medically underserved area. Yet anyone who practices as the only child neurologist, or part of a very small group, covering all of a state on the high plains or in northern New England, might disagree. Recent surveys show that practicing in such settings is viewed as stressful by those who do and undesirable by those who are starting. Incentivizing work in such areas through loan forgiveness might not be an entirely sufficient means of helping with this issue of maldistribution, but it is a necessary one. Experience in primary care settings suggests it can be very helpful in establishing a sustainable medical community. Regardless of issues of distribution, is the workforce we are creating likely to meet the needs of the country? If we assume for a moment that child neurologists are likely to work as parts of larger treatment teams as changes occur in the practice of medicine in this century, we need to consider what patients need to be under the direct care of a child neurologist, what patients are likely to need a single or intermittent consultation by a child neurologist with care being shared with a primary care provider, and what patients might be effectively managed within a primary care provider’s office if there were sufficient transfer of information and knowledge from a child neurologist to that primary care provider. No matter how much primary care can be optimized, it is unlikely that patients with certain disorders will ever have anyone except a child neurologist responsible for that portion of their care. Children with complex neurogenetic disorders, multiple sclerosis, intractable epilepsy, brain tumors, or neuromuscular disorders, for example, will continue to require their care come from child neurologists. There are children with other disorders that are likely to prompt a consultation with a child neurologist because they are not seen frequently enough by a primary care provider to produce clinical comfort and expertise. We could consider entities such as tic disorders, more readily controlled epilepsies, language disorders, cerebral palsy, or neurodevelopmental disabilities in this realm. Once a diagnosis has been



Education and Training of Child Neurologists and Workforce Issues

established, it is conceivable that a child neurologist could transfer the care of this patient back to a pediatrician, with some suggestions for the next steps, along with a willingness to either consult remotely with the provider or see the patient again if something does not go as predicted. Then there are disorders that are sufficiently prevalent that we would expect them to be the domain of a primary care provider, yet in many parts of the country are now routinely sent to child neurologists with minimal attempts by the primary care provider at management. Disorders such as attention deficit-hyperactivity disorder (present in 5% to 7.5% of the childhood population), headache (25% of the childhood population will seek medical consultation at least once for a headache), or febrile seizures, now prompt child neurology referral in many parts of the country. Given the prevalence of these disorders, no rational system of child neurology formation or workforce could possibly meet such a demand; it inevitably leads to issues of access, justice, and quality. These three domains interact in terms of access issues. If a child neurology practice or clinic is receiving large numbers of referrals for the third category, then access to appointments for the first category and sufficient time to manage the second category will inevitably suffer. There are certain experiences that suggest this might be changed. Intentional instruction, targeted continuing medical education, and mutually developed treatment paradigms with built-in specialists support for primary care providers have been demonstrated to decrease the rate of specialist referral, produce noninferior or better clinical outcomes, and enhance family satisfaction and engagement. In one study, overall costs were also driven down, thus meeting the so-called “triple aim” of the Institute for Healthcare Improvement (Berwick et al., 2000). The challenge with such models is one of scale (could these be extended over larger segments of the population) and compensation. (These studies were done under experimental conditions, and child neurologists were compensated for their time by the study; if these initiatives were to be extended, a way for third party payers to compensate child neurologists for information transfer without actually seeing a patient would need to be developed.) The evolution of Accountable Care Organizations, beyond the scope of this chapter, is likely to create incentives for such approaches. Shifting dynamics in demographics of child neurologists are also likely to change issues of access. The child neurology workforce is an increasingly female one, and this raises issues of work-life balance and the challenges of raising a family while practicing a demanding specialty. Recent studies have suggested that despite assertions of sharing domestic responsibilities in dual professional couples, greater than 50% of those tasks are usually performed by the woman in a differentgender couple. This, in turn, often leads to less than full-time employment, which for our considerations here would have influence upon total FTE in child neurology, and access to care.

FUTURE WORKFORCE ISSUES If we do some basic calculations, we can estimate the number of child neurologists that might be needed for the most optimistic model of distributed or shared care (which makes

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the lowest use of direct patient visits and maximizes the sharing of child neurology knowledge across various treatment paradigms as noted previously). If we assume that the average child neurologist in this second decade of the century is 0.6 FTE clinical (which would be the average based upon recent survey data), given a current membership of 1800, we have 1080 FTE child neurologists in terms of clinical practice. If we imagine that workforce seeing patients 5 days a week for 48 weeks each year, we have 240 patient-seeing days per FTE. The current childhood population of the United States is roughly 74 million. If we estimate that roughly 10% of that population will seek neurologic consultation at least once per year (given numbers of persons with intellectual disability, epilepsy, cognitive disorders, headache, and neurogenetics disorders), we find that the average child neurologist would need to see just over 28 patients per day in order to accommodate those needs (7.4 million ÷ (1080 x 240) = 28.5). If we are more conservative in that number and say that only 5% of the population will need to be seen by a child neurologist, this still leads to over 14 patients being seen each day. Both of these models presume a single annual visit, not currently viewed as sufficient for most neurologic disorders under the care of child neurologists. Thus our current workforce is not sufficient to cover the needs of the country. If the workforce continues to evolve in the direction of less than full-time clinical practice for most child neurologists, this gap will continue to grow. It is beyond the scope of this chapter to address means of addressing this situation. Although we have made enormous progress as a profession in terms of training that meets individual learning needs and through assessment can assure the public of the high quality of child neurologists, we face enormous challenges in access. REFERENCES The complete list of references for this chapter is available online at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Ashwal, S. (Ed.), 1990. The founders of child neurology. Norman Neurosciences in conjunction with the Child Neurology Society, Novato, CA. Berwick, D.M., Nolan, T.W., Whittington, J., 2000. The triple aim: care, health, and cost. Health Aff. 27 (3), 759–769. Child Neurology Milestones. . Child Neurology Society/American Academy of Pediatrics survey on Child Neurology. 2015. Unpublished data from surveyors. Johnston, K.C., 2003. Responding to the ACGME’s competency requirements: an innovative instrument from the University of Virginia’s neurology residency. Acad. Med. 78 (12), 1217–1220. Pediatrics Milestones. . Rust, R.S., 2011. Child neurology training in the 21st century. Semin. Pediatr. Neurol. 18 (2), 57–58. ten Cate, O., 2005. Entrustability of professional activities and competency-based training. Med. Educ. 39 (12), 1176–1177. Urion, D.K., et al., Submitted. Correlations between the child neurology Milestones and the Child Neurology Universal Curriculum. Manuscript in preparation for Neurology.

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APPENDIX A DENVER II

A Figure A-1ab.  Denver II. (From Frankenburg WK, Dodds JB, Archer P, et al. The Denver II: A major revision and restandardization of the Denver Developmental screening test. Pediatrics 1992;89:91.)

1304



1305

Appendix A Examiner: Date:

Denver II Months

2

4

6

9

12

Name: Birthdate: ID No.: 18 24

15

Years 3

4

5

6

R Prepare cereal R Brush teeth, no help R Play board/card games R 4

Dress no help

R Put on T-shirt

86% 15 Copy

Name friend R Wash and dry hands

16 Draw person 6 parts

R Brush teeth with help 3

15 Copy 14 Copy

Feed doll R Remove garment R Use spoon/fork

12 Copy Tower of 8 cubes 10 Imitate vertical line

R Imitate activities

Tower of 6 cubes

Play ball with examiner

Personal–Social

R Regard own hand 2 R Smile spontaneously 1 Smile responsively Regard face

24 Understand 4 prepositions

Scribbles

Speech all understandable

Put block in cup R Bang 2 cubes held in hands 9 Thumb-finger grasp Take 2 cubes

20 Know 4 actions 22 Use of 3 objects 23 Count 1 block 22 Use of 2 objects Name 1 color 21 Know 2 adjectives 20 Know 2 actions

Rake raisin 7 Look for yarn

Speech half-understandable

Fine Motor–Adaptive

Regard raisin

18 Point 4 pictures

5 Follow 180∞ Hands together 6 Grasp rattle 5 Follow past midline 5 Follow to midline

19 Body parts 6

R Jabbers R Combine syllables R Dada/mama non-specific R Imitate speech sounds

Language

28 Throw ball overhead Jump up

R Vocalizes Response to bell

Kick ball forward R 27 Walk up steps

(Check boxes for 1st, 2nd, or 3rd test)

R Walk backwards Walk well

Typical Yes No

Stand alone Stand-2 seconds

Compliance (See Note 31)

R Get to sitting Pull to stand Stand holding on

Interest in Surroundings

Sit–no support Pull to sit–no head-lag

Fearfulness

3

1

2

3

1

2

3

1

2

3

1

2

3

None Mild Extreme

Sit–head steady

Gross Motor

2

Alert Somewhat disinterested Seriously disinterested

Chest up–arm support Bear weight on legs

Attention Span

Head up 90∞ Head up 45∞ R Lift head Equal movements

2

1

Always complies Usually complies Rarely complies

R Roll over

B

TEST BEHAVIOR

Runs

Stoop and recover

R Single syllables

Hops

Balance each foot 1 second 29 Broad jump

R 3 words

R Dada/mama specific

R Laughs

Balance each foot 4 seconds

Balance each foot 3 seconds Balance each foot 2 seconds

18 Point 2 pictures R 6 words R 2 words

30 Heel-to-toe walk Balance each foot 5 seconds

18 Name 1 picture R Combine words

R 1 word

R “Ooo/aah”

Balance each foot 6 seconds

18 Name 4 pictures

Reaches

R Squeals

23 Count 5 blocks

Name 4 colors

8 Pass cube

Turn to voice 17 Turn to rattling sound

26 Opposite-2

25 Define 5 words

Tower of 2 cubes Dump raisin, demonstrated

R Feed self Work for toy

25 Define 7 words

21 Know 3 adjectives

Tower of 4 cubes

R Indicate wants

88%

11 Thumb wiggle

R Drink from cup

R Play pat-a-cake

+

16 Draw person 3 parts

R Help in house

R Wave bye-bye

demonstrated

13 Pick longer line

R Put on clothing

Appropriate Somewhat distractable Very distractable

4

6

9

12

15

18

Months Figure A-1ab, cont’d

24

3 Years

4

5

©1969, 1989, 1990 W.K. Frankenburg and J.B. Dodds © 1978 W.K. Frankenburg

May pass by report Footnote no. (See back form)

Percent of children passing 25 50 75 90 R Test item 1

6 Continued

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Appendix A

CHECKLIST FOR DOCUMENTATION OF BRAIN DEATH EXAMINATION IN INFANTS AND CHILDREN

Figure A-2.  Checklist for documentation of brain death examination in Infants and Children.



Appendix A

Figure A-2, cont’d

1307

Continued

1308

Appendix A

Figure A-2, cont’d

Index Page numbers followed by “f” indicate figures, “t” indicate tables, “b” indicate boxes, and “e” indicate online content.

A

AAN. see American Academy of Neurology (AAN) Abasia  689 Abducens nerve  7–9, 8f, e13–e14, e13f, e13t Abetalipoproteinemia  1082–1083, e2414–e2415 Abscess brain. see Brain abscess central nervous system  893–894 Absence epilepsy, physiology of  e1217– e1218, e1217f and abnormal neuronal firing  508–509, 510f Absence nonconvulsive status epilepticus  550 Absence seizures  525–528, e1251–e1256 atypical  526 behavioral changes with  526 childhood absence epilepsy and  408, 517, e1252 classification of  e1252t clinical features of  e1251–e1252, e1251t differential diagnosis of  526t, e1252– e1253, e1254t electroencephalographic findings of  527, 527f–528f, e1253–e1254, e1253f–e1254f etiology of  e1253 eyelid myoclonia in  e1252 initial evaluation of  527, e1253 juvenile  528 juvenile absence epilepsy and  517, e1252 juvenile myoclonic epilepsy and  408, e1252 myoclonic absence in  e1252 pathophysiology of  e1254–e1255, e1255f prognosis of  528, e1256 treatment of  527–528, e1256 typical  526 Abusive head trauma (AHT)  785, 791, 794–803, e366–e367, e1773–e1774, e1774f, e1811–e1838 acute presentation of  795, e1813 early posttraumatic seizures  795 autonomic and neuroendocrine responses of  e1826–e1827 behavioral sequelae of  e1814 biochemical markers of  e1827–e1828 biologic factors of  794, e1812 brain injuries in  e1818–e1821 cardiac arrest and  808, e1845 clinical assessment of  799–800, e1826–e1827 clinical features of  795, e1813–e1814 cognitive and executive function of  e1814 developmental differences predisposing immature neuraxis to  794, 795b, e1811–e1812, e1812b diagnosis of  800–802, 801b, e1829–e1831 dating by neuroimaging in  e1830–e1831 evaluating history in  e1830, e1830b

Abusive head trauma (AHT) (Continued) general considerations in  e1829–e1830, e1830b lucid interval of  e1830 medicolegal issues in  e1831 timing in  e1830 differential diagnosis of  797–798, e1823–e1825 birth trauma  798 falls  798 neurometabolic disease  798 specific findings  798–799 unintentional injury  798 differential of specific findings of  e1825–e1826 evaluating history of  801, 801b general examination of  e1826 historical perspective of  794, e1811 history of  e1826 hypoxia-ischemia and  794–795, e1812–e1813 laboratory evaluation of  800, e1827–e1828 biochemical markers  800 mechanical factors of  794, e1811–e1812 mechanisms of  794–795, 795b, e1812–e1813 medicolegal issues of  802 mortality predictors of  e1814 motor sequelae of  e1815 neuroimaging and radiographic evaluation of  e1828–e1829 neurologic examination of  799, e1826 autonomic and neuroendocrine responses  799–800 neurometabolic disease and  e1825 neuropathology of  e1815 pathologic features of  796–797, 796b, e1815–e1823, e1815b extracranial injuries  796, e1815 intracranial injuries  796–797, e1815– e1821, e1816f ocular  797, e1822–e1823 spinal injuries  797, e1823 physical examination of  799 postmortem examination of  800, e1829, e1829f predictors of outcome  795, e1813–e1814, e1814b responses to  794, e1812 sequelae of  795–796, e1814–e1815 behavioral  796 cognitive and executive function  796 motor  796 neuropathology  796 subacute and chronic presentation of  795, e1813 terminology in  794, e1811 timing of  801 dating by neuroimaging  801–802 lucid interval  801 unintentional injury in  e1824–e1825 visual sequelae of  e1814

ACAD9 deficiency  e2551 Academic achievement, dyslexia and  445, e1072 Academic difficulties, Tourette syndrome and  e1666–e1667 Academic planning, for childhood epilepsy  640 Academic underachievement, in childhood epilepsy  636–637 Acamprosate  480 Acanthamoeba spp.  910–911, e2083–e2084 ACC. see Anterior cingulate cortex (ACC) Accessory devices, for hearing impairment  e111 Accidental falls  e367, e367f Accommodation, for dyslexia  446 Aceruloplasminemia  482t–486t Acetaminophen abuse in  e2693 for pain management  1257, 1257t, e2848–e2849 Acetazolamide  601t–602t for Andersen-Tawil syndrome  1155–1156 for Dravet syndrome  406 for familial hemiplegic migraine  409 for hyperkalemic periodic paralysis  1154 for hypokalemic periodic paralysis  1155 for intracranial hypertension  819 ketogenic diets and  628–629, e1455 for moyamoya  852 for renal diseases  1223–1224, 1226, e2764–e2765 Acetazolamide-responsive sodium channel myotonia  1151–1152, 1152t, e2605– e2606, e2606t clinical features of  1152 genetics  1152, 1152t laboratory tests in  1152 pathophysiology of  1152 treatment for  1152 Acetohexamide ataxia and  e2685b toxicity  1199b Acetone sensorium changes  e2682b toxicity  1196b Acetyl CoA  337 N-Acetylaspartate (NAA)  140 Acetylcholine  1173 and efferent neurotransmission  e2643 Acetylcholine receptors (AChRs)  1098 antibodies  1100 deficiency, primary  1094 kinetic defects in  e2445–e2446 nicotinic  405 Acetylcholinesterase endplate, deficiency  1093–1094 inhibitors  1100 and ASD  468 for juvenile myasthenia gravis  e2460–e2461 N-Acetylcysteine (NAC)  145, e332

1309

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Index

α-N-Acetylgalactosaminidase deficiency  e812 N-Acetylglutamate synthase deficiency  e711 Acetylsalicylic acid (ASA) sensorium changes  e2682b toxicity  1196b Achalasia-addisonianism-alacrima syndrome. see Allgrove syndrome Achenbach System of Empirically Based Assessment  4, 68t–69t, e5, e143t–e146t Achievement, nonverbal learning disabilities and  438, e1061–e1062 Achondroplasia  240 AChRs. see Acetylcholine receptors (AChRs) Acid α-glucosidase  309–310 deficiency, infantile type  e732–e733, e732f Acid-base, in coma  776 Acid ceramidase deficiency  326 Acid maltase deficiency  1133t, e2539–e2542 adult  309–310 biochemistry in  e2541–e2542 clinical features of  e2539–e2541 diagnostic testing in  e2541–e2542 inheritance in  e2541 juvenile  310 laboratory tests in  e2541 molecular genetics in  e2541–e2542 pathology and pathophysiology of  e2541 treatment of  e2542 genes encoding  1132–1133 Acidemias, organic  e671–709 Acidopathies, organic  172–174 Acidosis, respiratory, in drowning  808–809 Acquired afferent baroreflex failure  1178 Acquired brain injury  1253 Acquired epilepsies  590–593 Acquired epileptic aphasia  574, e1345 Acquired heart disease, neurologic conditions with  e2714t, e2723, e2724t cardiac defects in, genetic disorders with  e2723 energy production, disorders of  e2725 inborn errors of metabolism  e2723–e2725 inherited neuromuscular disorders with cardiac complications  e2726 storage disorders  e2725–e2726 Acquired peripheral neuropathies  1081– 1085, e2409–e2425 anatomy in  1081 Bell’s palsy  1081 brachial plexus  1081–1082, e2412, e2413f facial nerve paralysis in  e2409–e2412 metabolic  1082–1083, e2412–e2417 abetalipoproteinemia  1082–1083, e2414–e2415 acute intermittent porphyria (AIP)  1082, e2413–e2414 alpha-lipoprotein deficiency  e2415 Chédiak-Higashi syndrome  e2416–e2417 congenital pernicious anemia  1082, e2414 diabetes mellitus  1082, e2412 Krabbe’s disease  1083, e2415–e2416 metachromatic leukodystrophy  1083, e2416 peroxisome biogenesis disorders  1083, e2416 Refsum’s disease  1083, e2416 Tangier disease  1083 uremic neuropathy  1082, e2412–e2413 vitamin deficiency  1082, e2414

Acquired peripheral neuropathies (Continued) recurrent facial paralysis in  e2412 toxic  1083–1084, e2417–e2419 antibiotic-induced  1084, e2417 chemotherapeutic agent-induced  1084, e2418 diphtheria  1083, e2417 heavy metal  1084, e2418–e2419 nitrous oxide-induced polyneuropathy  1084, e2417–e2418 pyridoxine-induced  1084, e2417 serum sickness  1083, e2417 vaccine-induced polyneuropathy  1084, e2418 vasculitic  1084–1085, e2419–e2420 Acrocephaly  e568 Acroparesthesia  326 Acrylamide causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b ACTH. see Adrenocorticotropic hormone (ACTH) Actigraphy in disorders of excessive sleepiness  e1529 for excessive sleepiness assessment  672 Actin  1031 in congenital myopathies  1124t–1125t Actinomyces spp.  908 Actinomycosis  908, e2069 Actinopathies  e2528–e2529, e2529f Activated autologous macrophages, for spinal cord injury  e1887 Activation syndrome  491 Active stimulation paradigms  e1732 disorders of consciousness and  767 Activities and participation, health outcome measures of  e2904t Activities Scale for Kids questionnaire  1292, e2905 Acute autonomic and sensory neuropathy  1179 Acute bilirubin encephalopathy, neuropathology of  e2801 Acute cerebellar ataxia  31, 701–705 autoimmune disorders and  704 causes of  701–704, 702b of childhood  e63 clinical evaluation of  701 intoxication and  703, 703b investigations in  704–705 mass lesions and  703 metabolic/genetic  703 other neurologic disorders and  703 psychogenic  703–704 toxicology in  704 trauma and  703 treatment and prognosis  705 urinary catecholamines/MIBG scintigraphy in  704 vascular  703 Acute disseminated encephalomyelitis (ADEM)  39, 702, 759, 761f, e80–e81, e1715–e1716, e1718f etiology, influenza virus  919 multiphasic  e1724 recurrent  e1724 Acute drug-induced movement disorders  729–731 diagnosis of  731 treatment of  731–732 Acute dystonia, antipsychotic medications and  e1182, e1182t

Acute encephalopathy IEMs and  278–279 metabolic disorders and  e658–e659 porphyria and  1233 in systemic juvenile idiopathic arthritis  e2162–e2163 Acute fulminant metabolic diseases  172– 175, e405–e413 fatty acid oxidation defects  e411f, e412–e413 fructose-1,6-biphosphatase deficiency  e412 glutamine synthetase deficiency  e412, e412f maple syrup urine disease  e405–e409, e409f organic acidopathies  e409–e410 primary lactic acidosis, resulting from oxidative phosphorylation defects  e410–e412, e411f–e412f urea cycle disorders  e412f, e413 Acute inflammatory demyelinating polyneuropathy  1178 Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)  1086, 1087t see also Guillain-Barré syndrome (GBS) Acute intermittent porphyria (AIP)  1082, 1233, e2413–e2414 Acute kidney injury (AKI)  1215–1216, e2738–e2742 calcium abnormalities in  e2740–e2742 magnesium abnormalities in  e2740–e2742 potassium abnormalities in  e2740, e2741t sodium disorders in  e2738–e2740 water disorders in  e2738–e2740 Acute metabolic decompensation  290 Acute motor axonal neuropathy (AMAN)  1087, 1087t, e2785 Acute motor-sensory axonal neuropathy (AMSAN)  1086, 1087t Acute nonrecurring spontaneous vertigo  e121–e122 Acute ophthalmoparesis  1087t Acute pandysautonomia  1087t Acute posttraumatic headache  654–655 Acute sensory neuropathy  1087t Acute symptomatic perinatal arterial ischemic stroke  147–151, e339–e345 acute management of  149 clinical presentation of  148 diagnosis of, neuroimaging  148–149, 148f epidemiology of  147, 148f outcomes and rehabilitation of  149–151 cerebral palsy  149–150 nonmotor disabilities  150 outcome prediction  150 psychology and mental health  150–151 recurrence  150 pathophysiology and potential risk factors of  147–148 Acute symptomatic seizures  130–131, e310–e311 discontinuation of medication for  e317 medication discontinuation for  135 treatment of  134f, 135, 136f, e315–e317, e316f Acute therapy, for migraine  e1495 Acyclovir for herpes simplex virus  900 for renal diseases  1224, e2765 Acyl-CoA oxidase deficiency  e870 AD dHMN type I  e2400

AD dHMN type II  e2400 AD dHMN type VII  e2400 AD dHMN V  e2400 Adamantinomatous tumors  1006, e2265 ADAMTS-13 deficiencies  e2757 Adaptation, functional recovery through  1249 Adaptive Behavior Assessment System  68t–69t, e143t–e146t Adaptive behavior scales, of neuropsychological measure  68t–69t Adaptive technology, for spinal cord injury  828–829 Adderall for ADHD  454 attention deficit-hyperactivity disorder and  e1086 Addison disease  351 adrenoleukodystrophy with  e867 ADEM. see Acute disseminated encephalomyelitis (ADEM) Adenine  260 Adenine nucleotide translocator, mutations in  342, e849 Adenosine, in flow-metabolism coupling  845 Adenosine diphosphate (ADP)  1131 Adenoviruses  896b, e2043 ADHD. see Attention deficit hyperactivity disorder (ADHD) AdoCbl defects  378, e928 Adolescent autosomal-dominant focal epilepsy with auditory features in  e1234 autosomal-dominant nocturnal frontal lobe epilepsy in  e1234 electroclinical syndromes in  e1349–e1363 additional diagnostic considerations in  e1359–e1360 classification of  e1349 compliance and behavioral issues in  e1350 epidemiology of  e1349–e1350 focal epilepsies in  e1356–e1359 generalized epilepsies in  e1351–e1356 ontogenesis of  e1349 psychosocial and cognitive implications of  e1349–e1350 treatment of  e1360–e1361 epilepsy-aphasia syndromes in  e1233 familial focal epilepsy with variable foci in  e1234–e1235 focal epilepsies  e1356–e1359 autosomal-dominant nocturnal frontal lobe epilepsy in  e1359 autosomal-dominant partial epilepsy with auditory features in  e1357– e1358, e1359f mesial temporal lobe epilepsy with hippocampal sclerosis in  e1356– e1357, e1357f–e1358f generalized epilepsies in  e1351–e1356 with convulsions  e1354, e1355f juvenile absence epilepsy in  e1353– e1354, e1354f juvenile myoclonic epilepsy in  e1351– e1353, e1351f–e1353f headache in  647–655, e1490–e1505 classification of  e1490–e1491 epidemiology of  e1491–e1492 evaluation of  e1492–e1493 management of  e1493–e1500 nonpharmacologic treatment for  e1494–e1495

Index Adolescent (Continued) pathophysiology of  e1492 pharmacologic therapies for  e1494– e1500, e1494t, e1497t specific secondary  e1495–e1496 health outcome measurement and  e2905 idiopathic generalized epilepsies in  e1233–e1234 metabolic disorders in  e665–e668 motor function testing in  1049, e2334–e2336 outcome measurement in  1292 phonologic deficit in  e1072 Adolescent onset epilepsy, autosomal dominant nocturnal frontal lobe  408 Adrenal insufficiency  e2633 Adrenarche  1165–1166 defined  e2628 normal physiology of  e2628–e2631 Adrenocorticotropic excess  e2632, e2633f Adrenocorticotropic hormone (ACTH)  1165, e1284, e2632 challenge test, for opsoclonus myoclonus syndrome  939, e2150, e2151f deficiency  1168–1169, e2632–e2633 excess  1168 for infantile spasms  541–542, 541t in opsoclonus myoclonus syndrome  941– 942, 942t Adrenoleukodystrophy  350–351, e865t with Addison disease  351 adolescent cerebral form of  351 adrenomyeloneuropathy  351 adult cerebral form of  351 asymptomatic patients with biochemical defect of  351 biochemical and molecular basis  351 childhood cerebral form of  351 current and future outlook of  353–354 neonatal  349–350, e863–e866 pathogenesis of  353 symptomatic heterozygotes  353 therapy for  353 X-linked  349, 751–753, e866, e1692f, e1693 biochemical and molecular basis of  e866 clinical and pathologic features of  351–354, e867–e869, e867t, e868f pathogenesis of  e869 therapy for  e869 Adrenomyeloneuropathy  351, e867 MRI studies in  352f Adult GAA deficiency  e734 Adult neurologist/internist, referral to  1274 Adult-onset leukoencephalopathies  758 Adult rehabilitation program, referral to  1274 Adulthood disorders with neurologic sequelae  e2874–e2875 potentially lethal  e2873–e2874 with serious manifestations  e2874 Advanced magnetic resonance techniques, for encephalopathy  140, e324 Adverse drug reactions  e2696–e2699 drug administration, technique of  e2696–e2697 drug interactions in  e2697 method of preparation  e2696 neuroteratology in  e2697–e2699, e2698t pharmacogenetic susceptibility in  e2697 Aedes spp. Aedes aegypti  905 Aedes albopictus  905

1311

Aerobic endurance, resistance exercise, and physical therapy, for mitochondrial diseases  1138 Aerobic exercise, for ADHD  455–457 Afferent autonomic pathways  1173, e2644 African sleeping sickness  913, e2094–e2095, e2095f Agalsidase  326 Aganglionic megacolon  1182 AGAT deficiency  482t–486t Age neurocognitive deficits and  e2293 as risk factor for neurocognitive deficit  1024 Age of onset  1 Agenesis cerebellar  206 of corpus callosum  194–197, e453–e460, e455f association of, with autism and related neurodevelopmental disorders  196, e459–e460 clinical manifestations of  196 development of  196 epidemiology of  195 etiology of  196 genetic  196 nongenetic  196 imaging and  196 management of  196–197 prenatal diagnosis  254 prenatal diagnosis and prediction of outcomes  195–196 Ages and stages questionnaire  4, e5 Aggressive immunotherapy, for LEMS  e2466–e2467 Agitation in coma  776 impairment of consciousness and  e1751 Agnosia auditory  434t, 435 cortical localization of  e1025t Agouti-related protein (AgRP)  1165, 1170f Agrin myasthenia  1095, e2446 AGTR2 gene mutation  421t AHS. see Alpers-Huttenlocher syndrome (AHS) AHT. see Abusive head trauma (AHT) aHUS. see Atypical hemolytic-uremic syndrome (aHUS) Aicardi-Goutières syndrome  752f, 755–756, e1698–e1699 AIDP. see Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) AIP. see Acute intermittent porphyria (AIP) Airway coma  776 spinal cord injury  826 AIS. see Arterial ischemic stroke (AIS) Akathisia  1200 antipsychotic medications and  e1182, e1182t tics and  741 AKI. see Acute kidney injury (AKI) Akinetic mutism  770t, 771, e1737t, e1740 Alacrima, achalasia, and mental retardation (AAMR) syndrome  1182 Alacrima, congenital  e2657 Alagille syndrome  e651 Alagille syndrome 1, congenital heart defects and  1206t Alanine  336–337 Alanine aminotransferase (ALT), in DMD  1108

1312

Index

Alanine-glyoxalate aminotransferase  e861 ALARA principle  78, e166 Albendazole for cysticercosis  1146 for gnathostomiasis  914 for trichinellosis  e2099–e2100 Alberta Infant Motor Scales  e2900 Alberta Perinatal Stroke Parental Outcome Measure  e345 Albinism, ocular/oculocutaneous  e75 Albuterol  1063, e2368 Alcohol sensorium changes  e2682b for spasticity  1252 toxicity  1196b Aldolase A deficiency  1132b, e2547 Alemtuzumab, for multiple sclerosis  764 Alexander disease  598, 751, 752f, 757, 1182, e1691, e1692f, e2656 Alexia, acquired  443 ALG1-CDG (Ik)  320, e752t–e760t, e761 ALG2-CDG (Ii)  e752t–e760t, e760–e761 ALG2 myasthenia  1096, e2448 ALG3-CDG (Id)  e752t–e760t, e760 ALG6-CDG (Ic)  320, e752t–e760t, e760 ALG8-CDG (Ih)  e752t–e760t, e760 ALG9-CDG (II)  e752t–e760t, e761 ALG12-CDG (Ig)  e752t–e760t, e760 ALG13-CDG (Is)  e752t–e760t, e762 ALG14 myasthenia  1096, e2448 Algorithm, for medulloblastoma  e2206f Alice-in-Wonderland syndrome  901 Aliskiren  e2755b Alkaloids, abuse in  e2693–e2694 Allgrove syndrome  1182, e2656 Allopurinol, sensorium changes  e2682b Allopurinol toxicity  1196b Almotriptan  650, 650t Alpers-Huttenlocher syndrome (AHS)  342, e849 Alpers’s syndrome  341, 1236, e2800 Alpha-actin  1031 Alpha-adrenergic agonists, for ADHD  454–457, e1086–e1087, e1087t–e1089t adverse effects  455 Alpha-adrenergic receptors  e2643 Alpha-fetoprotein (AFP), in ataxia-telangiectasia  694 Alpha-lipoprotein deficiency  e2415 see also Tangier disease Alpha2-agonists  e1164–e1165 Alphaviruses  e2045–e2046 Alport syndrome  49, e104 ALS. see Amyotrophic lateral sclerosis (ALS) Alternate belief systems  1242, e2817 Alternative-pathway therapy, for urea cycle disorders  303, e711t, e718 Aluminum, associated with Parkinsonism  e2684b Aluminum compounds associated with tremor  e2685b in ataxia  e2685b sensorium changes  e2682b Aluminum phosphide associated with tremor  e2685b in ataxia  e2685b Aluminum toxicity  1196b, 1198b–1200b, e2747–e2748 and encephalopathy  1218, e2747–e2748 AMA Code of Ethics  1267 AMAN. see Acute motor axonal neuropathy (AMAN) Amantadine, for parkinsonism  e1615 “Amaurotic family idiocy”  390

Amblyopia  37, e78 Amebas  e2080t Amebiasis, cerebral  e2079 Amebic infections  910–912 amebic meningoencephalitis, primary  910 of central nervous system  e2079–e2085 cerebral amebiasis in  e2079 granulomatous amebic encephalitis in  e2083–e2085 primary amebic meningoencephalitis in  e2079–e2083 granulomatous amebic encephalitis  910–911 malaria  912 toxoplasmosis  911 Amebic meningoencephalitis, primary  910, e2079–e2083 clinical characteristics, clinical laboratory tests and diagnosis of  e2082–e2083, e2082f epidemiology, microbiology and pathology of  e2079–e2082, e2082f management of  e2083 American Academy of Neurology (AAN)  418, 1276, e1900, e1901b in neuroimaging  648–649 in pediatric migraine, management of  649–653 process  1278–1281, 1279t, e2884–e2887 choosing topics and panelists  e2884 collecting and grading evidence  e2884– e2886, e2885t drawing conclusion  e2886 writing recommendations  e2886– e2887, e2887t American Association of Poison Control Centers (AAPCC)  1204 American Association on Mental Retardation  418 American Board of Psychiatry and Neurology (ABPN)  1300 American College of Obstetricians and Gynecologists (ACOG)  138, e321 American Heart Association (AHA)  e349 American Spinal Injury Association (ASIA)  821, 821b classification of spinal cord Injury  e2841b Americans with Disability Act of 1990 (P.L. 101-336)  1285 Amiloride  e2755b α-Amino-3-hydroxy-5-methylisoxazole-4propionic acid. see AMPA Amino acid, metabolic disorders of, epilepsies and  594–596 L-amino acid decarboxylase deficiency (L-ADD)  176, e417–e418, e417f Amino acid neurotransmitter disorders  359–360, e882–e883 GABA transaminase deficiency  359 succinic semialdehyde dehydrogenase  359 D-Amino acid oxidase  e861 Amino acids and inborn errors of metabolism  482t–486t metabolism  e861 Aminoacidemias  286–297, e671–709 biopterin disorders  287, e677–e678 diagnosis of  e671–e672 glycine encephalopathy  e683–e685 Hartnup’s disease  e687–e688 hepatorenal tyrosinemia  287, e678–e679 histidinemia  e688 homocystinurias  e685–e687

Aminoacidemias (Continued) inheritance and genetic counseling in  286, e672–e673 maple syrup urine disease  e679–e683 phenylketonuria  e673–e677 physical findings of  e671 signs and symptoms of  e671 sulfite oxidase deficiency  e687 treatment of  e672 tyrosinemia, categories of  e679 Aminoacidopathies  279t, e659t Aminoacyl-tRNA synthetases, mutations of  341 Aminoglycosides  e2368, e2694 associated with paralysis and muscular rigidity  e2684b causing peripheral neuropathy  e2684b in myasthenia gravis  1103b neuroteratology  1203t toxicity  1197b–1198b, 1201 Aminolevulinic acid (ALA)  1233 Aminophylline toxicity  1200b tremor and  e2685b Aminopterin, neuroteratology  1203t Amiodarone in ataxia  e2685b causing peripheral neuropathy  e2684b myopathies and  e2683b Parkinsonism and  e2684b toxicity  1197b–1200b tremor and  e2685b Amish founder mutation  374 Amish infantile epilepsy  e752t–e760t Amish lethal microcephaly  374, e920–e921 Amitriptyline  491, e2825t for ADHD  455t–457t causing peripheral neuropathy  e2684b for migraine  652t pharmacogenetics  1246t toxicity  1197b Amlodipine  e2755b Ammonium chloride sensorium changes  e2682b toxicity  1196b Amobarbital test, in epilepsy surgery  e1427 AMP  1131 AMPA  405 AMPA receptors  508 Amphetamines abuse in  1199, e2690 for excessive daytime sleepiness  675 L- and D-, mixed salts of, for ADHD  453, 455t–457t myopathies and  e2683b sensorium changes  e2682b toxicity  1196b–1197b Amphiphysin  1124t–1125t Amphotericin B for aspergillosis  909 for blastomycosis  908 for cryptococcosis  907 for histoplasmosis  908 Amplitude-integrated EEG (aEEG)  141–142 AMSAN. see Acute motor-sensory axonal neuropathy (AMSAN) Amylo-1,4→1,6 transglucosidase deficiency  e736–e737 Amylo-1,6-glucosidase deficiency  310–311, e735–e736 Amyloidosis  1222, e2759–e2761, e2759b, e2760t Finnish-type (type V)  e2760 renal  e2761

Amyotrophic lateral sclerosis (ALS)  1069– 1071, 1071t, e2382, e2382t juvenile  341 “Anal wink”  18, e36–e37 Analgesia, for pain management  1258, e2850 Analgesic rebound headaches  e1495 Analgesics, renal toxicity of  1225t, e2765t Anaplasma phagocytophilum  e2073t–e2074t Anaplasmosis  e2078 Anatomic covariance  99, e258 Anatomic gastrointestinal disorders  1229–1231 Anatomic megalencephalies  e495, e497t–e499t Ancillary testing for OMS  939 for opsoclonus myoclonus syndrome  e2150 Andersen-Tawil syndrome  1153t, 1155–1156, e2610–e2612, e2611f, e2622 clinical features of  1155 genetics  1155 laboratory tests for  1155 pathophysiology of  1155 treatment for  1155–1156 Andersen’s disease  311 biochemistry of  311 clinical characteristics of  311 clinical laboratory tests of  311 management of  312 pathology of  311 Anemia breath-holding spells  e1508 iron deficiency  854 iron deficiency, sinovenous thrombosis and  860, 861f pallid breath-holding spells and  658 sinovenous thrombosis and  860, e1956, e1956f Anencephaly  188–189, 770–771, e437–e438 differential diagnosis of  189, e438 pathogenesis of  188–189, e438 pathology of  189, e438 Anesthesia, for mitochondrial diseases  1138 Anesthetic agents, in myasthenia gravis  1103b Anesthetics, inhaled, for refractory status epilepticus  549t Aneuploidy  270–272, e614t, e641 XXX  272 XXY  272 Aneurysms  869–870 in intracranial hemorrhage  e1979 traumatic  785–786 Angelman syndrome (AS)  242–243, 245–246, 246t, 273, 274t, 479t, e591–e592, e591t, e646–e648, e649f, e650t central hypotonia and  1055t, e2345–e2346 and infantile onset epilepsies  558t–560t treatment of  e1138t Angiitis, primary, of central nervous system  851–852, 874, e1935, e1937f Angiofibromas  427 Angiogenesis, in cerebrovascular system  841, e1921 Angiography  85, e192 catheter for arteriovenous malformations  866 for sinovenous thrombosis  862 cerebral  835 for measurements of cerebral perfusion  e1910

Index Angiography (Continued) computed tomographic  835 conventional, in arterial ischemic stroke  854 digital subtraction  836 magnetic resonance. see Magnetic resonance angiography for traumatic brain injury  787, e1782 Angiokeratoma  328 in Fabry disease  e784, e784f lysosomal storage diseases and  e783 Angiostrongylus spp.  913–914, e2100 A. cantonensis  913, e2080t, e2100 Angry responses, in conveying empathy  1240 Anhidrosis congenital insensitivity to pain with  e2654 in pediatric autonomic disorders  1175 Animal models/studies autism  e1099–e1100 ketogenic diet  626, e1451 myotonic dystrophies  e2599 neurologic disease  114–122, e286–e298 genetically engineered models  e287–e293 genome engineering using CRISPR-Cas9 technology  e292–e293, e293f knock-out and knock-in mice  e289– e292, e291f–e292f spontaneously occurring mutant animals  e286–e287, e287t transgenic mice  e287–e289, e288f–e290f neuronal ceroid lipofuscinosis  e956–e957 protein-energy malnutrition  386 Aniridia  e75 Anisocoria, lightning and  809 Anisotropic diffusion  82 Anisotropy, increases in  101 Ankle-foot orthotics  1251f for spasticity  e2834, e2834f Anoctaminopathy  1115, e2493 Anorexia nervosa  1178 Anosmia  63 ANS. see Autonomic nervous system (ANS) Antacids, for gastroesophageal reflux  1161 Antalgic gait  32, e65 Antecedent conditions, behaviors, and consequences  476 Anterior cingulate cortex (ACC)  1187, e2666, e2667f Anterior horn cell disease, in peripheral hypotonia  e2348 Anterior horn cells  1057, 1065, e2374, e2375f Anterior nucleus of thalamus, deep-brain stimulation  620 Anti-AChR antibodies  1100 in autoimmune myasthenia gravis  e2458–e2460 Anti-Hu antibody  e2135 Anti-infectious medications, drug-induced movement disorders associated with  733, e1647 Anti-MuSK antibodies  1100 in autoimmune myasthenia gravis  e2460 Anti-N-methyl-D-aspartate receptor encephalitis  931, e2137, e2143 Anti-NMDA receptor encephalitis  934–935, 1179, e2652 in disorders of excessive sleepiness  e1535–e1536 Antiangiogenic therapy, for pediatric low-grade glioma  990, e2241

1313

Antiarrhythmics sensorium changes  e2682b toxicity  1196b Antibasal ganglia antibodies (ABGA)  709, e1600–e1601 Antibiotic-induced neuropathy  1084, e2417 Antibiotics  1201–1202, e2694 for acute bacterial meningitis  887–888 associated with myoclonus  e2685b causing peripheral neuropathy  e2684b in myasthenia gravis  1103b sensorium changes  e2682b toxicity  1196b–1197b Antibody testing, for myasthenia gravis  1100–1105, e2458–e2460 Antibody titers, for myasthenia gravis  e2318 Anticholinergic syndrome  1193 toxicity  1196b, 1198b–1199b toxidrome  1193 Anticholinergic agents associated with Parkinsonism  e2684b in ataxia  e2685b for dystonia  712 sensorium changes  e2682b Anticipation  e1570 Anticoagulant, for arterial ischemic stroke  855 Anticoagulation for arterial ischemic stroke  855–856, e1945 for sinovenous thrombosis  e1963–e1964 Anticoagulation therapy (ACT), for sinovenous thrombosis  862 Anticonvulsant hypersensitivity syndrome, in children  609–610 Anticonvulsants  490t in myasthenia gravis  1103b for paroxysmal kinesigenic dyskinesia  e1629 for posttraumatic seizures  789–790 therapy, acute, for traumatic brain injury  e1788–e1789 Antidepressants  491–492, e1165–e1173 abuse in  e2692 in ataxia  e2685b for attention deficit-hyperactivity disorder  e1087t–e1089t for cataplexy  675–676 for migraine  652t myoclonus and  e2685b Parkinsonism and  e2684b selective serotonin reuptake inhibitors  491–492 sensorium changes  e2682b serotonin-norepinephrine reuptake inhibitors  492 toxicity  1196b, 1198b–1199b, 1200–1201 tricyclic  491 Antidiuretic hormone (ADH)  1165, e2636–e2637 inappropriate secretion of, bacterial meningitis and  e2013–e2014 Antidotes, for coma  776, e1750 Antiepileptic drugs (AEDs)  e1202 for absence seizures  527–528 adverse effects of  e1132 in ataxia  e2685b for autistic spectrum disorder  e1109t– e1110t, e1112 benzodiazepines  e1203 dose of  e1203 enhancing adherence to  502 for febrile seizures  522

1314

Index

Antiepileptic drugs (AEDs) (Continued) for generalized seizures  525 for migraine  652t neuroteratology  1203t nonbenzodiazepines, for status epilepticus  547–548 optimal length of  504, e1206 optimal rate of taper of  504 Parkinsonism and  e2684b prediction of seizure outcomes in  e1204– e1206, e1204t routines of care and  501–502, e1203–e1204 for seizures adverse effects of  475 withdrawal of  475 sensorium changes  e2682b side effects of, monitoring for  502 social outcome of  e1206–e1207, e1207t start of  501–502 selection of  501 starting of  e1202–e1204 therapeutic range of  e1203 toxicity  1196b, 1198b–1200b tremor and  e2685b when to stop  503–504 withdrawal of  e1132 Antifreeze components  1196b, e2682b Antifungal agents associated with Parkinsonism  e2684b in ataxia  e2685b sensorium changes  e2682b toxicity  1196b, 1198b–1199b Antihistamines in ataxia  e2685b for migraine  652t Parkinsonism and  e2684b sensorium changes  e2682b toxicity  1196b, 1198b–1200b tremor and  e2685b Antihypertensives for migraine  652t sensorium changes  e2682b toxicity  1196b Antiinflammatory therapy, for acute bacterial meningitis  888 Antimicrobials in ataxia  e2685b for brain abscess  893–894 toxicity  1199b Antineoplastics  1202, e2695–e2696 in ataxia  e2685b causing peripheral neuropathy  e2684b myoclonus and  e2685b sensorium changes  e2682b toxicity  1196b–1197b, 1199b Antioxidants, for mitochondrial diseases  1138–1139 Antiparasitic agents in ataxia  e2685b causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b, 1199b Antiphospholipid antibodies (APAs) in arterial ischemic stroke  877 in vascular thrombus  e1998–e2000, e2000t Antiphospholipid antibody syndrome  955, e2183–e2184 Antiplatelet therapy  856 for arterial ischemic stroke  e1945 Antipsychotics abuse in  e2691–e2692 associated with Parkinsonism  e2684b

Antipsychotics (Continued) atypical  494–495, e1184–e1189, e1184t movement disorders and  728–732, 730t–731t high-potency  494 low-potency  494 sensorium changes  e2682b toxicity  1196b, 1198b typical  493–494, e1181–e1184, e1181t–e1182t movement disorders and  728–732, 730t–731t Antipyretics, for febrile seizures  522, e1244 Antiseizure drugs  600–611, 601t–602t, e1270t–e1271t, e1360, e1391–e1416, e1473–e1477 absorption in  e1391–e1395 activating effects  638 adverse drug reactions to  608–610, e1409–e1412 anticonvulsant hypersensitivity syndrome  609–610 to central nervous system  608 gastrointestinal  608–609 gingival hyperplasia  609 increased seizures  609 managing  610, e1411–e1412 monitoring  606–607 osteomalacia  609 tremor and movement disorders  609 adverse psychiatric effects of  e1474 behavioral effects of, older vs. newer  e1475 for childhood epilepsy adverse psychiatric effects  638 on behavior, attention, and mood  638–640 behavioral and cognitive effects of the older versus newer  638–639 effective medication use  638 fear of side effects  638 forced normalization of  638 general effects  638–640 mood disorders and  638 psychosis  638 psychotropic effects  638 discontinuation of  610, e1412 dosage formulations of  604t–605t, 605, e1406–e1407 drug concentrations of measuring  607–608 monitoring  607–608 obtaining  607 drug-induced movement disorders and  733, e1647 drug interactions  603, e1401f, e1405 absorption  603 metabolism  603 protein binding  603 for epilepsy associated with brain tumors  593 for focal cortical dysplasia  583 forced normalization in  e1474 gastrointestinal effects of  e1410 for genetic generalized epilepsies  581 gingival hyperplasia in  e1410 idiosyncratic reactions of laboratory tests for  608 managing  610 increased seizures in  e1410 mechanism of action of  e1221–e1223, e1222f–e1223f, e1405–e1406, e1406t mechanisms of  511

Antiseizure drugs (Continued) metabolism and elimination  e1397– e1398, e1397f, e1398t monitoring  605–608, e1407–e1409, e1408b adverse effects  606–607 clinical efficacy  605–606, 607f drug concentrations  607–608 mood disorders in  e1474 “optimal therapeutic ranges”  607 pharmacodynamics of  600, e1404, e1404t dose-response or concentration-response concept  600 tolerance  600 pharmacokinetic principles of  600, 603f, e1391–e1398, e1392t–1395t physiologic factors affecting  600–603 general considerations  600–603 infants and children  603 neonates  603 physiologic factors in  e1404–e1405, e1404t protein binding in  e1396–e1397, e1396f psychosis in  e1474 psychotropic effects of  e1474 in renal failure  1225–1226, e2766–e2768 barbiturates  e2767 benzodiazepines  e2768 carbamazepine  e2767 ethosuximide  e2767 gabapentin  e2767–e2768 lamotrigine  e2767 levetiracetam  e2767 oxcarbazepine  e2767 phenytoin  e2766–e2767 valproate  e2767 zonisamide  e2767 routes of administration of  604t–605t, 605, e1406–e1407 sedating effects  638 testing of  e1221 volume of distribution in  e1395–e1396, e1396t Antisense oligonucleotides (ASOs)  1063 for SMA  e2368–e2369, e2369f Antispasticity medications, oral  e2835t Antithrombotic therapies, for arterial ischemic stroke  855–856 Antitubercular drugs causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b Antitumor therapy, for opsoclonus myoclonus syndrome  940–941, e2154 Antiviral agents  e2694–e2695 sensorium changes  e2682b toxicity  1196b Antoni A fibers  1010–1011 Antoni B fibers  1010–1011 Anus anatomy of  1189–1190 functional anatomy of  e2672, e2673f Anxiety  1233, e2789 and selective serotonin reuptake inhibitors  491–492 tic disorders and  742 Tourette syndrome and  e1666 Anxiety disorders, and developmental language disorders  435 Anxiolytics  e1173–e1175 sensorium changes  e2682b toxicity  1196b Apert syndrome  233 Apgar scoring  e40t

Aphasia, cortical localization of  e1025t Apicomplexa  e2080t Apicomplexan infections, of central nervous system  e2086–e2093 babesiosis  e2092–e2093, e2093f malaria  e2088–e2092 toxoplasmosis  e2087–e2088, e2087f Aplasia cutis congenita (ACC)  238, e577–e578, e578f Apnea testing  834 for brain death  e1905–e1907, e1906t, e1907b in newborns  e1914 for newborns  837 technique for performing  834 Apneic threshold  834 Apoptosis  804, e331, e1769 abusive head trauma and  794 defects in  e2566–e2567 posttraumatic  781 triggering of  805–806 Apparent diffusion coefficient (ADC)  97–98, e257 maps  82 Apparent life-threatening event  683–684, e1545–e1553 definition of  683, e1545 diagnostic testing for  685, e1547 differential diagnosis of  683–684, 684b, e1545–e1546, e1546b epidemiology of  683, e1545 etiology of  683–684, 684b, e1545–e1546 evaluation of  684–685, e1546–e1547, e1546b history of  684, 684b home monitoring of  685, e1547 inpatient versus outpatient management of  685, e1547 physical examination for  684 risk factors for  683, e1545 risk of death in  685 risk of SIDS in  685 Appetite regulation disorders of  1170–1171, 1170f hypothalamic disorders of  e2635–e2636, e2635f Appetite suppression, due to stimulants  453 Approaches to personalized medicine  1244– 1247, e2821–e2828 disease stratification  1245 future prospects  1246–1247, e2826–e2827 genome sequencing  1246, e2826–e2827 genomic diagnosis  1244, 1245t, e2821–e2823 genetic and genomic variants and disease  e2822–e2823, e2822t genetic contribution to disease  e2821–e2822 newborn screening  1245–1246, e2825 patient engagement and  1246–1247, e2827 pharmacogenetics  1245, 1246t, e2824–e2825 prevention of disease  1245–1246, e2825–e2826 risk assessment  1246, e2825–e2826 targeted treatment  1244–1245, e2823–e2824 therapeutics  1244–1245, e2823–e2825 Aprataxin (APTX)  694–695 Apraxia cortical localization of  e1025t oculomotor  692

Index Aquaporin-1 (AQ1)  e2739 Aquaporin 2 (AQP-2)  1171 Aquaporin-4 (AQ4)  e2739 altered water transport through  301 Aquaporin-9 (AQ9)  e2739 Aquaporins, in urea cycle disorders  301 Aquinas, Thomas  1264 AR dHMN-J  e2401 AR dHMN type III  e2400 AR dHMN type IV  e2400 AR dHMN VI  e2400 Arachnoid cysts  180–181, 226–232, e422–e424, e551–e566 clinical characteristics of  e562–e563 posterior fossa  e563 sellar region  e563 sylvian fissure/middle cranial fossa  e562–e563 complications of  e563 epilepsy  e563 neuropsychiatric disorders  e563 subdural hematoma and hygroma  e563 definition of  e562, e562f, e562t intracranial  e562–e563 management of  e563 posterior fossa  253 spinal  825, e1883 Arbaclofen  480 Archicerebellum  e1555 Arcuate nucleus  1170f Arenaviruses  896b, 904, e2053–e2054 Arginase 1  298 Argininemia  300, 424, 482t–486t, e713 Argininosuccinic aciduria  300, 482t–486t, e713 ARHGEF6 gene mutation  421t “Arhinencephaly”  e449 Aripiprazole  494–495, e1184t, e1187–e1188 for ASD  466, 467t–468t for tic disorders  745t Arnold-Chiari malformation, prenatal diagnosis  253 Aromatic L-amino acid decarboxylase (AADC)  1181–1182, e879–e880, e879f deficiency  1181–1182 Aromatic L-amino acid decarboxylase deficiency (ALAD)  357–358, 357f, 482t–486t, 712, e2655 Arousal  767 confusional  668 disorders of, from NREM sleep  667–669 Arousal patterns  91, e225 Array comparative genomic hybridization (aCGH), for progressive encephalopathies  428 Arrhythmia, cardiac, periodic paralysis with  e2610–e2612, e2611f ARSA gene, metachromatic leukodystrophy and  753 Arsenic  e2689 poisoning  1197–1198 renal toxicity of  1225t, e2765t Artemisia annua  e2091 Artemisinin  e2091 for malaria  912 Arterial baroreflex  1174, 1175f, e2644 Arterial circulation  848 in arterial ischemic stroke  e1931, e1932f–e1935f circle of Willis  848 middle cerebral artery  848 vertebrobasilar system  848 Arterial dissection  852 cervicocephalic  873–874, 873t traumatic  785–786

1315

Arterial infarctions  130–131 Arterial ischemic stroke (AIS)  848–857, 1210, e1931–e1952 burden of  848, e1931 in CHD  e2719–e2720 clinical features and diagnostic delays of  854, e1941–e1943, e1942t coagulation disorders in  877–880, e1997–e2002, e1999f, e2000t acquired thrombophilia  877–879, e1997–e2001 genetic thrombophilia  879–880, e2001 sickle cell disease  880, e2001–e2002 economic and social burden of  e1931 emotional, behavioral and socialization problems after  e1947 epidemiology of  848, e1931 incidence of  e1931 mortality in  848, e1931 neuroimaging for  854, e1943 angiography  854 computed tomography  854 MRI  854 outcomes and chronic management  856– 857, e1946–e1947 sequelae  856, e1946–e1947 stroke recurrence  857, e1947 pathophysiology of  848–849, e1931–e1933 arterial circulation  848, e1931, e1932f–e1935f infarction, mechanisms of  849, e1933 thromboembolism, mechanisms of  848, e1931–e1933 psychosocial and social support for  e1947 risk factors for  849–854, 850t, e1933– e1941, e1936t arteriopathies  849–852, e1934–e1939 cardiac  852–853, 853f, e1939, e1940f infection  849, e1934 prothrombotic and hematological disorders  853, e1940–e1941 sickle cell disease  853–854, e1941 treatment of  854–856, e1943–e1946 antiplatelet therapy  856 antithrombotic therapies  855–856, e1944–e1945 malignant cerebral edema  856, e1945–e1946 stroke unit care and neuroprotection  855, e1943–e1944 thrombectomy  855 thrombolysis  855, e1944 Arterial presumed perinatal stroke  151, 151f, e346, e346f Arterial spin labeling (ASL)  83, e188–e189 Arteriopathies  849–852 arterial ischemic stroke and  e1934–e1939 congenital or genetic  e1939 focal or transient cerebral  e1934–e1935, e1934f primary angiitis of central nervous system with cerebral  e1935, e1937f cerebral. see Cerebral arteriopathies congenital  852 dissection. see Arterial dissection focal cerebral  849–850 genetic  852 moyamoya. see Moyamoya disease primary angiitis of central nervous system and other conditions associated with  851–852 of sickle cell disease  e1989 transient cerebral  849–850, 849f

1316

Index

Arteriovenous fistulas  866–868 in intracranial hemorrhage  e1973–e1975 associated conditions and genetic syndromes of  e1973–e1974, e1979b epidemiology of  e1973 evaluation of  e1974 outcome of  e1975 pathogenesis of  e1973 presentation of  e1974 treatment of  e1974–e1975 Arteriovenous malformations  866, 867f in intracranial hemorrhage  e1970–e1973 associated conditions and genetic syndromes in  e1971, e1971t epidemiology of  e1970–e1971 evaluation of  e1971, e1972f outcome of  e1973 treatment of  e1972–e1973 Arthralgias  1142 Arthrinium mycotoxin  1198b Parkinsonism and  e2684b Arthrogryposis  1054, 1065 motor neuron disease with  1066t–1068t, 1069, e2381 Arthrogryposis multiplex congenita  1059 Articulation disorders  433–434, e1054–e1055 ARX gene mutations  421t, 515, e1282 and infantile onset epilepsies  558t–560t and Ohtahara syndrome  554 Arylsulfatase deficiency  327 ASA. see Acetylsalicylic acid (ASA) Ascending reticular-activating system  770 ASCL1 gene, mutation in  1182 Ascorbic acid  e928 ASDs. see Autistic spectrum disorders (ASDs) Aseptic meningitis  892, 896, e2023, e2023t ASIA/IMSOP Spinal Cord Impairment Scale  821, 821b, e1876–e1877, e1876b Asialotransferrin  318 L-Asparaginase in CNS leukemia  1017 toxicity  1202 Asparagine synthetase deficiency  176, e418 Aspartate aminotransferase (AST), in DMD  1108 Aspartylglucosaminuria  482t–486t Aspartylglycosaminuria  330, e772t–e773t, e809–e810 Asperger syndrome nonverbal learning disabilities and  e1063–e1064 nonverbal learning disorders  437 neuroimaging findings in  439–440, 439t Aspergillosis  908–909, e2069–e2070, e2069f Aspergillus spp.  908–909, e2066t Asphyxia birth, cerebral palsy and  735–736 classic features of  799 Aspiration, for craniopharyngioma  e2267, e2268f Aspirin  856 for pain management  1257, 1257t, e2848–e2849 and Reye’s syndrome  e2797 ASS1 deficiency  e712 Assistive devices, for hearing impairment  50, e110 Astrocytes  508 astrocytic glutamate transporters, downregulation of  301 cerebral blood flow and  814 in hyperammonemic encephalopathy  301

Astrocytoma  1013t low-grade  1015–1016, 1015f pilocytic  362 Turcot’s syndrome and  e2790 Asymmetric tonic neck reflex (ATNR)  17, e35–e36 Asynergia  689 AT/RT. see Atypical teratoid/rhabdoid tumor (AT/RT) Ataluren, for fatty acid oxidation disorders  e2563 Ataxia  689, e1556, e1597 acute cerebellar. see Acute cerebellar ataxia acute onset of  31, e63 autosomal dominant inherited  695–698, 696t–697t, e1561t–e1562t, e1570 autosomal recessive inherited syndromes in  690 autosomal recessive spastic, of CharlevoixSaguenay  692, 693t cerebellar  896–897 channelopathies and  e978t, e982–e983 childhood-onset  e1570 early onset, with ocular motor apraxia and hypoalbuminemia  694–695 episodic  409, 698, 698t–699t familial episodic  e122 vertigo and  56 hereditary  690–699, 690t hereditary spastic  699, 699t IEMS and  282 lysosomal storage diseases and  e782 management of  699 metabolic disorders and  e665 nonhereditary causes of  690, 691b, e1557, e1558b optic  703 progressive encephalopathy and  e1037t–e1040t sensory  703 spinocerebellar  695–698 toxic causes of  1199b with vitamin E deficiency  e1565 Ataxia-oculomotor apraxia type 1 (AOA-1)  e1602 type 2 (AOA-2)  e1602 Ataxia-oculomotor apraxia 3  e1567 Ataxia-telangiectasia  692–694, 694f, e1565–e1567, e1602 clinical manifestations of  e1565–e1566, e1566f genetics of  e1566 laboratory findings of  e1566 pathology of  e1566 treatment of  e1567 Ataxia telangiectasia (ATM) gene  e1566 Ataxia-telangiectasia-like disorder 1  694, e1567 Ataxia-telangiectasia-like disorder 2  e1567 Ataxic cerebral palsy  e1656 Ataxin-1  e1571 Ataxin-2  e1571 Ataxin-3  e1572 Ataxin-7  e1573 Ataxin-8  e1573 Ataxin-10  e1574 Atenolol  e2755b Athabascan brainstem dysgenesis syndrome (ABDS)  207 Athetosis  707t, e1597–e1598 cerebral palsy and  e1655 Atlanto-axial instability (AAI)  474, e1130

Atomoxetine  489, e1160t–e1161t, e1163–e1164 for ADHD  454, 455t–457t, 732, e1086, e1087t–e1089t for ASD  467t–468t, 468 toxicity  1201 Atonic seizures  529, e1257–e1258 electroencephalographic findings in  529 and Lennox-Gastaut syndrome  571, e1340, e1341f ATP7A gene, mutation in  1182 ATP13A2 mutations  402, e951t–e952t, e967 ATPase 6 mutation  e2561 ATPases  1131 Atrial septal defects (ASD)  852 Atrophy of basal ganglia and cerebellum, hypomyelination with  e1688–e1689 cerebellar  203 Atropine abuse in  e2693–e2694 for breath-holding spells  e1508–e1509 for pallid breath-holding spells  658–659 Attention, nonverbal learning disabilities and  438–439 Attention deficit. see Attention deficit hyperactivity disorder (ADHD) Attention deficit hyperactivity disorder (ADHD)  97, 102t, 103, 150, 447–458, 1232, 1271, e266–e271, e267f, e1076–e1093, e2788–e2789 celiac disease and  e2783 in childhood epilepsy  636 coexisting conditions with  449, 451, e1078, e1082–e1083 and developmental language disorders  436 diagnosis of  e1076–e1078, e1077b–e1078b, e1083 and controversies in  447–449 stepped approach to  447, 449b diagnostic criteria for  447, 448b diagnostic evaluation of  452 electroencephalography in  452 imaging studies in  452 laboratory studies in  452 sleep studies in  452 functional imaging  450 genetic studies for  450–451 neurobiology of  449–451, e1078–e1082 clinical neurophysiology  e1080–e1081 functional imaging  e1080 genetic studies  e1081–e1082 potential causes of  e1082 structural imaging  e1079–e1080 nonstimulant medications for  489–491 and nonverbal learning disorders  438 nutritional factors in  451 outcome of  457, e1087–e1089 overdiagnosis of  447 potential causes of  451 seizures in, treatment of  476 stimulants for  489, 490t structural imaging  450 tic disorders and  742 Tourette syndrome and  e1665–e1666 transitional care and  e2872–e2873 treatment for  452–457, e1083–e1087 biofeedback programs  452–453, e1083–e1084 dexmethylphenidate  454, e1085–e1086 dextroamphetamine  454, e1086 drug-induced movement disorders associated with  732–733, e1646

Attention deficit hyperactivity disorder (ADHD) (Continued) methylphenidate  453, e1085 nonpharmacologic therapies  452, e1083 noradrenergic potentiation  454–457, e1086–e1087 pharmacologic therapy  453, 455t–457t, e1084, e1087t–e1089t sleep  452, e1083 stimulant medications  453, e1084–e1085 Atypical absence seizures, and LennoxGastaut syndrome  571, e1339–e1340 Atypical antipsychotics  e1184–e1189, e1184t aripiprazole  e1187–e1188 clozapine  e1188–e1189 olanzapine  e1186 risperidone  e1185–e1186 ziprasidone  e1187 Atypical cerebral palsy, inborn errors of metabolism and  e1153–e1154 Atypical hemolytic-uremic syndrome (aHUS)  1222, e2757–e2758 Atypical teratoid/rhabdoid tumor (AT/ RT)  958t, 960t, 995–999, e2251–e2256 chemotherapy for  998, e2254–e2255 clinical presentation of  995–996, e2251–e2252, e2252f–e2253f future directions for treatment of  999, e2255 genetics of  996–997, e2253–e2254 histopathology of  996, 996f–997f, e2252, e2253f historical background of  995, e2251 imaging  995–996, 996f incidence of  995, e2251 radiation for  998, e2255 radiographic findings of  e2251–e2252, e2252f–e2253f staging of  997–998, e2254 therapeutic interventions for  997–998, e2254 therapy for, toxicity of  998–999, e2255 Audiometry, objective  45, 45f Auditory-evoked potentials (AEPs)  45, 810, e97–e99, e98f, e243–e244, e244f coma and  777 hypoxic-ischemic encephalopathy and  e1849 Auditory function, evaluation of  44–45, e95–e99 behavioral methods  e95–e97 cross-check principle  e95 imaging for  e99 objective methods  e97–e99 supra-threshold testing  e96–e97 Auditory impairment  e2801–e2802 Auditory nerve  10, e16 Auditory neuropathy spectrum disorder (ANSD)  43, 46, e94, e100 Auditory scene analysis (ASA)  43, e89 Auditory steady-state evoked potentials (ASSEPs)  e98 Auditory system, anatomy and physiology of  43, e89–e94, e91f Auditory thresholds  e95–e96, e96f Auras in focal seizures  533 of generalized tonic-clonic seizures  524 Aurora B  993 Aurora kinase B, in diffuse intrinsic pontine glioma  e2244–e2245 Austin disease  e797–e798 Australian whispering dysphonia  e1606

Index Authoritative narrative content  e2913–e2914 Autism association of agenesis of corpus callosum with  196 in childhood epilepsy  636 mumps, measles and rubella (MMR) vaccine and  e2128 Autism Diagnostic Interview-revised (ADI-R)  242–243, e1104–e1105 Autism Diagnostic Observation Schedule (ADOS)  242–243 Autism Diagnostic Observation Schedule™second edition (ADOS-2)  e1104–e1105 Autistic spectrum disorders, childhood epilepsy and  636 Autistic spectrum disorders (ASDs)  97, 413, 459–471, 1232, e264–265, e266f, e1094–e1126, e2788 animal models  462, e1099–e1100 awareness of  460–461 clinical features of  459–460, e1094–e1097 onset patterns  e1096–e1097, e1097t persistent deficits in social communication and social interaction  459, e1094–e1096 restricted, repetitive patterns of behavior, interests, or activities  459, e1096 clinical testing for  465, e1107–e1108 definitive evaluation of hearing in  465 electroencephalography  465, e1107 hearing and vision  e1107 lead levels  465, e1107 metabolic  465, e1108 neuroimaging studies  465, e1107–e1108 tests of unproven value  465, e1108 coexistent medical conditions  465–466, e1108 epilepsy in  465–466 gastrointestinal problems in  465 sleep disturbances in  465 developmental encephalopathies and  242–243, e587–e588 diagnostic instruments for  463 educational and behavioral interventions in  469–470, e1113–e1115 epidemiology of  460–462, e1097–e1102 autoimmune factors  461, e1098–e1099 neonatal intensive care and prematurity  461, e1098 parental age and other factors in  461 parental age and socioeconomic factors  e1098 sibling studies  461, e1098 genetics of  462, e1101–e1102 neuroimaging for  462, e1101 neurologic evaluation in  464–465, e1106–e1108 large head size and somatic overgrowth in  465 motor disturbances in tone, gait, praxis, and stereotypies  465 neuropathology of  462, e1100 neurotransmitters and  462, e1100–e1101 new diagnosis of recommendations for child with  463–464 speaking with parents about  463 nonverbal learning disabilities/disorders and  437, e1063–e1064, e1063t neuroimaging findings in  439–440, 439t onset patterns in  459–460, 461t

1317

Autistic spectrum disorders (ASDs) (Continued) pharmacologic therapy for  466–469, 467t–468t, e1108–e1112, e1109t–e1110t antiepileptic drugs  468, e1112 cholinesterase inhibitors  468, e1112 complementary and alternative medicine  469, e1112–e1113 medications to treat hyperactivity in  468 neuroleptic agents  466, e1110–e1111 opiate antagonists  466, e1111 serotonin reuptake inhibitors  466–468, e1111 stimulants  e1111–e1112 red flags for  463, 463b resources for families and practitioners  470, e1115–e1116 screening and diagnostic evaluation for  462–464, e1102–e1106, e1104f screening instruments for  463, 464f treatment of  e1145 vaccines and  461–462, e1099 Autoantibodies  932, e2140 associations with epilepsy  933, e2141– e2142, e2142t methodology of  932, e2140 in OMS  940 for opsoclonus myoclonus syndrome  e2153 pathogenic mechanisms of  932–933, e2140–e2141 Autoimmune autonomic disorders  1178–1179 Autoimmune autonomic ganglionopathy  1179, e2652 Autoimmune disorders  932, e2140 autistic spectrum disorders  e1098–e1099 chorea associated  709 Tourette syndrome  743 Autoimmune encephalitides  931 Autoimmune encephalitis  548 clinical and investigative features of, in patients with seizures  935b identification of  933–934 movement disorders associated with  934– 935, 936t syndromes  933 Autoimmune encephalitis syndromes in immune-mediated epilepsy  e2141 movement disorders and  e2143–e2145, e2144t Autoimmune epilepsy  e2142–e2143, e2143b Autoimmune lymphoproliferative syndrome  948, e2166 Autoimmune movement disorders  934–936, 936t, e2143–e2145 autoimmune encephalitis  934–935, 936t PANDAS  935–936 PANS  935–936 Sydenham chorea  935 Tourette syndrome  935–936 Autoimmune myasthenia gravis  1098, e2452–e2467 categories of  e2454–e2455, e2455f clinical and laboratory tests in  e2455–e2467 antibody testing  e2458–e2460 edrophonium (tensilon) test  e2455–e2457 electrophysiologic testing  e2457–e2458 clinical classification of  e2454, e2454b clinical features of  e2453–e2454 neurologic examination of  e2455, e2456t treatment of  e2460, e2461f

1318

Index

Autoimmunity, systemic, in neuromyelitis optica  765 Automated guidelines and protocols  1297 Automated otoacoustic emissions (aOAEs)  e97 Automated search, advantage of  1297 Automaticity, lack of  445 dyslexia and  e1072 Automatisms in absence seizures  526 in focal seizures  533 Autonomic disorders  1175–1183 abnormal gastrointestinal motility in  1174–1175 autoimmune  1178–1179 classifications of  1176t diagnosis of  1174–1175 functional  1176–1178 genetic  1179–1183 genitourinary symptoms in  1175 history taking in  1174–1175 metabolic  1178 ocular symptoms in  1175 orthostatic intolerance in  1174–1175 orthostatic tachycardia, orthostatic intolerance with  1174 respiratory symptoms in  1175 syncope in  1174 thermoregulatory abnormalities in  1175 Autonomic dysfunction  1173–1183 genetic disorders with  1182–1183 secondary to focal disease  1178 Autonomic dysreflexia  827, 1178, e1890 Autonomic nervous system (ANS) anatomy of  1173–1174, 1174f, e2642–e2645 afferent autonomic pathways in  e2644 central nervous system integration and  e2644–e2645, e2644f efferent autonomic pathways in  e2642– e2643, e2643f disorders of  e2642–e2659. see also Autonomic disorders autoimmune  e2651–e2652 clinical examination and autonomic testing for  e2646–e2648 clinical history taking in  e2645–e2646 diagnosis of, clinical approach to  e2645–e2648 functional, unknown origin  e2648–e2657 genetic  e2652–e2657 pediatric  e2648, e2649t secondary to focal disease  e2651 dysfunction in cyanotic breath-holding spells  657 in pallid breath-holding spells  658 embryologic development of  e2642 physiology of  1173–1174, e2642–e2645 Autonomic neuropathy, acute  e2652 Autonomic pathways afferent  e2644 efferent  e2642–e2643, e2643f efferent neurotransmission in  e2643 parasympathetic  e2643 sympathetic  e2642–e2643 Autonomy, as precepts of natural law  1264 Autophagosomes, in Pompe disease  309–310 Autophagy  e1844 hypoxic-ischemic encephalopathy and  808

Autoregulation of cerebrovascular system  e1925–e1926, e1926f intracranial hypertension and  e1859, e1860f, e1863 Autosomal-dominant axonal neuropathies (CMT2)  1076–1080, e2398–e2405 Autosomal-dominant demyelinating neuropathies (CMT1)  1074–1076, e2396–e2397 Autosomal-dominant dopa-responsive dystonia  357, e878–e879 Autosomal-dominant focal epilepsy with auditory features (ADFEAF)  517, e1234 Autosomal dominant inheritance  278t Autosomal dominant KUFS  398–399, e962–e963 Autosomal-dominant lateral temporal lobe epilepsy (ADLTE)  e1234 Autosomal-dominant limb-girdle muscular dystrophies  e2494–e2496 with cardiac involvement  e2494 caveolinopathy  e2494 laminopathy  e2495 without cardiac involvement  e2494 Autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE)  408, 517, 579–580, e981, e1234 in electroclinical syndromes  e1359 Autosomal dominant nonsyndromic hearing loss (ADNSHL)  46 Autosomal-dominant partial epilepsy with auditory features (ADPEAF)  579, e1357–e1358 Autosomal dominant progressive external ophthalmoplegia  695 mutations in  343 Autosomal-recessive dopa-responsive dystonia  358, e880–e881 Autosomal recessive GPI-anchor deficiency  e752t–e760t Autosomal-recessive guanosine triphosphate cyclohydrolase deficiency  357 Autosomal recessive inheritance nonsyndromic hearing loss (ARNSHL)  e101–e102 Autosomal recessive KUFS disease  402, e967 Autosomal-recessive limb-girdle muscular dystrophies  e2484–e2490 Autosomal-recessive neuropathies (CMT4)  1077, e2399 Autosomal recessive nonsyndromic hearing loss (ARNSHL)  46 Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)  692 Autosomal-recessive thiamine pyrophosphokinase deficiency  373–374 Autosomes  257, 268 Average scaled scores, of neuropsychological testing  66, e141 AVP/NPII gene mutation  1171, e2637 Awareness  767 Axial compression, spinal cord injury and  820 Axillary freckling  e889f Axonal disconnection  781 Axonal regeneration  1249 Axons  1173 Azathioprine  e2825t for CIDP  e2437 for juvenile myasthenia gravis  e2463 for Lambert-Eaton myasthenic syndrome  1104 for multiple sclerosis  764

Azathioprine (Continued) for myasthenia gravis  1102 for neuromyelitis optica  765 pharmacogenetics  1246t

B

B-mode scanning  e163 B vitamins  1218 B4GALT1-CDG (IId)  e752t–e760t, e764 Babesiosis  e2092–e2093, e2093f Baclofen  e2835, e2835t abuse in  e2691 in ataxia  e2685b dysautonomia  e2832 for dystonia  712, e1611 sensorium changes  e2682b for spasticity  472, 1251t intrathecal  473 spinal cord injury and  828 for tic disorders  745t toxicity  1196b, 1199b, 1200 Bacteremia  883 Bacterial infections  883–894, e2008–e2030 aseptic meningitis in  e2023 Bartonella  892, e2023–e2024 brain abscess and  893–894, e2025–e2027 central nervous system abscess  e2025–e2027 epidural abscesses  e2027 inflammatory myopathies and  1146, e2592 leprosy. see Leprosy meningitis. see Aseptic meningitis; Bacterial meningitis Mycoplasma pneumoniae  892, e2024 spinal epidural abscess and  894 Bacterial meningitis acute  883–889, e2008–e2019 cerebrospinal fluid analysis for  884–885 chemoprophylaxis for  889 clinical manifestations of  883–884, 884b complications of  885–886 brain abscess  886 deafness and cranial nerve damage  886 extraaxial fluid collections  886 hydrocephalus  886 neuronal damage  886 pathophysiologic changes  885–886 seizures  886 septic shock and disseminated intravascular coagulation  886 diagnostic evaluation of  884–885 epidemiology of  883 immunization for  889 infection of implantable devices and  884 laboratory testing for  884–885 lumbar puncture for  884 neonatal  884 neuroimaging for  885 pathogenesis of  883 pathology of  886 prevention of  889 prognosis of  888–889 recurrent  889, e2019 chronic (subacute)  889–892, e2019–e2022 leptospirosis  891–892, e2022 Lyme disease  891, e2022

Bacterial meningitis (Continued) syphilis  890, e2021–e2022 tuberculous meningitis  890, e2020–e2021 clinical manifestations of  e2009–e2011, e2009b clinical prediction models for  e2012–e2013 complications of  e2013–e2015 brain abscess as  e2015 deafness and cranial nerve damage as  e2014 extraaxial fluid collections as  e2015 hydrocephalus as  e2014 neuronal damage as  e2014 pathophysiologic changes as  e2013–e2014 seizures as  e2014 septic shock and disseminated intravascular coagulation as  e2015 diagnostic evaluation of  e2011–e2013 cerebrospinal fluid analysis in  e2011– e2012, e2012t laboratory testing in  e2012 neuroimaging in  e2012, e2013f epidemiology of  e2008 pathogenesis of  e2008–e2009 pathology of  e2015, e2015f prevention of  e2018–e2019 prognosis of  e2018 recurrent  e2018–e2019 stroke and  e341 treatment of  886–888, e2015–e2018 antibiotics  887–888, e2016–e2017, e2017t antiinflammatory therapy  888, e2017–e2018 fluid therapy  888, e2018 general care  886–887 Balamuthia mandrillaris  910–911, e2083–e2085 Balance, physiologic basis of  52, 53f, e116, e117f see also Vertigo Balanced translocation  e614t Ballism  707t, 709, e1603 Ballismus  e1598 Banded chromosomal analysis, in genetic diagnosis  1245t Bandlike intracranial calcification with simplified gyration and polymicrogyria  756, e1699 Baneberry  1196b, e2682b Bannayan-Riley-Ruvalcaba syndrome  216 Baraitser-Winter syndrome (BWS)  e519 Barbiturates  511, 1200 abuse in  e2691 for antiseizure drug therapy in children  e1398 for febrile seizures  e1244 intracranial pressure and  789 in renal failure  1226, e2767 for sedation  1258 sensorium changes  e2682b toxicity  1196b for traumatic brain injury  e1787 Bardet-Biedl syndrome, with kidney malformation  1224t, e2764t Barium myopathies and  e2683b toxicity  1197b Baroreceptors  1171 Baroreflex failure, acquired afferent  e2651 Barry Albright Dystonia Scale  472

Index Barth syndrome  282, 341, e848 peripheral hypotonia and  1055t–1056t Barthel Index  778, 779t, e1754, e1755t Bartonella spp.  892 B. henselae  e2023 in bacterial infections, of nervous system  e2023–e2024 Basal foramina, anomalies of  e582 Basal ganglia atrophy of, hypomyelination with  750 in movement disorders  e1594–e1596, e1595f–e1597f Basal ganglia encephalitis  935, e2143, e2144f Basilar impression  240–241, e582–e583 Bathrocephaly  241, e583 “Batten disease”  390 “Battle sign”  782, 787 Battle v Pennsylvania  1284, 1284t, e2894 Battle’s sign  799 Bayley Infant Neurodevelopmental Screener  e1001t–e1004t Bayley Infant Scales of Development III (BSID III)  68t–69t, e143t–e146t Bayley Scales of Infant and Toddler Development (Bayley-III, 3rd edition)  1292, e2905 Bayley Scales of Infant Development  e1001t–e1004t Baylisascaris procyonis  913, e2098, e2098f BDNF gene, mutation in  1182 Beare-Stevenson cutis gyrata syndrome  235 “Beaten copper” appearance, of skull  e570f–e571f Becker muscular dystrophy (BMD)  1106– 1111, e2472–e2482, e2621 clinical features of  1107–1108, e2475 dystrophin protein in  e2472 dystrophinopathy therapeutics for  e2478– e2479, e2478f genotype-phenotype correlations in  1109, e2476–e2477 laboratory features of  1108–1109, e2475–e2476 management of  1109–1110, e2477–e2478 medical  e2477–e2478 nonmedical  e2478 muscle biopsy in  1109, e2477 “reading frame rule” in  e2472–e2473, e2473f–e2474f serum CK levels found in  1039t see also Duchenne muscular dystrophy (DMD) Becker’s disease  1150–1151, 1151t see also Myotonia congenita Beckwith/Wiedemann syndrome, with kidney malformation  1224t, e2764t Bed-sharing, sudden infant death syndrome and  687 Bedding accessories, sudden infant death syndrome and  687 Bedwetting. see Nocturnal enuresis Behavior, neurodevelopmental disorders and  476–477, e1133–e1135 assessment of  476 management of, general principles of  476 psychopharmacology  476–477 Behavior Assessment System for Children  e143t–e146t Behavior Assessment System for Children-2  68t–69t Behavior Rating Inventory of Executive Functioning  68t–69t, e143t–e146t Behavior rating scales, of neuropsychological measure  68t–69t

1319

Behavioral assessment screening tools, in children  e993t Behavioral assessment system for children, second edition  4, e5 Behavioral disorders in cerebral palsy  740 posttrauma  791 Behavioral disturbances in acquired brain injury  1253 posttraumatic  796 Behavioral methods, for evaluation of auditory function  44–45, e95–e97 Behavioral problems in benign epilepsy with centrotemporal spikes  572 in childhood epilepsy  637, 640 Behavioral screening instruments  e9t Behçet’s disease  947t, 955, e2182 Behçet’s syndrome  851, 889 Behr syndrome  695 Belladonna  1199b in ataxia  e2685b Bell’s palsy  1081 etiology, influenza virus  919 Benazepril  e2755b Beneficence, as precepts of natural law  1265 Benign childhood epilepsy with centrotemporal spikes  637 Benign epilepsy of infancy  565 differential diagnosis of  565 EEG findings in  565 in electroclinical syndrome, infantile onset  e1325–e1327 etiology of  565 neuroimaging of  565 neurologic findings  565 outcomes for  565 seizures in  565 treatment of  565 Benign epilepsy with centrotemporal spikes  572–573 clinical characteristics  572 EEG findings in  572, 573f etiology of  573 prognosis of  573 treatment for  573 Benign familial infantile epilepsy (BFIE)  514, 565, e1228 differential diagnosis of  565 EEG findings in  565 in electroclinical syndrome, infantile onset  e1325–e1327 etiology of  565 neuroimaging of  565 neurologic findings  565 outcomes for  565 seizures in  565 treatment of  565 Benign familial infantile-neonatal seizures  e981 Benign familial neonatal epilepsy (BFNE)  132, 513, 553–554, e312, e1226 clinical features of  553 diagnosis of  553 differential diagnosis of  553 electroclinical syndrome and  e1309– e1310, e1309t, e1310f etiology of  553 management of  554 prognosis of  553–554 Benign familial neonatal-infantile epilepsy (BFNIE)  514, e1228 Benign familial neonatal seizures  e980

1320

Index

Benign hereditary chorea  e1601–e1602 Benign idiopathic dystonia of infancy  725t, 727, e1639 Benign idiopathic neonatal seizures (BINS)  132, e312 Benign myoclonic epilepsy of infancy (BMEI)  538, e1273 EEG for  538 treatment and outcome for  538 Benign myoclonus of early infancy  724– 725, 725t Benign neonatal seizures, in electroclinical syndrome  e1308, e1309t Benign neonatal sleep myoclonus  724–727, 725t, e1636–e1639 Benign paroxysmal torticollis  725t, 726–727, e1638–e1639 Benign paroxysmal vertigo  703 Benign rolandic epilepsy  572–573, e1342–e1343 clinical characteristics  572 EEG findings in  572, 573f etiology of  573 prognosis of  573 treatment for  573 Benzedrine, attention deficit-hyperactivity disorder and  e1084 Benzene sensorium changes  e2682b toxicity  1196b Benznidazole, for Chagas disease  913 Benzodiazepines  490t, 492, 511, e1159t, e1173–e1174, e1174t, e1203, e2835 abuse in  e2691 for antiseizure drug therapy in children  e1398 for Dravet syndrome  406 for febrile seizures  e1244 for juvenile myoclonic epilepsy  539, e1276 in renal failure  1226, e2768 for sedation  1258 sensorium changes  e2682b for status epilepticus  545–546, e1297–e1300 toxicity  1196b, 1200 Benztropine, associated with Parkinsonism  e2684b Bereavement  1262 Berger, Hans  e1731 Beta activity, of EEG  e220 Beta agonists sensorium changes  e2682b toxicity  1196b Beta blockers associated with myopathies  e2683b associated with paralysis and muscular rigidity  e2684b in myasthenia gravis  1103b sensorium changes  e2682b toxicity  1196b–1198b Beta-ketothiolase deficiency  295, e696 Beta-lactam antibiotics  1202, e2694 Betaine  295 Bethanechol Parkinsonism and  e2684b toxicity  1198b Bethlem myopathy  1121, e2508 serum CK levels found in  1039t BH4, in central nervous system  e875–e877 Bickerstaff brainstem encephalitis (BBE)  1087t Bielschowsky bodies  311 Bifunctional enzyme deficiency  e870

Bilateral peripheral vestibular loss, vertigo and  57, e122 Bilateral perisylvian polymicrogyria (BPP), and megalencephaly capillary malformation syndrome  587 Bilateral striatal necrosis, from SLC25A19 mutations  e920–e921 Bilateral vestibular schwannomas  1010 Bile acids  347 synthesis  347, e860 Bilirubin  1236 Bilirubin encephalopathy  1236 Bilirubin-induced neurologic dysfunction (BIND)  1236 Bilirubin neurotoxicity clinical manifestations of  e2801–e2802 laboratory testing of  e2802 management of  e2802 BIN1 gene, mutations in  1127 Binocular rivalry  e1733 disorders of consciousness and  767–768 Biochemical markers, abusive head trauma and  800 Bioenergetic substrates, utilization of, in exercise  e2537–e2538, e2538b Biofeedback for pediatric migraine  649, 654 programs, for ADHD  452–453, e1083–e1084 Biogenic amine disorders  279t, e659t Biologic therapy for CNS tumors  961, e2197–e2198 gene therapy  961 immunotherapy  961 Biologic toxins  1194–1195, 1195t, 1196b, e2686–e2687 Biomarkers  581 in electroclinical syndromes, adolescent onset of  e1359–e1360 Biopsy, in germinoma  e2260–e2261 Biopterin disorders  287, e677–e678 Biosynthetic defects  131, e311 Biotin  378, e918t–e919t, e929–e930 deficiency  e930 dependency  e930 pathways in metabolism of  293f–294f Biotin- responsive basal ganglia disease  e920 Biotin-dependent holocarboxylase synthetase deficiency  378, e930 Biotin-responsive basal ganglia disease  373, 379, 482t–486t, e930 Biotinidase deficiency  295, 378, 482t–486t, e694–e695, e930, e1704–e1705 and infantile onset epilepsies  560t–562t Bipedal ambulation  e60 Birth asphyxia, cerebral palsy and  735–736 Birth control pill, sinovenous thrombosis and  861f Birth trauma  798 abusive head trauma and  e1825 Birth weight, cerebral palsy and  735 Bismuth sensorium changes  e2682b toxicity  1196b Bismuth subgallate sensorium changes  e2682b toxicity  1196b Bitter taste  e129t, e130–e131 “Black-out spells”  40–41 Black widow spider venom  1198b Black widow spider venom, associated with paralysis and muscular rigidity  e2684b Bladder, flaccid paralysis of  823 Bladder dysfunction, myelomeningocele and  e434

Blake’s pouch cyst  199–202 prenatal diagnosis of  253, e607–e608, e608f Blastomycosis North American  908 South American  908 Blastomycosis dermatitidis  908, e2066t Bleeding disorders, trauma and  e368–e369 Bleomycin, intracystic  1007 for craniopharyngioma  e2267–e2268 Bloch-Sulzberger syndrome  371, e905–e906 Blogs  1295, e2908 Blood-brain barrier of cerebrovascular system  842–843, e1922–e1923, e1923f disruption, bacterial meningitis and  e2013 Blood oxygen level-dependent (BOLD) technique  83 Blood supply, in spinal cord  e1873–e1874 Blunt trauma  e360 “Blurred vision”  e77–e78 BMD. see Becker muscular dystrophy (BMD) Board of Education of the Hendrick Hudson Central School District, Westchester County, et al. v. Rowley  1284–1285, 1284t, e2894 Bobble-head doll syndrome  716, e1618 Body temperature in coma  776 hypothermia and  776 impairment of consciousness and  e1750 “BOLD” effect  83, e188–e189 Bone disease, trauma and  e368 Bone marrow stromal cells (BMSCs), for spinal cord injury  e1888 Bone marrow transplantation, adrenoleukodystrophy and  353 “Bone spicule” pattern, of retinal pigment epithelium  38 Bonnet-Dechaum-Blanc syndrome  371 Bony spine, anatomy of  e1873 Boric acid sensorium changes  e2682b toxicity  1196b Borrelia burgdorferi, in Lyme disease  891 Bosley-Salih-Alorainy syndrome (BSAS)  207 The Boston Circulatory Arrest Trial (BCAT)  1210–1211, e2721 Boston craniosynostosis  235 Botulinum immune globulin (BIG)  1195 Botulinum toxin  1194–1195 arterial ischemic stroke and  856 associated with paralysis and muscular rigidity  e2684b hypertonia and  e1129 for spasticity  1252, e2836, e2836b for tic disorders  745t for Tourette syndrome  e1671 toxin injections, for spasticity  473 type A, for spasticity  472 Botulism  1098, 1104, 1194–1195, e2467, e2686–e2687 foodborne  1104–1105 infantile  1104 wound  1105 Bowel dysfunction, myelomeningocele and  e434 Box jellyfish  1196b Box jellyfish, sensorium changes  e2682b Box thorn  1196b, e2682b Brachial plexus  1081–1082 acquired peripheral neuropathies in  e2412, e2413f neuropraxia  823, e1880

Brachial plexus injury  158, e364–e365, e364t, e365f Brachycephaly  234, e568 Bradykinesia  713–714, e1599 Brain anomalies, structural, prenatal diagnosis of  e597–e612 arterial circulation in  848 coronal section of, representation of  219f development of abnormalities  131–132 basic principles of  e986–e988, e989f development of ionic channels and membrane properties in  509–510 and development of neurotransmitters, receptors, and transporters  510–511 epileptogenesis in  511 excitability mechanisms  129, e308 increased seizure susceptibility of  509–511 normal, prenatal assessment of  e597 nutrition and  e942–e949, e943b, e943t preterm, injury to  161–170, e372–e400 seizures effect on  e308 imaging for  127, 1042 immature  e308 monitoring of  125–127, 126f and seizure management  e303–e305, e304f normal posterior fossa  249–250 prenatal assessment  249 plasticity  e988 prenatal diagnosis of abnormalities of corpus callosum  252 of agenesis of corpus callosum  254 of Arnold-Chiari  253 of brainstem anomalies  254 of Chiari type II  253 of complex cortical malformations  252 of Dandy-Walker malformation  253 of molar tooth-related syndromes  254 of periventricular nodular heterotopia  252 of posterior fossa anomalies  253–254 of ventriculomegaly  250 of vermis hypoplasia/agenesis  253–254 seizure susceptibility of  e1218–e1221, e1218t, e1219f structural maturation of  e1220 and seizure susceptibility  511 symptomatic involvement, in neuromyelitis optica  764 Brain abscess  893–894, e2025–e2027 acute bacterial meningitis and  886 bacterial meningitis and  e2015 clinical manifestations and diagnosis of  893, 893f, e2025–e2026, e2026f complications and outcomes of  e2026–e2027 epidemiology, pathogenesis and pathology of  e2025 epidemiology and pathogenesis of  893 neurosurgical management and antimicrobial therapy for  893–894, e2026 Nocardia spp. and  908 Brain anomalies, structural, prenatal diagnosis of  249–254 Brain biopsy, for progressive encephalopathies  428, e1026–e1027 Brain cancers, transitional care and  e2874–e2875

Index Brain death  769f, 770t, 772, 831–839, e1737t, e1740, e1740f, e1900–e1920 ancillary neurodiagnostic studies of  e1907–e1913, e1908t brain tissue oxygenation in  e1913 comparison of EEG and CBF studies in  e1913, e1913t electroencephalogram in  e1908–e1910, e1909t evoked potentials in  e1913 measurements of cerebral perfusion in  e1910–e1913, e1910t clinical examination of  e1904–e1907 apnea testing in  e1905–e1907, e1906t, e1907b brainstem examination in  e1904– e1905, e1905b, e1905t cerebral unresponsivity in  e1904 in comatose patient  837–838, 838f declaration of  832b diagnosis of  832b ancillary studies  834–836 brain tissue oxygenation  836 electroencephalogram  831, 834–836, 836t evoked potentials  836 measurements of cerebral perfusion  835–836 outcome after  833 discussions with family members and staff  838–839 EEG and  e238 epidemiology of  831–833, e1902–e1904 etiologies of  831–833, e1902, e1902t historical perspective of  831, 832b–833b, e1900–e1902, e1901b, e1903b–e1904b incidence of  831, e1902, e1902f legal definition of  831, e1902 neurologic evaluation of  833–834, e1904–e1907 apnea testing  834 brainstem examination  833–834 cerebral unresponsivity  833 duration of observation periods  834, 837 number of examinations and examiners  833–834 in newborns  836–839, e1914–e1916 ancillary studies  837 clinical examination of  837 epidemiology of  837 organ donation and  839 outcome after diagnosis of  e1902–e1904 Brain disorders brain energy failure  804–806, 805f gray matter  390–404 white matter acute central nervous system  759 relapsing demyelinating disorders  761–765 Brain edema, bacterial meningitis and  e2013 Brain-focused care  123, e299 Brain herniation  775–776, e1747–e1749 historical perspective of  775, e1747 syndromes of  775–776, e1747–e1749 central downward herniation  775 infratentorial (cerebellar) herniation  775–776 intracranial pressure and  817t transtentorial downward herniation  775 uncal herniation  775 Brain inflammation, effect of immunotherapy on  940

1321

Brain injuries  797 brain swelling  797 cerebral infarction. see Infarction, cerebral etiology of, in term newborn  e321 hemispheric swelling  797 hypoxic-ischemic in preterm infant  145–146 in term newborn  138–146, e321–e338 mechanisms of  804–808 autophagy  808 brain energy failure  804–806, 805f calcium-mediated injury  806, 806f excitotoxic injury  806 formation of oxygen radicals  807 genetic damage and regulation  808 intracellular enzymes, activation of  806 neuroinflammation, glia, and neurovascular unit  807–808 nitric oxide synthesis, activation of  806–807, 807f phospholipase release of free fatty acids  806 neonatal, cerebral palsy and  736–737 pattern of  e323f, e324–e325 prevention of, resuscitation and supportive care in  e302 progression of  e325 sinovenous thrombosis and  859–860, e1955, e1956f–e1957f Brain malformations  235 brain imaging recognition for  180–181, 180f, e422–e424, e423f classification of  179–181, 180b–181b, e422–e424, e423b–e424b environmental factors and  181, e424 epidemiology of  179, e422 genetic counseling for  181–182, 182t, e424–e425, e425t neurologic disorders and  181, e424 overview of  179–182, e422–e426 prominent, developmental encephalopathies and  242, e587 Brain perfusion  e324 for encephalopathy  140 Brain-related proteins, for opsoclonus myoclonus syndrome  940, e2153 Brain size disorders  208–217, e484–e509 megalencephaly (macrocephaly)  e493–e504 microcephaly  e484–e493, e485t Brain swelling, abusive head trauma and  797, e1818 Brain Talk  1295 Brain tissue oxygenation  836 Brain tumors. see Tumors Brain volume, in congenital heart defects  e2714–e2716, e2717f Brainstem development, disorders of  199–207, 200t–202t, e466–e483, e467t–e469t disorders affecting  204–207, e478–481 predominantly  207 examination  833–834 leukoencephalopathies and  757–758 in sudden infant death syndrome  e1549 Brainstem anomalies, prenatal diagnosis of  254 Brainstem disconnection (BD)  207, e480–e481 Brainstem dysfunction, in SLE  950, e2170 Brainstem glioma  960t Brainstem implants  e111 for hearing loss  51

1322

Index

Brainstem lesions  e14 ophthalmoplegia in  9 Branched-chain amino acids, pathways in metabolism of  293f–294f Branched-chain keto acid dehydrogenase (BCKAD)  172 Brancher enzyme deficiency  311–312, e736–e737 genes encoding  1132–1133 Branching enzyme deficiency  e2546–e2547 Breath-holding spells  656–659, e1506–e1509 clinical features of  656, e1506 clinical laboratory tests for  656, e1506 genetics of  658, e1508 pathophysiology of  656–658, e1506–e1508 treatment of  658–659, e1508–e1509 Brief infant toddler social emotional assessment  4 Brill-Zinsser disease  e2076 Bromides sensorium changes  e2682b toxicity  1196b Bromocriptine  e2632 sensorium changes  e2682b toxicity  1196b Bromodeoxyuridine (BrdU)  109 Brown-Séquard syndrome  824, e1881 Brown v the Board of Education  1283, 1284t, e2893 Brown-Vialetto-Van Laere (BVVL) disease  1066t–1068t, 1068, e2380–e2381 Brown-Vialetto-Van Laere syndrome  482t–486t Brown-Vialetto-Van-Laere syndrome-1 (BVVLS1)  374 Brudzinski’s sign  883, 896 Brushfield spots  272 Buckeye  1196b, 1199b associated with myoclonus  e2685b in ataxia  e2685b sensorium changes  e2682b Bulbar weakness, predominant, motor neuron diseases with  e2380–e2381 Bumetanide, for ASD  467t–468t, 468 Bunyaviruses  896b, e2049 Bupropion  492, e1171t, e1172 for ADHD  455t–457t Parkinsonism and  e2684b toxicity  1198b Burke-Fahn-Marsden Dystonia Rating Scale  472 Burn toxin, renal toxicity of  1225t, e2765t Buspirone  492, e1174–e1175 for ASD  466, 467t–468t in ataxia  e2685b Parkinsonism and  e2684b toxicity  1198b–1199b Busulfan myoclonus and  e2685b toxicity  1199b Butterbur, for headache prevention  e1501 Butyl alcohol in ataxia  e2685b toxicity  1199b Butyrophenones, for cyclic vomiting syndrome  1229

C

C-kit, in germinoma  1001 13 C MR metabolic imaging, high grade glioma  982

Cabergoline  e2632 CACNA1H, mutations in  517 CACNB4, gene mutations in  578 CADASIL  756, e1699–e1700 Cadmium, renal toxicity of  1225t, e2765t Caenorhabditis elegans  114 Café-au-lait spots  363, 427, e889f Caffeine headache and  650 myopathies and  e2683b toxicity  1197b Cajal bodies  1061 Calcifications bilateral occipital  757 cerebroretinal microangiopathy with  756 intracranial associated with leukoencephalopathy  756 bandlike with simplified gyration and polymicrogyria  756 leukoencephalopathy with  756 Calcifying leukoencephalopathies  755–757, e1698–e1700 Aicardi-Goutières syndrome in  e1698–e1699 bandlike intracranial calcification with simplified gyration and polymicrogyria in  e1699 bilateral occipital calcifications with  e1700 with calcifications and cysts  e1699 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in  e1699–e1700 cerebroretinal microangiopathy with calcifications and cysts in  e1699 Cockayne syndrome in  e1699 cytomegalovirus (CMV) in  e1699 dihydropterine reductase deficiency in  e1700 familial hemophagocytic lymphohistiocytosis in  e1700 27-hydroxylase deficiency  e1700 intracranial calcification associated with  e1700 spondyloenchondrodysplasia in  e1699 Calcinosis  1141 Calcium abnormalities  1215–1216, 1217b, e2740–e2742 in DMD  1106 handling cerebrovascular system and  844, e1924 Calcium ATPase  1131 Calcium carbonate, for gastroesophageal reflux  1161 Calcium channel blocker, indications, Dravet syndrome  406 Calcium channel periodic paralysis  1153t Calcium channels development of  509–510 low-threshold (T-type)  509 neuronal voltage-gated  506 Calcium gluconate, for hyperkalemic periodic paralysis  1154 Calcium-mediated injury  806, 806f Calculators  1297 California Verbal Learning Test-Children’s version  68t–69t, 71, e143t–e146t Caloric testing  e119, e119f for neurological examination, of coma  e1746 Calpainopathy  1114–1115, e2488f, e2491–e2492

Calvariectomy  233, e567 Camphor myoclonus and  e2685b sensorium changes  e2682b toxicity  1196b, 1199b Campylobacter jejuni  e2785 Canada, special education in  1286–1287, e2897 Canadian Charter of Rights and Freedoms  1286–1287 Canadian Occupational Performance Measure (COPM)  e2901 Canavan disease  295, 595, 754–755, e696–e697, e697f, e1382, e1696 in central hypotonia  e2347 peripheral hypotonia and  1055t–1056t Cancer, in disorders of excessive sleepiness  e1534 Cancer-associated retinopathy  930 Candesartan  e2755b Candida spp.  909, e2066t C. albicans  909 Candidiasis  909, 1146, e2070, e2071f Cannabinoids  1200 Cannabis, abuse in  1198, e2689–e2690 CAPN3 gene, mutations in  1114 Captopril  e2755b Parkinsonism and  e2684b toxicity  1198b Caput succedaneum  20, 156, e39, e360 Carbamates for antiseizure drug therapy in children  e1398–e1399 associated with paralysis and muscular rigidity  e2684b insecticides  1195, 1196b sensorium changes  e2682b Carbamazepine  493, 511, 601t–602t, e1176t, e1178–e1179, e1475, e2825t for antiseizure drug therapy in children  e1398–e1399, e1399f behavioral and cognitive effects of  639 for familial hemiplegic migraine  409 mood disorders in  638 myoclonus and  e2685b pharmacogenetics  1246t pharmacokinetics of  604t–605t rectal administration of  606t for renal disease  e2763–e2764, e2767 in renal failure  1226 toxicity  1199b Carbamoyl-phosphate synthase 1 deficiency  298–299, e711 Carbamoyl phosphate synthetase (CPS) deficiency  482t–486t N-Carbamyl-L-glutamate  e718 Carbidopa for afferent baroreflex failure  1178 for hereditary sensory and autonomic neuropathies type 3  1181 indications, tyrosine hydroxylase deficiency  358 sepiapterin reductase deficiency  358 Carbinols sensorium changes  e2682b toxicity  1196b Carbohydrate metabolism diseases associated with primary abnormalities in  305–315, e723–e748 fructose metabolism  306–307, e726–e727

Carbohydrate metabolism (Continued) galactose metabolism  305–306, e723–e726 glycogen storage diseases  e727–e741, e728t disorders of  e660t Carbohydrate stores  1131 Carbon monoxide in ataxia  e2685b causing peripheral neuropathy  e2684b Parkinsonism  e2684b sensorium changes  e2682b toxicity  1196b–1199b Carbon tetrachloride associated with tremor  e2685b in ataxia  e2685b toxicity  1199b–1200b Carbonic anhydrase inhibitors  852 for hyperkalemic periodic paralysis  1154 Carbonic anhydrase VA deficiency  482t–486t Carboplatin-etoposide chemotherapy  1003 Carboplatin toxicity  1202 Card agglutination trypanosomiasis test  913 Cardiac abnormalities, in sudden infant death syndrome  e1548–e1549 Cardiac arrest  804, e1839, e1840t cardiopulmonary resuscitation  805t etiology of  805t delayed postanoxic myoclonic seizures  810 delayed posthypoxic injury  809 hypoxic-ischemic encephalopathy and  e1839, e1845–e1847 major disorders causing  808–809, e1845t abusive head trauma  808, e1845 drowning (submersion injury)  808– 809, e1846 electrical shock  809, e1847 lightning and electrical injuries  809, e1846–e1847 strangulation injury  809, e1846 sudden infant death syndrome  808, e1845–e1846 neurologic complications after  809–810, e1847–e1848 delayed postanoxic myoclonic seizures  810 delayed posthypoxic injury  809 paroxysmal sympathetic hyperactivity  810 postischemic seizures  809–810 neurologic prognosis after  810–811, e1848–e1850 electroencephalography  810 neuroimaging  810–811 somatosensory-and auditory-evoked potentials  810 postcardiac-arrest syndrome  804 sudden, in children and adolescents  809, e1847 ventricular fibrillation and  809 Cardiac arrhythmia, periodic paralysis with  e2610–e2612, e2611f Cardiac mechanism, in proposed mechanisms for sudden unexpected death in epilepsy  e1485 Cardiomegaly, in Pompe disease  310 Cardiomyopathy  427 DMD and  1110, 1161, e2477–e2478 ketogenic diet and  e1456 lysosomal storage diseases and  e782 Cardiopulmonary resuscitation (CPR) cardiac arrest and  805t cardiovascular support and  811

Index Cardiopulmonary resuscitation (CPR) (Continued) drowning and  808 extracorporeal membrane oxygenation and  812 for hypoxic-ischemic encephalopathy  e1852–e1853 Cardiovascular drugs, in myasthenia gravis  1103b Cardiovascular manifestations, mucopolysaccharidoses and  327–328 Cardiovascular-mediated syncope  660, e1512 Cardiovascular support  811 Care, transitional, for children with neurologic disorders  e2871–e2879 Carisbamate, for infantile spasms  e1287 Carnitine, for fatty acid oxidation disorders  1136, e2553–e2554, e2563 Carnitine acylcarnitine translocase deficiency  e2551 Carnitine deficiency  292 Carnitine disorders  279t, e659t Carnitine palmitoyltransferase deficiency type II (CPT II)  1132b, e2350–e2351 peripheral hypotonia and  1055t–1056t Carnitine supplementation, ketogenic diet and  e1455–e1456 Carnitine uptake studies, in fatty acid oxidation disorders  e2555 Carvedilol  e2755b Case-based ethics  1266 Case studies, special education law and  e2897 CASK, mutations in  514 Castor oil, sensorium changes  e2682b Castor oil toxicity  1196b Casuistry  1266, e2862 Cat scratch disease (CSD)  892, e2023 Cataplexy narcolepsy with  674–675 treatment of  675–676, e1533 Cataracts congenital  e73 hypomyelination with  749f, 750, e1685f, e1688 galactokinase deficiency and  306 Catastrophic spinal cord injuries  825–826 Catathrenia  670, e1526 Catecholamine-secreting tumors  1178, e2651 Catecholamines synthesis and catabolism of  e876f urinary, in acute cerebellar ataxia  704 Cathepsin A  330 Catheter angiography (CA) for intracranial hemorrhage  e1974 for sinovenous thrombosis  862 Cathinones (bath salts)  1200 Catholic moral theory  1265 Cat’s eye syndrome, with kidney malformation  1224t, e2764t Cauda equina injuries  825, e1883 Caudal vermal lesions  689 Caveolae  1116 Caveolin  1034, e2307 Caveolin-3  1116 Caveolinopathy  1116, e2489f, e2494 Cavernous malformations, in intracranial hemorrhage  868–869, e1976–e1978, e1977f epidemiology of  e1976–e1977 evaluation of  e1977–e1978 genetic syndromes of  e1971t, e1977 outcome of  e1978

1323

Cavernous malformations, in intracranial hemorrhage (Continued) pathogenesis of  e1976 presentation of  e1977 treatment of  e1978 Cavum septum pellucidum  e462 Cayman type cerebellar ataxia  e1569 CbD-MMA/HC deficiency  377–378 CBF. see Cerebral blood flow (CBF) CbIA-MMA deficiency  378 CbIB-MMA deficiency  378 CbIC deficiency  377–378 CbID-HC deficiency  378 CbID-MMA deficiency  378 CbIE deficiency  378 CbIG deficiency  378 CbIJ deficiency  377–378 CD3 monoclonal antibody, renal transplantation complications and  1220 CDKL5 disorder  244, e589 CDKL5 gene mutations and infantile onset epilepsies  558t–560t and Ohtahara syndrome  554 Cefepime toxicity  1202 Cefotaxime, for acute bacterial meningitis  888 Ceftriaxone for bacterial meningitis  888 for Lyme disease  891 Celiac disease  1231, e2783–e2784 bilateral occipital calcifications with  757 Cell death, neonatal brain injury  145 Cell-surface paradigm  932 Cell therapy, for urea cycle disorders  e719 Cell transplantation, for spinal cord injury  e1887–e1888 Cells, in CSF  76, e156, e156t Cellular electrophysiology  e1210–e1218 development of ionic channels  e1211 excitation-inhibition balance in  e1210 glial mechanisms in  e1216–e1217 ionic channels in  e1211 membrane properties, development of  e1218–e1219 neurotransmitters, receptors, and transporters in  e1219–e1220, e1220f structural correlates in  e1210–e1211 synaptic physiology in  e1212–e1214 synchronizing mechanisms in  e1215–e1216 voltage-dependent membrane conductance in  e1211–e1212 Cellular model systems  119–120, e293– e295, e294f Cellular models, of neurologic disease  114– 122, e286–e298 cell lines and primary neuronal cultures  e293–e295, e294f novel human cell model  e295 Central auditory nervous system (CANS)  43, e89, e93–e94 Central auditory processing disorder (CAPD)  43 Central core disease (CCD)  1123 serum CK levels found in  1039t Central facial nerve palsy  e2409 Central herniation  817t Central hypotonia  1054, 1055t, e2344 common causes of, distinguishing features of  e2345t peripheral and  e2342t specific causes of  e2345–e2348 Canavan disease as  e2347 chromosomal abnormalities as  e2345–e2347

1324

Index

Central hypotonia (Continued) creatine deficiency disorders as  e2347 MeCP2-related disorders as  e2347 N-glycosylation, congenital disorders  e2348 Pelizaeus-Merzbacher disease as  e2347 peroxisomal disorders as  e2347 Smith-Lemli-Opitz syndrome as  e2347 Central nervous system (CNS)  107 abscess  893–894, e2025–e2027 acute, demyelination  759 adverse drug reactions to, of antiseizure  608 BH4 in  355, e875–e877 complications of, myelomeningocele and  e434 diseases/disorders treatment of  937, e2146 vertigo and  57, e122 infections  131, e310 EEG and  e238–e239 leukemia and  1018 in SLE  950 in systemic lupus erythematosus  e2170 integration of  1174, e2644–e2645, e2644f leukemia  1017–1018, e2282–e2283, e2283f motor neuron disease with  e2380 shunt infection  e2010 tumors, posttreatment neurologic sequelae of  1021–1027, e2287–e2298, e2288f vasculitis, cerebral arteriopathies and  874–875 fibromuscular dysplasia  875 primary  874 secondary  874–875 Central or transtentorial downward herniation  775 Central spinal syndrome  824, e1881 Central sulcus  249 Centromeres  259 Centronuclear myopathies (CNMs)  1127– 1128, e2524–e2528 serum CK levels found in  1039t Cephaloceles  e438 Cephalohematoma  20, 156–157, e39, e360–e361 abusive head trauma and  796 Cerebellar agenesis  206, e480 Cerebellar astrocytoma  960t Cerebellar ataxia  896–897 acute  e1585–e1592 causes of  e1585–e1588, e1586b cerebrospinal fluid examination of  e1588 clinical evaluation of  e1585, e1586b computed tomography of  e1588, e1588f electromyography and electroencephalography for  e1588–e1589 investigations in  e1588–e1589 magnetic resonance imaging of  e1588, e1588f toxicology of  e1589 treatment and prognosis of  e1589–e1591 urinary catecholamines/MIBG scintigraphy for  e1589, e1590f autosomal recessive, type 1  e1568 Cayman type  e1569 progressive encephalopathy and  e1043t–e1044t

Cerebellar (ataxic) dysarthria  689, e1556 Cerebellar atrophy (CA)  203, e473, e473f, e474t Cerebellar cognitive affective syndrome  689, e1557 Cerebellar cortex  e1554, e1556f sensorimotor representation in  e1557f Cerebellar degeneration  926t, 929–930 paraneoplastic  e2135–e2136 Cerebellar disorders  199–207, 200t–202t, e466–e483, e467t–e469t Cerebellar dysfunction  e1556–e1557 language and logic of  689 management of  699, e1580 Cerebellar dysplasias  203–204, e473–e474, e475t, e476f Cerebellar function  13 in infants  16 Cerebellar gait  31, e63–e64 differential diagnosis of  e63 Cerebellar hemispheres, disruption of  689 Cerebellar hemorrhage  165, e384, e384f Cerebellar herniation syndromes  775–776 Cerebellar hyperplasia  204, e475–e477 Cerebellar hypoplasia  e470, e1567–e1568 global, with involvement of vermis and hemispheres  e472, e472t lissencephaly with  e518–e520 primarily affecting vermis  199–203, e470–e472 unilateral  e472 Cerebellar mutism  689, e1556 Cerebellar tonsillar herniation  e1772 Cerebellar vermis  249 Cerebellitis  e1588f infectious/postinfectious  e1585 inflammatory. see Inflammatory cerebellitis metabolic/genetic  e1587, e1587t paraneoplastic  e1586–e1587 vascular  e1587 Cerebellum atrophy of, hypomyelination with  750 disorders affecting  199–206, e470–e480 dysplastic  253 function of  e1555 hereditary ataxias and  689–700, e1554–e1584 leukoencephalopathies with  757–758 structure of  e1554–e1555, e1555f, e1557f Cerebral angiography, in brain death determination  835 Cerebral arteriopathies  871–876, e1986–e1996 arteriopathy of sickle cell disease in  e1989 central nervous system vasculitis and  874–875, e1991–e1993 fibromuscular dysplasia  875, e1992–e1993 primary  874, e1991 secondary  874–875, e1991–e1992 cervicocephalic arterial dissection for  873–874, 873t, e1989–e1991, e1990f, e1990t classification schemes of  e1986 diagnosis of  875, e1993 focal  871, e1986, e1987f follow up for  875, e1993 importance of  871 moyamoya  871–873, 872f, 872t, e1986–e1989, e1987t, e1988f of sickle cell disease  873 transient  871, e1986, e1987f Cerebral artery middle  848 posterior  848

Cerebral autoregulation  813, 814f, e1858, e1860f in cerebrovascular system  846, 846f intracranial hypertension on  813–814 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. see CADASIL Cerebral blood flow (CBF)  813 acute bacterial meningitis and  886 in brain death determination  836, 836t changes in, bacterial meningitis and  e2014 coma and  777 hyperemic phase of  808 hypoxic-ischemic encephalopathy and  808 intraventricular hemorrhage and  162 no reflow of  808 regulation of  814 Cerebral contusions  785, e362–e363, e363f abusive head trauma and  797, e1820 white-matter contusional tears and  797 “Cerebral diaschisis”  e342 Cerebral disease, nystagmus caused by  e82 Cerebral edema galactose-1-phosphate uridyltransferase deficiency and  305 malignant  856 malignant, arterial ischemic stroke and  e1945–e1946 as symptom of water intoxication  e2738–e2739 Cerebral energy metabolism, disorders of  e658 inborn error of metabolism  277–278 Cerebral folate deficiency (CFD)  597, e1385 and infantile onset epilepsies  560t–562t Cerebral folate receptor-α deficiency  482t–486t Cerebral folate transport deficiency  381, e936 Cerebral infarction, abusive head trauma and  797, e1820 Cerebral laceration  785 Cerebral lesions, cerebral palsy and  736 Cerebral malaria  e2090 Cerebral mantle  249 Cerebral metabolism developing brain and  781 hypoxic-ischemic encephalopathy and  808 intracranial pressure and  815–816 Cerebral oxygen saturations  e2719 Cerebral oxygenation  777 Cerebral palsy  707, 712, 734–740, 1232, e1650–e1662, e2789 after neonatal seizures  137, e317 ataxic  e1656 atypical, inborn errors of metabolism presenting with  487 choreoathetotic  e1655 classification of  e1654–e1659 comorbidity spectrum of  739–740, e1659 current definition of  e1651 definition of  734–735 diagnostic assessment of  735, 736f, e1651–e1653, e1652f dystonia and  e1609 dystonic  e1655–e1656 epidemiology of  735, e1653 etiologic spectrum of  735–737, e1653–e1654 extrapyramidal  e1655–e1656 functional classification of  737–739, 737f–739f, e1656–e1659, e1657f–e1658f

Cerebral palsy (Continued) history of  e1650–e1651 hypotonic (atonic)  e1656 inborn errors of metabolism and  e1153–e1154 life expectancy for  e1653 mixed  e1656 perinatal arterial ischemic stroke and  e343–e344 presentation of  735, e1651–e1653 preterm infants and  736 prevalence of  e1653 quality of life and  e1659–e1660 risk factors for  735–736 seizures in, treatment of  476 syndromes of  737 transitional care and  e2874 Cerebral perfusion in brain death determination  835 cerebral angiography  835 computed tomographic angiography and perfusion  835 digital subtraction angiography  836 magnetic resonance angiography  835–836 magnetic resonance imaging  835–836 magnetic resonance spectroscopy  836 positron emission tomography  836 radionuclide imaging  835 transcranial Doppler  836 xenon computed tomography  836 intracranial hypertension and  e1858 measurements of  e1910–e1913, e1910t cerebral angiography for  e1910 computed tomographic angiography and perfusion for  e1911–e1912 digital subtraction angiography for  e1912 magnetic resonance imaging and magnetic resonance angiography for  e1912 magnetic resonance spectroscopy for  e1913 positron emission tomography for  e1912–e1913 radionuclide imaging for  e1910–e1911, e1911f transcranial Doppler for  e1912 xenon computed tomography for  e1912 Cerebral perfusion pressure (CPP)  789 for traumatic brain injury  e1786–e1787, e1794–e1795 Cerebral salt wasting (CSW)  1215, e2738 Cerebral sinovenous thrombosis (CSVT)  131, 1210, e310, e2721 coagulation disorders in  e1999f, e2002–e2004 acquired thrombophilia as  e2002–e2003 genetic thrombophilia as  e2003–e2004, e2003t neonatal  152–154, e348–e350 clinical presentation and diagnosis of  e348–e349, e349f–e350f management of  e349–e350 outcomes of  e350 pathophysiology and risk factors  e348 Cerebral unresponsivity  833, e1904 Cerebral venous system, anatomy of  859f Cerebral vision impairment  40, e81 Cerebrocerebellum  e1555 Cerebrohepatorenal syndrome of Zellweger syndrome  349f

Index Cerebroretinal microangiopathy, with calcifications and cysts  756, e1699, e1701 Cerebrospinal fluid (CSF) acute cerebellar ataxia and  704, e1588 analysis of  76–77, e155–e159 for acute bacterial meningitis  884–885 appearance  76, e155–e156 cells  76, 76t, e156, e156t glucose  76, e157 immunologic analysis  77 microorganisms  76, e156–e157 neurometabolic studies  77 for neuromuscular disorders  e2318 protein  76–77, 77t, e157–e159, e158f, e158t in CIDP  e2435 in demyelination  759–760 diagnostic sampling of  74–76, e152–e155 complications  75–76, e154–e155, e155f contraindications and cautions  74, e153 indications  74, e152–e153 procedure  74–75, e153–e154, e153f–e154f drainage  789 for traumatic brain injury  e1787 examination of  e150 formation, flow, and absorption  73–74, 74f, e150–e152, e151f–e152f, e151t function of  74, e152 in GBS  e2430–e2431 history of  e150 hypocretin-1 levels  674 in disorders of excessive sleepiness  e1530–e1531 in narcolepsy  675, 675f immunologic analysis of  e159, e159f neurometabolic studies of  e159 proteomics, multiple sclerosis and  e1722 secretion of, major processes involved in  74f in viral infections  898 Cerebrotendinous xanthomatosis  482t–486t, 757 Cerebrovascular contractility, of cerebrovascular system  e1923–e1925 Cerebrovascular diseases/disorders  e1997– e2007, e1998f acute symptomatic perinatal arterial ischemic stroke  147–151 arterial ischemic stroke  877–880 acquired thrombophilia  877–879 genetic thrombophilia  879–880 sickle cell disease in  880 arterial presumed perinatal stroke  151, 151f cerebral sinovenous thrombosis  152–154, 880–881 acquired thrombophilia  880–881 genetic thrombophilia in  881 coagulation disorders and  877–882, 878f–879f hemorrhagic stroke  881–882 in newborn  147–155, e339–e358 acute symptomatic perinatal arterial ischemic stroke  e339–e345 arterial presumed perinatal stroke  e346, e346f neonatal cerebral sinovenous thrombosis  e348–e350 perinatal intracerebral hemorrhage  e350–e352 periventricular venous infarction  e347– e348, e347f–e348f presumed perinatal stroke  e345–e346

1325

Cerebrovascular diseases/disorders (Continued) perinatal intracerebral hemorrhage  154–155 periventricular venous infarction  151–152, 152f presumed perinatal ischemic stroke  151 SLE-associated  950, e2170 Cerebrovascular events in central nervous system posttreatment sequelae  e2289f, e2290 CNS tumors and  1023–1024 Cerebrovascular reactivity  815, e1863, e1925–e1926 Cerebrovascular resistance (CVR)  813, e2717 Cerebrovascular system  841–847 autoregulation of  e1925–e1926, e1926f brain vascular formation and differentiation  841–843, e1921–e1923 angiogenesis  841, e1921 blood-brain barrier  842–843, e1922– e1923, e1923f endothelial differentiation  842–843, 843f, e1922–e1923, e1923f smooth muscle differentiation  841–842, 842f, e1921–e1922, e1922f vasculogenesis  841, e1921 calcium handling and contractile apparatus of  e1924 cerebrovascular contractility of  e1923–e1925 contractility in  843–845 calcium handling and contractile apparatus  844 ion pumps and channels  844 vasoactive ligands and receptors  844–845 development and function of  e1921–e1930 flow-metabolism coupling of  e1925 hypercapnic vasodilatation of  e1925 hypoxic vasodilatation of  e1925 ion pumps and channels of  e1924 neurovascular mechanisms of  846–847, e1926 reactivity in  845–847 autoregulation  846, 846f flow-metabolism coupling  845 hypercapnic vasodilatation  845 hypoxic vasodilatation  845–846 vasoactive ligands and receptors of  e1924–e1925 whole brain cerebrovascular reactivity of  e1925–e1926 Cervical cord neuropraxia  823, e1880–e1881 Cervical nerve root neuropraxia  823, e1880 Cervical seat-belt syndrome  820 Cervical spine immobilization  827, e1889 Cervicocephalic arterial dissection  873–874, 873t for cerebral arteriopathies  e1989–e1991, e1990f, e1990t Cervicomedullary syndrome  823–824, e1881 Cestodes  914–916, e2080t, e2101–e2104 coenurosis  915, e2104 cysticercosis  915, e2102–e2104 diphyllobothriasis  e2101 echinococcosis  914–915, e2101–e2102 paragonimiasis  916 schistosomiasis  915–916 sparganosis  914, e2101

1326

Index

Cethrin (BA-210), for spinal cord injury  e1888–e1889 Chagas disease  912–913, e2093–e2094 Challenge Module  1292 Chance fracture  820 Channelopathies  405–411, 1148–1156, e977–e985, e978t, e2595–e2615 associated with clinical syndromes in pediatric neurology  406t epilepsy syndromes  405–408, e977–e980 childhood absence epilepsy  408 developmental delay, epilepsy and neonatal diabetes  407–408 juvenile myoclonic epilepsy  408 familial pain syndromes  408–409, e981–e982 clinical features of  408 congenital indifference to pain  408 erythromelalgia  408 genetics/pathophysiology of  408 inherited erythromelalgia, primary erythermalgia  408 paroxysmal extreme pain disorder  408 primary erythermalgia  408 treatment of  408–409 generalized epilepsy with febrile seizures plus  407 KCNQ2 encephalopathy  407, e980–e981 migraine/ataxia syndromes  409–410, e982–e983 familial hemiplegic migraines  409 myotonic dystrophies  1148–1149 acetazolamide-responsive sodium channel myotonia. see Acetazolamide-responsive sodium channel myotonia mode of inheritance of  1148 myotonia congenita. see Myotonia congenita type 1  1148, 1149t type 2  1148–1149, 1149t periodic paralyses  1152–1156, 1153t Andersen-Tawil syndrome  1155–1156 hyperkalemic  1153–1154 hypokalemic  1153t, 1154 paramyotonia congenita  1154–1155 thyrotoxic  1156 Chaperones, for fatty acid oxidation disorders  e2563 Charcot-Marie-Tooth (CMT) disease  1073, e2390 classification of  1073, e2391t–e2393t clinical sequelae of  1073 definition of  1073 diagnostic strategies of  1074, 1075f–1076f genetic testing of  1074, 1075f–1076f pathophysiology of  1073–1074 prevalence of  1073 serum CK levels found in  1039t specific forms of  1074–1080, e2396–e2405 type 1  1074–1076 type 1A  1074 type 1B  1074–1075 type 1C  1075 type 1D  1075 type 1E  1075 type 2  1076–1080 type 2A  1077 type 4  1077 type 4A  1077 type 4B1/B2/B3  1077 type 4C  1077

Charcot-Marie-Tooth (CMT) disease (Continued) type 4F  1077–1080 type HNPP  1075–1076 X-linked  1076 Charcot-Marie-Tooth neuropathy type 1A  275, e651 CHARGE syndrome  48, e103–e104, e2630 congenital heart defects and  1206t CHD. see Congenital heart defects (CHDs) CHD2 gene mutations  516 and infantile onset epilepsies  558t–560t Chédiak-Higashi syndrome  e2416–e2417 Chelation therapy, for ASD  469 Chemical senses. see Smell; Taste Chemical shift selective saturation (CHESS)  e176–e178 Chemokines, in OMS  940 Chemoprophylaxis, for acute bacterial meningitis  889, e2019 Chemotherapeutic agent-induced neuropathy  1084, e2418 Chemotherapeutic medications  e1647 drug-induced movement disorders and  733 Chemotherapy for atypical teratoid/rhabdoid tumor  e2254–e2255 for CNS tumors  961 for ependymomas  e2220–e2221 for germinoma  e2259–e2260 for medulloblastoma  e2205–e2206 in neurocognitive deficits  e2293 other agents used in  e2696 for pediatric low-grade glioma  e2238– e2240, e2239f as risk factor for neurocognitive deficit  1024 for tumors  e2197, e2198t Cherry-red spot lysosomal storage diseases and  323, e782 in Tay-Sachs disease  e781f Cheyne-Stokes respiration  775, e1748 Chiari I malformation (CIM)  204, e475– 477, e477f Chiari II malformation  187–188, e435–e436 classification of  187, e435, e435f, e435t clinical features of  187–188, e435–e436, e436b clinical manifestations of  188b myelomeningocele and  e435–e436 pathophysiology of  e435 prenatal diagnosis of  253 treatment of  188, e437 Chiari malformation  e1495 Chickenpox  e2041 Chikungunya virus  905, e2057–e2058 Child behavior checklist  4 Child development  413, 1292 Child Development Inventory  e1001t–e1004t Child-Neuro listserv  1295, e2908 Child neurology milestones  1300–1301, 1301t Child Neurology Society  1298 in neuroimaging  649 Child symptom inventory  4, e5 Childhood absence epilepsy (CAE)  104, 408, 517, 569–570, 637, e981, e1252, e1336–e1338, e1337f clinical characteristics of  569 EEG findings for  569, 570f etiology of  569 genetics of  569 prognosis of  570 treatment for  569–570

Childhood acute onset neuropsychiatric symptoms (CANS)  e1668 Childhood Autism Rating Scale (CARS™)  e1105 Childhood epilepsy academic planning for  640, e1477 academic underachievement  636–637, e1471–e1472 adults with, social and occupational adjustment of  640–641 antiseizure medications for adverse psychiatric effects  638 on behavior, attention, and mood  638–640 behavioral and cognitive effects of the older versus newer  638–639 effective medication use  638 fear of side effects  638 forced normalization of  638 general effects  638–640 mood disorders and  638 psychosis  638 psychotropic effects  638 autism and autistic spectrum disorders in  e1472 behavioral disorders in  636–637, e1471–e1473 management of  640–641 outcomes  637 treatment of  e1477–e1478 cognitive disabilities in  636–637, e1471 management of  640–641 outcomes  637 treatment of  e1477–e1478 disorders that may mimic  e1203b and generalized seizures  525 learning disabilities in  636–637, e1471–e1472 Lennox-Gastaut Syndrome (LGS) and  637 occupational planning and adjustment in  e1477–e1478 peer relationships and  640, e1477 psychiatric disorders in  e1472 school inclusion in  640, e1477 scoring system for  e1204t social adjustment of adults in  e1473 social isolation in  640, e1477 teasing and  640, e1477 treatment of attention-deficit disorders in  e1477 Childhood sleep  91 Children anticonvulsant hypersensitivity in  e1411, e1411b anticonvulsant hypersensitivity syndrome in  609–610 antiseizure drug therapy in  600–611, 601t–602t, e1391–e1416 absorption in  e1391–e1395 discontinuation of  e1412 metabolism and elimination in  e1397– e1398, e1397f monitoring of  e1407–e1409 pharmacodynamics in  e1404, e1404t pharmacokinetic principles of  e1391– e1398, e1392t–1395t physiologic factors in  e1404–e1405, e1404t protein binding in  e1396–e1397, e1396f volume of distribution in  e1395–e1396, e1396t

Children (Continued) differential diagnosis of vision loss in  e78–e81 with epilepsy, mortality in  642–645 comorbid neurologic conditions in  642 drowning and  642 epidemiology of  642–643 five categories of  643t prevention of not related to seizures  645 related to seizures  644–645 status epilepticus and  642 suicide and  642 epilepsy in  e1197–e1201 mortality in  e1482–e1489 epilepsy in, mortality in epidemiology of  e1482–e1483 five categories of  e1483t prevention of not related to seizure  e1487 related to seizure  e1486–e1487 sudden unexpected death in  e1483, e1483b examination of, with vision loss  e71 olfaction, clinical significance of  61b, 62t, 63–64 psychopathology in, with PNES  632–633 routine immunization, schedule of  919t seizures and epilepsy in ancient disease in modern times  497 new conceptual and practical definitions  497–498 overview of  497–500 seizures in  e1197–e1201 taste, clinical significance of  60–62, 60b, 62t transient episodic vision loss in  e83, e84t types of focal seizures in  531–535, e1262–e1267, e1264b vision assessment in  33–34, e69, e70f vision loss in  37–40, e77–e81 transient episodic  40–41, 41t–42t Children’s Coma Scale  772, 772t, e1741, e1742t Children’s Friendship Training (CFT) program  469, e1114 CHIME syndrome  e752t–e760t Chimeric antigen receptor T cells (CAR T cells), in CNS leukemia  1018 China, special education in  1287, e2897–e2898 Chloral hydrate for sedation  1258 sensorium changes  e2682b Chloral hydrate toxicity  1196b Chlorambucil myoclonus and  e2685b toxicity  1199b–1200b tremor and  e2685b Chloramphenicol  e2694 causing peripheral neuropathy  e2684b toxicity  1197b, 1201 Chloride channel myotonia  e2603t, e2604–e2605 Chlorophenoxy herbicides  1197b, 1199b associated with myoclonus  e2685b causing peripheral neuropathy  e2684b Chloroquine associated with paralysis and muscular rigidity  e2684b causing peripheral neuropathy  e2684b for dermatomyositis  1143 in myasthenia gravis  1103b

Index Chloroquine (Continued) myopathies and  e2683b neuroteratology  1203t toxicity  1197b–1198b Chlorothiazide  e2755b Chlorpromazine  494 in myasthenia gravis  1103b Chlorthalidone  e2755b Cholesterol biosynthesis, disorders of  279t, e659t and inborn errors of metabolism  482t–486t Cholesterol biosynthesis defects  177, e419 Cholesteryl ester storage disorder  e772t– e773t, e798–e799 Choline  384t, 388 developing brain and  e943t, e947 Choline acetyltransferase (ChAT) deficiency, endplate  1092–1093 Cholinergic agents sensorium changes  e2682b toxicity  1196b Cholinergic toxidromes  1193–1194 Cholinesterase inhibitors for ASD  468, e1112 associated with paralysis and muscular rigidity  e2684b Cholinesterase inhibitors toxicity  1198b Chondrocranium  233, e567 Chondrodysplasia punctata, rhizomelic  347–348, 348f Chorea  707–709, 707t, 708b, e1598, e1600–e1603 associated with systemic illness  709, e1603 autoimmune disorders and  709 benign hereditary  e1601–e1602 causes of  e1601b genetic  709 medication-induced  709, e1602 in SLE  950, e2169 Sydenham’s  708–709, e1600–e1601 treatment of  709, e1603 Choreoathetotic cerebral palsy  e1655 CHRNA2, mutations in  517 CHRNA4, mutations in  517 CHRNA7, gene mutations in  578 CHRNB2, mutations in  517 Chromatin  257, e613 Chromium, renal toxicity of  1225t, e2765t Chromosomal aberrations, in DIPG  993 Chromosomal abnormalities  269–271, e634–e656, e639t central hypotonia and  1055t, e2345–e2347 fertility problems  e640 incidence of  271, e638 intellectual disability. see Intellectual disability malignancy and  e640 in megalencephaly  e504 numerical  270, e637 aneuploidy  270 monosomy  270 mosaicism  271 polyploidy  270 trisomy  270 prenatal diagnosis. see Prenatal diagnosis stillbirth/neonatal death  271, e640 structural  e637–e638, e645–e653, e647t Chromosomal microarray  261, e618t, e620–e621, e621f

1327

Chromosomal structural rearrangements  257–259 Chromosomes  268–276, e634–e656 analysis of  259, e614–e623, e615f, e634–e637, e2822t banding  268, e634–e635, e635f G-banding  268 indications for  e638–e640, e638b karyotype  268 methods of  268–269 multiple congenital anomalies  269, e638 preparation  268, e634 autosomes  268 rearrangements of, structural  e613–e614, e614t sex chromosomes  257, 268 short arm of  264f structure  268 Chromosome 9q subtelomeric deletion  274, e650 Chromosome 15q disorders  245–247, e591–e592, e591f Chromosome 15q11q13, disorders associated with  246f Chromosome number  258, 268 Chromosome rearrangements  272 deletions and duplications of  270 insertions  270 inversions  270 isochromosomes  271 ring chromosomes  270–271 translocations of  270 Chronic arthropathies  945–946 Chronic bilirubin encephalopathy  e2801 Chronic drug-induced movement disorders  729–731 diagnosis of  731 treatment of  732 Chronic encephalopathies with multiorgan involvement  176–177, e419 cholesterol biosynthesis defects  e419 congenital disorders of glycosylation  e419 peroxisomal disorders  e419 without multiorgan involvement  176, e418–e419 glutaric aciduria  e418–e419 hyperphenylalaninemia  e418, e418f succinic semialdehyde dehydrogenase deficiency  e415f, e418 Chronic impairments, coma and  776–777 Chronic infantile neurologic cutaneous and articular syndrome (CINCA)  946–947, e2165 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)  1086, 1090–1091, e2434–e2438 antecedent events of  1090, e2434 cerebrospinal fluid in  1090 childhood immunotherapy  1090–1091 outcome  1091 clinical features of  1090 corticosteroids for  1090 diagnostic criteria and clinical features of  e2434–e2435, e2435b diagnostic criteria of  1090 electrodiagnosis in  1090 epidemiology of  1090, e2434 first-line, treatments  1090 immunotherapy for  e2436–e2437

1328

Index

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (Continued) laboratory evaluation of  1090, e2435–e2436 cerebrospinal fluid and electrodiagnosis in  e2435 magnetic resonance imaging in  e2436 pathogenesis in  e2436 pathology in  e2435–e2436, e2435f magnetic resonance imaging (MRI) in  1090 outcome of  e2437–e2438 pathogenesis of  1090 pathology of  1090 second-line immunosuppressants for  1091 serum CK levels found in  1039t treatments of  e2436 Chronic intestinal pseudoobstruction (CIPO)  1230 Chronic kidney disease  1216–1218, e2742–e2746, e2742t myopathy of  1219, e2750–e2751 Chronic leukoencephalopathy  1024, e2290, e2291b, e2291t, e2292f–e2293f Chronic motor tic disorder  741 Chronic skeletal muscle weakness  e2551 Chronic subdural effusions, abusive head trauma and  e1817, e1817f–e1818f Chronic subdural hematomas, abusive head trauma and  e1817 Chronic tic disorder  e1664 Chronic vocal tic disorder  741 Chronobiology  581 in electroclinical syndromes, adolescent onset of  e1359 Churg-Strauss syndrome  947t, 953, e2179 CIDP. see Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) Cimetidine for gastroesophageal reflux  1161 myopathies and  e2683b toxicity  1197b Cingulate herniation  817t Ciprofloxacin toxicity  1200b tremor and  e2685b Circle of Willis  848 Circulation coma  776 impairment of consciousness and  e1750 Cirrhosis, and urea cycle disorders  301 Cisapride sensorium changes  e2682b toxicity  1196b Cisplatin causing peripheral neuropathy  e2684b neuroteratology  1203t toxicity  1197b Cisplatin-based chemotherapy  1003 Cisterna magna, in Arnold-Chiari malformation  253 Citalopram  492, e1168, e1168t for ADHD  455t–457t for ASD  466, 467t–468t Citrin deficiency  e712–e713 Citrobacter spp., in brain abscess  893 Citrullinemia  299–300, 482t–486t, e712–e713 type II  299–300 Classic adult CPT II deficiency  e2550–e2551 Classic maple syrup urine disease  288, e680 Classic plasmalemmal carnitine transporter defect  e2550

Classical phenotype  1073 ClC-2 related leukoencephalopathy  755, e1697–e1698 CLCF1 gene, mutation in  1183 CLCN1 gene, mutations in  1151 Cleidocranial dysplasia  237 Climbing stairs, motor function testing  1049, e2336 Clindamycin, for toxoplasmosis  1146 Clindamycin, in myasthenia gravis  1103b Clinical cytogenetics  e653 Clinical practice guidelines (CPGs)  1276 Clinician-patient relationship  1239, e2813 ClinVar database  1297 CLN1 disease  397, e951t–e952t, e954t– e955t, e957–e960 clinical description of  397, e957–e959 clinical trials of  e959–e960 diagnostic evaluation of  e959 genetics and pathology of  e959 CLN2 disease  397–398, e951t–e952t, e954t–e955t, e960–e961 clinical description of  397–398 genetics and pathology of  398 CLN3 disease  398, e951t–e952t, e954t– e955t, e961–e962 clinical description of  398 CLN4 disease  398–399, e951t–e952t, e962–e963 CLN5 disease  399, e951t–e952t, e963 CLN6 disease  399–400, e951t–e952t, e964 CLN7 disease  400, e951t–e952t, e964–e965 CLN8 disease  400–401, e951t–e952t, e965 CLN10 disease  401, e951t–e952t, e954t– e955t, e965–e966 CLN11 disease  401–402, e951t–e952t, e954t–e955t, e966–e967 CLN12 disease  e951t–e952t, e954t–e955t, e967 CLN13 disease  e951t–e952t, e954t–e955t, e967–e968 CLN14 disease  403–404, e951t–e952t, e968–e970 Clobazam  e1476 behavioral and cognitive effects of  639–640 for Lennox-Gastaut syndrome  572 Clofibrate, associated with myopathies  e2683b Clofibrate toxicity  1197b Clomiphene sensorium changes  e2682b toxicity  1196b Clomipramine  491 for ADHD  455t–457t for ASD  467t–468t Clonazepam  601t–602t, e2835t Parkinsonism and  e2684b for paroxysmal nonkinesigenic dyskinesia  e1630 pharmacokinetics of  604t–605t rectal administration of  606t for restless legs syndrome  682, e1543 for spasticity  1251t for tic disorders  745t toxicity  1198b Clonidine  490, e2755b for ADHD  455t–457t, e1086–e1087, e1087t–e1089t for postural orthostatic tachycardia syndrome  665 sensorium changes  e2682b side effects of  490–491 for tic disorders  745t toxicity  1196b

Clonus, focal  533 Clopidogrel  856, e2825t pharmacogenetics  1246t Clorazepate  601t–602t, e2835t for spasticity  1251t Closed-loop responsive electrical brain stimulation  620 Clostridium botulinum  1104 Cloverleaf skull  236, e570f–e571f, e572–e573 Clozapine  495, e1184t, e1188–e1189 myoclonus and  e2685b toxicity  1199b Cluster headache  648 Clusterin  993 Cluttering  434, e1054–e1055 Clutton’s joints  890–891 CMDs. see Congenital muscular dystrophies (CMDs) CMS. see Congenital myasthenic syndromes (CMS) CMT. see Charcot-Marie-Tooth (CMT) disease CMT1A  e2396–e2397 CMT1B  e2397 CMT1C  e2397 CMT1D  e2397 CMT1E  e2397 CMT1F  e2397 CMT2A  e2398 CMT2B  e2398 CMT2C  e2398 CMT2D  e2398 CMT2E  e2398 CMT2F  e2398 CMT2K  e2398–e2399 CMT2L  e2398 CMT2M  e2399 CMT2O  e2399 CMT4A  e2399 CMT4B1 neuropathy  e2399 CMT4B2  e2399 CMT4B3  e2399 CMT4C  e2399 CMT4F  e2399 CMT4J  e2399 CMTX  e2397 CNS-directed delivery strategies, in highgrade glioma  e2231 CNS embryonal tumors  e2212, e2213f CNS inflammatory mediators, opsoclonus myoclonus syndrome (OMS)  940 CNTNAP2 disorders  247 Coagulation candidates  e376, e376t Coagulation disorders  853, 877–882, e1997–e2007, e1998f in arterial ischemic stroke  877–880, e1997–e2002, e1999f, e2000t acquired thrombophilia  877–879 genetic thrombophilia  879–880 sickle cell disease  880 in cerebral sinovenous thrombosis  880–881, e1999f, e2002–e2004 acquired thrombophilia  880–881 genetic thrombophilia  881 diagnostic testing for, cerebral palsy and  735 in hemorrhagic stroke  881–882, e1999f, e2004–e2005 Coats plus syndrome  756–757 Cobalamin  377, e918t–e919t, e926–e927 deficiency  377, 387, 482t–486t, e927, e1380–e1382 inherited metabolic epilepsies and  594–595

Cobalamin (Continued) dependency  377–378, e927–e928 developing brain and  e943t, e946 metabolism  e689f–e690f as nutrient  384t pathways in metabolism of  293f–294f Cobblestone complex, prenatal diagnosis of  252, e604 Cobblestone malformations  220–221, e521–e526, e521t antenatal diagnosis of  e525–e526 brain imaging of  e522–e524, e522f–e523f clinical features of  e524 genetic testing of  e521t, e525 neuropathology of  e521–e522 prognosis and management of  e524 syndromes, genetics, and molecular basis  e524–e525 Cobra venom  1198b associated with paralysis and muscular rigidity  e2684b Cocaine abuse in  1196b–1197b, 1198, e2689 myopathies and  e2683b neuroteratology  1203t sensorium changes  e2682b toxicity  1196b–1197b Coccidioides immitis  890, 907, e2065–e2066, e2066t Coccidioidomycosis  907–908, e2065–e2067 clinical characteristics of  e2066–e2067, e2067f epidemiology, microbiology and pathology of  e2065–e2066 management of  e2067 Cochlea  e92–e93, e93f Cochlear aqueducts  e93 Cochlear implants  e110 for hearing loss  50 meningitis after  884 Cochrane Database of Systematic Reviews  1297, e2915 Cockayne syndrome  694, 751, 756, e1690 in calcifying leukoencephalopathies  e1699 with kidney malformation  1224t, e2764t “Cocktail-party chatter”  413 Coenurosis  915, e2104 Coenzyme Q deficiency  1132b Coenzyme Q10, for headache prevention  e1501 Coenzyme Q10 defects  340 Coenzyme Q10 deficiency  482t–486t primary  e1568 Cofactors and inborn errors of metabolism  482t–486t and metabolite supplementation, for mitochondrial diseases  1138 Coffin-Lowry syndrome (CLS), in disorders of excessive sleepiness  e1535 COG complex  321 COG4-CDG (IIj)  e752t–e760t, e765 COG5-CDG  e752t–e760t, e765 COG6-CDG  e752t–e760t, e765 COG7-CDG (IIe)  e752t–e760t, e765 COG8-CDG (IIh)  e752t–e760t, e765 Cogan syndrome  947t, 953, e2178 Cognition, in nephrotic cystinosis  441 Cognitive abnormalities, hepatic encephalopathy  e2793 Cognitive and motor regression  424–430, e1019–e1050 brain biopsy in  e1026–e1027 definition of  e1019

Index Cognitive and motor regression (Continued) diagnostic approach for  e1027–e1028, e1027t–e1048t diagnostic evaluation of  e1022 epidemiology of  e1019 etiology of  e1019–e1022, e1020t–e1022t examination of  e1024, e1025t history of  e1022–e1024, e1023t IEMs and  284 laboratory testing for  e1024–e1026, e1026t management of  e1028–e1048 Cognitive behavioral therapy (CBT)  469 for headache  654 Cognitive deficits, communication and, in acquired brain injury  1253 Cognitive development, in CHD  e2730 Cognitive function, posttraumatic  796 Cognitive impairment  209, e2291–e2294 CNS tumor posttreatment sequelae  1024–1025 definition and measurement of  e2291–e2292 microcephaly and  e486 neurocognitive deficits, risk factors for  e2293–e2294 posttrauma  791 Cognitive screening instruments  e9t Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE)  e270 COL6A1 genes, mutations in  1116, 1121 COL6A2 genes, mutations in  1121 COL6A3 genes, mutations in  1121 Colchicine associated with myopathies  e2683b causing peripheral neuropathy  e2684b for dermatomyositis  1143 sensorium changes  e2682b toxicity  1196b–1197b Cold-induced sweating syndrome  1183, e2657 Cold water caloric tympanic membrane stimulation  e1905b Collagen VI-related dystrophies  e2491f, e2495, e2495f Collateral sprouting  1249 Collier sign  e556 Coloboma, ocular  e74, e74f–e75f Colon, anatomy of  1189–1190 Color vision, assessment of  34, e69 Colorado tick fever virus  e2049–e2050 Colorectal motility  1190 defecation and  e2672 COLQ gene, mutations in  1093 Coma  770, 770t, e1737, e1737t clinical neurophysiology of  e1756 etiology of  774b monitoring of  777, e1751–e1753 neuroimaging of  e1756–e1757 in nonconvulsive status epilepticus  550 nontraumatic injury and  e1756 outcome measurement for  777–778 prognosis of  778–779 clinical neurophysiology  779 nontraumatic injury  779 traumatic injury  778 traumatic injury and  e1754–e1756 treatment for  776–777 acid-base and electrolyte imbalance  776 agitation  776 airway, oxygenation, and ventilation  776 antidotes  776 body temperature  776 chronic impairments  776–777

1329

Coma (Continued) circulation  776 glucose  776 increased intracranial pressure  776 infection  776 seizures  776 Coma Recovery Scale-Revised (CRS-R)  e1743 Combined defects of Ado- and MetCbl  e928 Commissural tracts  e260 Communication cerebral palsy and  738, 740 and cognitive deficits, in acquired brain injury  1253 deficit in, and ASD  459 mode, for severe to profound hearing impairment  e109–e110 nonverbal  e2813–e2814 in palliative care  1260, 1260b skills  e2813–2814, e2814b in counseling children with neurologic disorders  1239, 1240b Communication and Symbolic Behavior Scales Developmental Profile™ (CSBS DP)  e1103 Communication Function Classification System (CFCS)  e1656–e1657, e1658f for cerebral palsy  738, 739f Comparative genomic hybridization array  269, 269f “Competency by design”  1300 Complementary and alternative medicine for ADHD  457 for ASD  469 Complete spinal cord injuries  823 Complex cortical malformations, prenatal diagnosis of  252 Complex hereditary spastic paraplegia  e752t–e760t Complex I deficiency  1132b, e2565 Complex II deficiency  1132b, e2565 Complex III deficiency  e2565 Complex IV deficiency  e2565 Complex V deficiency  e2565 Compliance, intracranial pressure and  813 Comprehensive Test of Nonverbal Intelligence (CTONI)  e143t–e146t, e1001t–e1004t Comprehensive Test of Nonverbal Intelligence 4  68t–69t Comprehensive Test of Phonological Processing  445 Compulsory Education Law (CEL), The  1287, e2897–e2898 Computed tomographic angiography for cerebral arteriopathies  e1990 for cerebral perfusion  835, e1911–e1912 Computed tomography (CT)  78–79, e166–e169, e167f–e173f for abusive head trauma  e1828 for acute cerebellar ataxia  704, e1588 ALARA principle  78, e166 for arterial ischemic stroke  854, e1940f, e1943 for generalized tonic-clonic seizures  525 for hydrocephalus  229, e558 for progressive encephalopathies  428 for sinovenous thrombosis  861, e1958f, e1961 for spinal cord injury  e1878 for traumatic brain injury  787, 787b, 788f, e1780–e1782, e1780b–e1781b, e1781f, e1795 for viral infections  898, 899f

1330

Index

Computer resources, impact of  1295–1298, e2908–e2918, e2909t–e2912t authoritative narrative content in  e2913–e2914 clinical discussions and groups in  1295– 1296, e2908–e2913 conflict of interest in  1298 diagnostic decision support  1296–1297, e2914–e2915 dissemination of original research  e2917 education in  1298, e2916–e2917 hardware  e2917 interoperability of  e2916 perspectives  1298, e2917–e2918 treatment decision support  1297–1298, e2915–e2916 Wikis  1296, e2914 Computerized dynamic platform posturography  54, 55f, e120–e121, e120f Concentration-response concept  e1404 Concussion  786, e1776–e1777 management of  790 postconcussive syndrome and  792 repeated  786 sports-related  103–104, 786, e267–e268 return to play following  790, 790t Conditional gene targeting  e290–e292 Conduct disorders, in childhood epilepsy  637 Conductive hearing loss  e99 Confidence intervals (CIs)  1279–1280 Conflicts of interest  1276 computer resources and  1298 Confusion  e1736–e1737 disorders of consciousness and  769 Confusional arousal  668, e1524 Congenital alacrima  1183, e2657 Congenital anomalies abnormal development associated with, and dysmorphic physical features  280–281 multiple  269 Congenital bilateral perisylvian syndrome, and developmental language disorders  432 Congenital cataracts  35, e73 Congenital central hypoventilation syndrome (CCHS)  1182, e2656 Congenital disorders of glycosylation (CDGs)  176–177, e419, e525 and infantile onset epilepsies  560t–562t Congenital fiber-type disproportion (CFTD)  1129, e2524, e2532 serum CK levels found in  1039t Congenital glaucoma  e74 Congenital heart defects (CHDs)  1205, e2713 adolescent and adult outcome in  1213, e2732–e2733 anatomic considerations in  1205, e2713 arterial ischemic stroke and  1210, e2719–e2720 behavior and social functions in  e2732 behavioral outcome in  e2730–e2731 brain volume in  e2714–e2716, e2717f cardiac care, neurologic management to  e2722 cerebral sinovenous thrombosis and  1210, e2721 cognitive development and  e2730 extracorporeal membrane oxygenation for  1211

Congenital heart defects (CHDs) (Continued) fetal circulation and  1205–1207, 1208f, e2713–e2716, e2716f grading system of  1206t, e2714t heart failure and, neurologic sequelae of  1211, e2721 heart surgeries and  1207–1208, e2718, e2718f higher order intellectual outcome and academic achievement in  e2732 hypoplastic left heart and  1205, 1207f, e2713, e2715f infectious endocarditis in  e2720–e2721, e2721f intellectual outcome in  e2731–e2732 intracranial hemorrhage and  1210, e2720 language development in  e2730 language outcome in  e2731–e2732 long-term outcomes in  1212–1213, 1213t, e2726–e2728, e2731, e2731t mechanical circulatory support devices for  1211, e2722 mononeuropathies  e2723 motor and visuomotor outcome in  e2731 myopathy  e2723 neurodevelopmental outcome in, assessment of  e2728, e2729t neurologic management specific to cardiac care  1211–1212 neuromotor development in  e2730 perioperative considerations in  1209, e2718 peripheral neuromuscular injury in  e2722 plexopathies  e2722–e2723 polyneuropathy  e2723 postnatal circulation and  1207–1211, e2718–e2722 postoperative neurologic findings in  1212, e2727–e2728 preoperative neurologic status  e2726– e2727, e2727t seizures and  1210–1211, e2721 short-term outcomes in  1212–1213, e2726–e2730 transitional circulation in  e2717 transposition of the great arteries and  1205, 1207f, e2713, e2715f white matter injury and  1209–1210, 1209f, e2718–e2719, e2719f Congenital heart disease  427, 805t Congenital hyperammonemia, and infantile onset epilepsies  560t–562t Congenital hyperinsulinism, and infantile onset epilepsies  560t–562t Congenital hypothyroidism  487, e1154–e1155 Congenital indifference to pain  e981 Congenital inflammatory myopathy  1145, e2590 Congenital insensitivity to pain with anhidrosis  e2654 Congenital intrinsic factor deficiency  482t–486t Congenital microcephaly  e484 Congenital miosis, spastic ataxia with  e1579 Congenital motor nystagmus  e82–e83 Congenital muscular dystrophies (CMDs)  1119, e2351, e2503f, e2504– e2505, e2505t, e2726 approach to  e2509 approach to patient with  1122 due to defective α-dystroglycan glycosylation  206, e478–e479, e479f α-dystroglycan, abnormalities of  1119– 1122, e2505–e2510

Congenital muscular dystrophies (CMDs) (Continued) extracellular matrix proteins, abnormalities of  1121 fukutin-related protein deficiency  1120 integrin α7 deficiency  1121 lamin A/C-associated  1121, e2509 LARGE gene  1120–1121 nesprin-associated  1121 serum CK levels found in  1039t Walker-Warburg syndrome  1120 Congenital myasthenic syndromes (CMS)  1092–1097, e752t–e760t, e2349, e2441–e2451 associated with congenital defects of glycosylation  e2447–e2448 with β2-laminin deficiency  1094 basic concepts of  e2441 caused by defects in endplate development/ maintenance  1095–1096 classification of  e2443, e2444t clinical features of  1093b clinical manifestations of  1092, e2441, e2442b with congenital defects of glycosylation  1096 diagnosis of  1092, 1093b, e2441–e2443, e2442b–e2443b endplate development in  e2446–e2447 other myasthenic syndromes  e2448 plectin deficiency and  1095 postsynaptic  1094–1095, e2445–e2446 fast-channel myasthenia  1094 kinetic defects, in acetylcholine receptor  1094 primary acetylcholine receptor deficiency  1094 slow-channel myasthenia  1094 sodium-channel myasthenia  1095 prenatal  1094–1095 presynaptic  1092–1093, e2443–e2444 serum CK levels found in  1039t synaptic basal lamina associated  1093– 1094, e2444–e2445 treatment of  1097, 1097t, e2448–e2449, e2448t–e2449t Congenital myopathies  1044, 1045t–1046t, e2326, e2349–e2350, e2519–e2536 classification of, by genes  e2520t–e2521t diagnostic testing for  e2523–e2525 genetics in  e2524 muscle biopsy in  e2523–e2524, e2523f muscle imaging in  e2524–e2525, e2526f diagnostics of  e2519–e2523, e2522f in early childhood  e2523 in infancy  e2519–e2523, e2522f general management of  e2532–e2533 cardiac  e2533 nutrition, gastrointestinal, and oromotor  e2533 orthopedic  e2533 physical therapy for  e2533 respiratory  e2532 myasthenic syndromes associated with  1096, e2448 serum CK levels found in  1039t specific subtypes of  e2525–e2532 centronuclear myopathies  e2525–e2528 congenital fiber-type disproportion  e2532 core myopathies  e2530–e2532 nemaline myopathies  e2528–e2530

Congenital neuropathies, spinal muscular atrophies and  e2362 Congenital pernicious anemia  1082, e2414 Congenital syphilis  e2021 Congenital uremic encephalopathy  1217, e2745–e2746 Congruence, concept of, in epilepsy surgery  616 Coning  776 Conjunctivae, in ataxia-telangiectasia  694, 694f Connective tissue disorders  949–952, e2164t, e2168–e2176, e2351 mixed  851, 952, e2175 peripheral hypotonia and  1055t–1056t scleroderma  951, e2174–e2175 Sjögren’s syndrome  952, e2175 systemic lupus erythematosus  949–951, 949b, e2168–e2174, e2168b, e2172f–e2174f Connectivity assessment strategies for  97–99, 98t, e256–e258, e257t categorization of disorders of  e260–e266 challenges for assessment of  e270–e271 age-specific atlases  e271 feasibility  e270 imaging during natural sleep  e271 in-scanner head motion  e270–e271 current clinical applications  e270, e271f disorders of, categorization of  100 effective  99 fetal development  e260–e261 environmental perturbations  e261 functional imaging of  e260–e261 microstructural studies of  e260 functional  98 microstructural  97 preterm birth results in long-term alterations in  e263–e264 dMRI studies provide evidence of microstructural abnormalities  e263 environmental factors of  e264, e264f functional studies  e263 graph theory and  e263–e264 role of  105, e270 in typically developing children  100–102, e261–e262 dMRI studies in  101 environmental factors on  102 functional maturation  101, e262 functional studies of  101–102 graph-theory analyses on  102 influence of genes and environment  101, e262 maturation of microstructural networks  e261–e262, e262f microstructural networks maturation  101 preterm birth results in long term alterations in  101 Conners Continuous Performance Test  e143t–e146t Consciousness  767, 769f alteration of  531 clouding of  769, e1736 definitions of  e1736–e1740 disorders of  767–780, e1731–e1763 definitions of  769–772 historical perspective of  767–769 neural correlates of consciousness and  767–769 neuroimaging for  779

Index Consciousness (Continued) historical perspective of  e1731–e1736 impairment of with activated mental state  769, e1737 akinetic mutism  770t, 771 brain death  769f, 770t, 772 brain herniation in  775–776 and childhood absence epilepsy  569 clinical evaluation of  e1744 diagnostic testing for  776, e1749 etiologies of  773, 774b, e1743, e1744b evaluation for  773–775, e1743–e1747 general physical examination of  773, e1745 history of  773, e1745 identification of cause of  773, e1744–e1745 locked-in syndrome  769f, 770t, 771 minimally conscious state  770t, 771, 771b, e1737–e1740, e1737t neurologic examination of  774–775, e1745–e1747 outcome measurement for  777–778, e1753–e1754 pathophysiology of  773, e1743 prognosis of  778–779, e1754–e1757 with reduced mental state  769–770, e1737 in tonic seizures  529 treatment of  776–777, e1749–e1751, e1749b vegetative state  769f, 770–771, 770b, 770t, e1737–e1740, e1737t loss of, in generalized tonic-clonic seizures  524 neural correlates of  e1732–e1736 rating scales for  772, e1740–e1743 Children’s Coma Scale  772, 772t FOUR Score Coma Scale  772, 773t Glasgow Coma Scale  772, 772t Pediatric Coma Scale  772, 772t Constipation  475 neurodevelopmental disorders and  e1131 in pediatric autonomic disorders  1174–1175 Constitution Act  1286–1287 Constraint induced movement therapy (CIMT)  856 for arterial ischemic stroke  e1946 for stroke  1254, e2839–e2840, e2840f Constraints, on speech and language learning  e111 Consultation, for intellectual disability  422 Contingent negative variation (CNV)  452 Continuous positive airway pressure (CPAP)  1160 Continuous spike and wave during sleep, epileptic encephalopathy with  573–574 Contractile apparatus, in cerebrovascular system  844 Contractile proteins  e2301–e2303, e2302f Contractures in BMD  e2478 in DMD  1110, e2478 Contrast enhanced CT venography (CVT), of sinovenous thrombosis  e1961 Contrast-enhanced dynamic susceptibilityweighted perfusion imaging  83 “Contre-coup” injury  781 Contusion, cerebral  e1776, e1776f Conus medullaris syndrome  824, e1881 Convection-enhanced delivery (CED)  983, e2231 Conventional angiography, of arterial ischemic stroke  e1943

1331

Conventional catheter angiogram (CCA), for arteriovenous malformations  866 Conventional hearing aids  e111 Conventional video EEG  e313, e313f Conversion disorder  32, e65, e1618 criteria for  631 treatment of  634 Conveying empathy  e2814, e2814b Convulsions, genetic generalized epilepsies with  577–578, 578f Convulsive syncope  662, e1515 Copper developing brain and  e943t as nutrient  384t Copperhead, sensorium changes  e2682b Coprolalia  741 Copropraxia  741 Copy number variants (CNVs)  272, 420 and ASD  462 Copy number variations  259, e617 CoQ10 deficiency  e2565–e2570 isolated myopathic form of  e2552 Core myopathies  1128–1129, e2350, e2524, e2530–e2532 Corencephalopathies  425 Cori disease  310–311, e735–e736 Corn lily  1196b sensorium changes  e2682b Cornea anomalies of  38, e78 opacity  35–36, e73–e74, e74f reflex  775 Corneal response  783 Corpora amylacea  311 Corpus callosotomy  617, e1430 Corpus callosum abnormalities of, prenatal diagnosis of  e603, e603f development of  196 imaging and  196 normal development of, prenatal assessment of  249 prenatal diagnosis of abnormalities of  252 Corpus callosum agenesis  194–197, e453–e460, e455f association of, with autism and related neurodevelopmental disorders  e459–e460 clinical manifestations of  e459–e460 development of  e456, e457f epidemiology of  e455 etiology of  e457–e459 genetic  e457–e459, e460t nongenetic  e459 historical background of  e455 imaging of  e456, e458f–e459f management of  e460 prenatal diagnosis and prediction of outcomes of  e455–e456 Cortex  e2665 maturation of  251f normal development of, prenatal assessment of  249 tic disorders and  743 Cortical atrophy, lysosomal storage diseases and  e782 Cortical blindness, postmeningitis  886 Cortical glioma high-grade  959t low-grade  959t Cortical malformations classification for  181b prenatal diagnosis of  e603–e607, e604f severe microcephaly with  210

1332

Index

Cortical minicolumns  462 Cortical resection, extratemporal  617 Cortical stimulation mapping  e1427–e1428 Cortical visual impairment structural cerebral anomalies causing  36– 37, e77 vision loss caused by  36, e76–e77 Corticosteroids for acute demyelination  760–761 for BMD  e2477 for chronic inflammatory demyelinating polyradiculoneuropathy  1090 for CIDP  e2436 for dermatomyositis  1143, e2588 for DMD  1109–1110, e2477 in GBS  e2434 for Guillain-Barré syndrome (GBS)  1089 for infantile spasms  541t, 542, e1284–e1286 for juvenile idiopathic arthritis  945–946 for juvenile myasthenia gravis  e2462–e2463 for Lambert-Eaton myasthenic syndrome  1104 for myasthenia gravis  1101–1102 myopathies and  e2683b for opsoclonus myoclonus syndrome  941, 942t, e2155 postnatal, white matter injury and  166 toxicity  1197b in myasthenia gravis  1103b Corticothalamic theory  569, e1336–e1337 Corticotropin-releasing hormone (CRH)  1165 in infantile spasms  e1282 Cortisol  1168 replacement  1169, e2633 Cotrimoxazole, indications, Whipple’s disease  e2790 Cottonmouth, sensorium changes  e2682b Coumarin anticoagulants, neuroteratology  1203t Counseling children with neurologic disorders and their families  1239–1243 alternate belief systems in  1242 clinician-patient relationship in  1239 communication skills in  1239, 1240b difficult patients  1242 empathy in  1240, 1240b family discord  1242 low health literacy in  1242 nonverbal communication in  1239–1240 providing information in  1240–1242 specific challenges in  1242–1243 spirituality and  1242 terminal illnesses in  1243 uncertain test results in  1242–1243 for febrile seizures  522 “Coup” injury  781 Cowden syndrome  216, 958t Coxiella burnetii  909, e2073t–e2074t CPGs. see Clinical practice guidelines (CPGs) CPP-115  e1287 Cranial bones thick  238, e579 thin  238, e578–e579 Cranial dermal sinus  237, e575–e576 Cranial epidural abscess  e2027 Cranial nerve damage acute bacterial meningitis and  886 bacterial meningitis and  e2014 Cranial nerve dysfunction, in SLE  950, e2170

Cranial nerve examination  7–10, e11–e17 abducens nerve  7–9, 8f, e13–e14, e13f, e13t auditory nerve  10, e16 facial nerve  9, e15, e15f glossopharyngeal nerve  10, e16 hypoglossal nerve  10, e16–e17, e16f oculomotor nerve  7–9, 8f, e13–e14, e13f, e13t olfactory nerve  7, e11–e12 optic nerve  7, e12–e13, e13f posttrauma  782 preterm infant  23–24 spinal accessory nerve  10, e16 term infant  21–22 trigeminal nerve  9, e14–e15, e15f trochlear nerve  7–9, 8f, e13–e14, e13f, e13t vagus nerve  10, e16 Cranial sutures  e567, e568f anatomy of  e568–e571 coronal, premature fusion of  233, 234f, e568 multiple, synostosis of  233 wide  236, e574 Cranial ultrasound  78, e163–e166, e164f–e165f for hydrocephalus  228–229, e557–e558 Cranial vault evaluation, term infant  20 Craniolacunae  238, e578–e579 Craniometaphyseal dysplasia  239f, e580f Craniopharyngiomas  959t, 1005–1008, 1006f, 1167, e2264–e2268, e2631 aspiration for  1007, e2267, e2268f clinical presentation of  1005, e2264 epidemiology of  1005, e2264 histopathology of  1006, e2264–e2266, e2266f intracystic therapy for  1007, e2267–e2268 bleomycin in  e2267–e2268 interferon in  e2268 intracavitary irradiation in  e2267 neuroimaging of  1005, e2264, e2265f obesity and  1170–1171 outcomes and quality of life in  1008, e2268 radical surgical resection for  1006–1007, e2266–e2267, e2266f subtotal resection with irradiation for  1007, e2267 treatment of  1006–1007, e2266–e2268 Craniostenosis  233, e567 Craniosynostosis  233–236, e567–e574 “beaten copper” appearance  e570f–e571f cloverleaf skull  236, e570f–e571f, e572–e573 coronal  235, e568, e568f fibroblast growth factor receptor 3-associated  235, e572 diagnoses of  e569t epidemiology of  234–236, e571–e572 familial  235, e572 lambdoid  233, e568f, e569 metopic  233, 235, e568f, e569 multiple sutural. see cloverleaf skull neurocognitive development  236, e573–e574 sagittal  233–235, 234f, e567, e568f secondary  235, e572 syndromes associated with  235t treatment and outcomes of  236, e573–e574 Craniotabes  238, e579 Cranium bifidum  237, 237f, e576–e577 Cre-Lox system  117–118, e290–e292

Cre recombinase  117–118, e290–e292 Creatine, and inborn errors of metabolism  482t–486t Creatine biosynthesis  596 and transport deficiencies  e1383 Creatine deficiency central hypotonia and  1055t, e2347 and infantile onset epilepsies  560t–562t Creatine kinase (CK) in dermatomyositis  1142 in DMD  1108 serum levels, in neuromuscular disorders  1039t, e2316, e2317t Creatine transporter defect  482t–486t Cree leukoencephalopathy  755 Creutzfeldt-Jakob disease  427 new variant  425–426 Cri du chat syndrome  274, e649 CRISPR-Cas9 technology, genome engineering using  118–119, 119f, e292–e293, e293f CRLF1 gene, mutation in  1183 Crohn’s disease  1231 Cromolyn sodium myopathies and  e2683b toxicity  1197b Cross-check principle  e95 Cross-check principle, for evaluation of auditory function  44 Crossed-extensor reflex  e50–e51 in preterm infants  24 Crotalid venom  1194 Crouch gait  30–31, e62 Crouzon syndrome  235 Cryptococcosis  907, e2065, e2066f Cryptococcus spp. C. gatti  907, e2066t C. neoformans  907, e2065, e2066f, e2066t CTNAP2 disorder  e592 CTNS gene, mutations in  1223, e2762 CTSD  e951t–e952t, e965–e966 CTSF  e951t–e952t, e967–e968 Cushing, Harvey  e1747 Cushing response  816t Cushing’s disease  e2632 Cushing’s syndrome  1168 Cutaneous examination, in infants  16–17, 16f Cutis aplasia  271 CXCL12  109–110 Cyanide causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b Cyanosis, in generalized tonic-clonic seizures  524 Cyanotic breath-holding spells  656–657 Cyanotic spells  e1506–e1507 Cyclic vomiting syndrome (CVS)  1229 episodic gastrointestinal disease and  e2777 Cyclin-dependent kinase-like 5 (CDKL5) epileptic encephalopathy associated with  514–515 Cyclobenzaprine sensorium changes  e2682b spinal cord injury and  828 toxicity  1196b Cyclophosphamide  e2696 for dermatomyositis  1144t for juvenile myasthenia gravis  e2464 for multiple sclerosis  764 for myasthenia gravis  1102 for neuromyelitis optica  765

Cyclophosphamide (Continued) for opsoclonus myoclonus syndrome  942, 942t, e2156–e2157 toxicity  1202 Cyclosporine  e2694 for dermatomyositis  1144t for juvenile myasthenia gravis  e2463 for myasthenia gravis  1102 myopathies and  e2683b for organ transplantation  1201 sensorium changes  e2682b toxicity  1196b–1197b, 1200b tremor and  e2685b Cyclosporine A for CIDP  e2437 renal transplantation complications and  1220 Cyproheptadine for cyclic vomiting syndrome  1229 for migraine  652t Cystathionine β-synthase deficiency  e686 Cystathionine beta-synthetase (CBS) deficiency  e1383 Cystic leukoencephalopathies  757 Cysticercosis  915, 1146, e2102–e2104, e2103f, e2592 clinical characteristics, clinical laboratory tests and diagnosis of  e2103–e2104, e2104f epidemiology, microbiology and pathology of  e2102–e2103, e2103f management of  e2104 Cystinosis  331, e772t–e773t, e818–e819 nephropathic  1223, e2762–e2763 and nonverbal learning disabilities  440 Cysts Blake’s pouch  253, e607–e608, e608f cerebroretinal microangiopathy with  756 hydatid  914 leptomeningeal  792 leukoencephalopathy with  756 Cytochrome oxidase deficiency  1132b Cytogenetic analysis, indications for  271, e638–e640 Cytogenetic syndromes  271–275 Cytogenetic testing, progressive encephalopathies and  428 Cytogenetics chromosome analysis  259 FISH  268 history of  257–259, e613–e614 molecular  259, 268–269 nomenclature  271 Cytogenomic microarray  e2822t in genetic diagnosis  1245t Cytokines  163 in hypoxic-ischemic encephalopathy  807–808 in OMS  940 Cytomegalovirus (CMV)  756, 901, e2040–e2041 in calcifying leukoencephalopathies  e1699 clinical manifestations of  901, e2040 in demyelination, white matter disorders with  e1701 diagnosis of  901, e2037f, e2040–e2041 treatment and outcome of  901, e2041 Cytopenia, lysosomal storage diseases and  e782 Cytoplasmatic tRNA synthetase defects, hypomyelination related to  750, e1687–e1688 Cytosine  261 Cytosine arabinoside  e2696 causing peripheral neuropathy  e2684b

Index Cytosine arabinoside toxicity  1197b, 1202 Cytoskeletal proteins  1032–1035, e2304– e2307, e2304f, e2305t caveolin  1034, e2307 dysferlin  1034, e2306–e2307 dystrophin  1032–1033, e2304–e2305 dystrophin-glycoprotein complex  1033– 1034, e2305–e2306 intermediate filaments  1034, e2307 merosin  1034, e2307 nuclear membrane proteins  1034–1035, e2307 sarcoglycans  1034, e2306 utrophin  1034, e2306

D

Dabrafenib  989–990 DAG1 gene, mutations in  1120 Dandy-Walker malformation  199–202, e470 prenatal diagnosis of  253, e607 “Dandy-Walker variant”  180–181, 253–254, e422 Danon disease  307, 323, e772t–e773t, e817 Dantrolene  e2835t sensorium changes  e2682b for spasticity  1251t toxicity  1196b Dantrolene sodium  e2835 Daphne  1196b sensorium changes  e2682b Dapsone causing peripheral neuropathy  e2684b toxicity  1197b DAT gene, and ADHD  450 DAX1 gene mutations  1167, e2630 Daydreaming, and absence seizures  527 Daytime bladder control  1184 Daytime bowel control  1184 DDC gene, mutation in  1181–1182 De Morsier’s syndrome  e2634 Deafness  e94–e95 bacterial meningitis and  886, e2014 lysosomal storage diseases and  e782 SLC26A4-related  48 Death in apparent life-threatening event  685 preparation for. see Palliative care Death camus  1196b sensorium changes  e2682b Debra P. v Turlington  1283, 1284t, e2893–e2894 Debrancher deficiency  310–311, e728t, e735–e736, e2544–e2545 adult type  311 childhood type  311 infantile type  311 Debrancher enzyme, genes encoding  1132–1133 Decerebrate posturing  775 Decision support software  1298 Decompressive craniectomy, for traumatic brain injury  e1787, e1788b Decorticate posturing  775 Deep-brain stimulation (DBS)  e1437 anterior nucleus of thalamus  620 for dystonia  473, 712 tic disorders and  745 Deep Hypothermic Circulatory Arrest (DHCA)  1208, e2718 Deep tendon reflexes (DTRs)  10–12, 1049, e19–e23, e25t, e2338 assessment of, in preterm infant  22 loss of  1219

1333

Default mode network (DMN)  97, 100, e260, e1736 disorders of consciousness and  768–769 Defecation, disorders of  1189, e2672–e2675 colorectal motility and  e2672, e2674f differential diagnosis of  1191, e2674– e2675, e2675b in extrinsic nervous system  e2673 in intrinsic nervous system  e2672–e2673 management of  1191, e2675 muscle contractions and  e2673–e2674, e2674f normal defecation patterns in  e2672 patient evaluation in  1190–1191 clinical studies  1191 history  1190–1191 neurologic examination  1191 patterns in  1189 Defective mitochondrial protein synthesis machinery  e2566 Defective phospholipid remodeling  e696 Deflazacort, in DMD  1109–1110 Degenerative arthritis, lysosomal storage diseases and  e783 Degenerative diseases/disorders EEG and  e239, e239f of gray matter  e950–e976 Dehydration bacterial meningitis and  885–886, e2013–e2014 ketogenic diets  629b sinovenous thrombosis and  860 Dehydroepiandrosterone (DHEA)  e2628 Dejerine-Sottas disease  1074–1075 Dejerine-Sottas syndrome  e2390 Dejerine type facial anesthesia  823–824 Delayed postanoxic myoclonic seizures  810 hypoxic-ischemic encephalopathy and  e1847–e1848, e1848t Delayed posthypoxic injury  809 hypoxic-ischemic encephalopathy and  e1847 Delayed puberty  1166 evaluation of  1167 functional hypogonadotropic hypogonadism  1167 hypogonadotropic hypogonadism with multiple hypothalamic/pituitary hormone deficiencies  1167 isolated congenital hypogonadotropic hypogonadism  1166–1167 management of  1167–1168 Delayed visual maturation  37, e77 Deletion analysis  e619, e620f Deletion syndrome 1p36  e648–e649 22q11, nonverbal learning disabilities and  e1065 22q11.2  e646 WAGR 11p13  e650 Deletions  260–261, 270, e637 involving distal 6p  e650 Delinquency, in childhood epilepsy  637 Delirium  769, 1194, e1737 Delis-Kaplan Executive Function System (D-KEFS)  e1001t–e1004t Delis-Kaplan Tests of Executive Function  68t–69t, 71, e143t–e146t Delphi technique  1280 Delta-9-THC, for tic disorders  745t Deltoid bursitis  923 vaccine injection and  e2129 Delusions  769, e1737 Dementia, lysosomal storage diseases and  e782

1334

Index

Demyelinating disorders  1301t acute central nervous system  759 laboratory investigations  759–760 magnetic resonance imaging for  760, 761f management of  760–761 optic neuritis  759–761, 761f polyfocal demyelination  759, 760f transverse myelitis  759, 761f relapsing  761–765, e1718–e1726 multiphasic acute disseminated encephalomyelitis  764 multiple sclerosis. see Multiple sclerosis neuromyelitis optica  764, 766f Demyelinating hereditary motor and sensory neuropathy type I (HMSNI or CMT1)  692 Demyelinating leukodystrophies, primary  e1691–e1696 Alexander disease in  e1691, e1692f Krabbe disease in  e1692f, e1695 metachromatic leukodystrophy in  e1692f, e1694–e1695 metachromatic leukodystrophy-like variants in  e1695 saposin A deficiency in  e1695 Sjögren-Larsson syndrome in  e1695–e1696 X-linked adrenoleukodystrophy in  e1692f, e1693 Demyelination acute central nervous system  e1715–e1718 clinical presentations of  e1716 investigations of child with  e1716–e1717 laboratory investigations of  e1716 magnetic resonance imaging of  e1716– e1717, e1719f management of  e1717–e1718, e1720f optic neuritis in  e1715, e1716f polyfocal demyelination/acute disseminated encephalomyelitis in  e1715–e1716, e1718f transverse myelitis in  e1715, e1717f white matter disorders with  751–758, e1691–e1704 adult-onset leukoencephalopathies in  e1703–e1704 calcifying leukoencephalopathies in  e1698–e1700 cerebroretinal microangiopathy with calcifications and cysts in  e1701 congenital cytomegalovirus (CMV) infection in  e1701 cystic leukoencephalopathies in  e1700 megalencephalic leukoencephalopathy with subcortical cysts (MLC) in  e1700–e1701 primary demyelinating leukodystrophies in  751–754, e1691–e1696 Rnase T2-deficient leukoencephalopathy in  e1701 with white matter vacuolization and intramyelinic edema  e1696–e1698 DEND syndrome. see Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome Dengue virus  905, e2057 Denny-Brown, Derek  925 Dental dysplasia  e2802 Dentate nuclei, disruption of  689 Dentatorubral pallidoluysian atrophy  e1577–e1578, e1617

Denver Developmental Screening Test-II (DDST-II)  4, 68t–69t, e5, e143t–e146t, e1001t–e1004t Denver Model  469, e1114 Deontology  1264–1267, e2860 DEPDC5 gene mutations  517 and infantile onset epilepsies  558t–560t Dependency  e2829 Wee Functional Independence Measure  e2829 Depolarizing conductances  506, e1211–e1212 Depression  1233, e2789 antiseizure medications and  638 and generalized seizures  525 tic disorders and  742 Tourette syndrome and  e1666 Wilson’s disease  e2798 Deprivation, protein-calorie  383 Dermacentor andersoni  e2075f Dermal sinus tract  190, e440, e441f Dermatomal somatosensory evoked potentials (dSSEPs), spinal cord injury and  e1880 Dermatomyositis  1141–1144, e2585–e2589 associated manifestations in  1141–1142, e2585–e2586 clinical features of  1141–1142, 1142f, e2585–e2586, e2586f corticosteroids for  1143 juvenile  1141, 1142f laboratory features of  1142–1143, e2586–e2587 blood tests  1142, e2586 electromyography  1142, e2586–e2587 muscle biopsy  1142–1143, e2587, e2587f other agents for  1143–1144 pathogenesis of  1143–1144, e2587 treatment of  1143, e2588–e2589 Descartes, René  e1731 “Designer mice”  116, e289 Desipramine  e2825t attention deficit-hyperactivity disorder and  e1086, e1087t–e1089t sudden death with  454, 455t–457t Desmin  1034 Detrusor muscle, hyperreflexia  827 Detrusor smooth muscle  1185 Developmental coordination disorder (DCD)  434 Developmental delay  269 Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome  407–408, 597, e980, e1384 Developmental disorders, undiagnosed  105 Developmental dyslexia  e1068 Developmental encephalopathies  e587– e596, e588f, e588t, e593f biological pathways involved in  e588–e589 definition of  e587 specific  e589–e592 Developmental language disorders  431–436, e1051–e1059 articulation and expressive fluency disorders in  433–434 phonological programming disorder  434 pure articulation disorders  433–434 stuttering and cluttering  434 verbal dyspraxia  434 child suspected with, evaluation of  435– 436, 436b

Developmental language disorders (Continued) diagnosis of  432–433, e1053–e1054, e1053b evaluation of the child with  e1056–e1057, e1056b factors associated with  432, e1052, e1052b genetics of  432, e1052–e1053 high-order  435 lexical syntactic syndrome  435 semantic pragmatic syndrome  435 neural substrates of language and  431, e1051 neuroanatomy of specific language impairment  e1051–e1052 normal language milestones  432b nosology of  433–435, 433b, e1054–e1056, e1054b, e1054t outcome of  435, e1056 in receptive and expressive language  434–435 phonological syntactic syndrome  434–435 verbal auditory agnosia  435 subtypes of  434t terms used in  433b treatment of  436, e1057 verbal dyspraxia  434t warning signs of  432, 433b Developmental Neurobiology  e449 Developmental pediatric psychogenic nonepileptic seizure  e1465 Developmental reflexes preterm infant  24–25, 25t term infant  20 Developmental scales, of neuropsychological measure  68t–69t Developmental venous anomalies, in intracranial hemorrhage  e1978–e1979 Dexamethasone  942t for acute bacterial meningitis  888 Dexmethylphenidate, for ADHD  454, 455t–457t, e1085–e1086, e1087t–e1089t Dextroamphetamine for ADHD  453–454, 455t–457t, e1086, e1087t–e1089t for excessive daytime sleepiness  675 Dextromethorphan associated with tremor  e2685b in ataxia  e2685b glycine encephalopathy  292 sensorium changes  e2682b toxicity  1196b, 1199b–1200b DHCA. see Deep Hypothermic Circulatory Arrest (DHCA) dHMNs. see Distal hereditary motor neuropathies (dHMNs) DHPR deficiency  482t–486t Diabetes insipidus (DI)  1001, 1171–1172, e2637 Diabetes mellitus  1082, 1178, e2412, e2651 and ADHD  451 Friedreich ataxia and  e1564 maternal, neuroteratology  1203t Diagnostic and Statistical Manual of Mental Disorders (DSM), historical perspective of  e1094 Diagnostic software  e2915 Diagnostic technologies, genomic  e618– e623, e618t, e624t Diagnostic transcranial magnetic stimulation  622, e1438–e1439 Dialeptic seizures  e1265 Dialysis  1218

Dialysis-associated complications  e2746–e2751 Dialysis-associated seizures  e2747 Dialysis disequilibrium syndrome  1218, e2747 3,4-diaminopyridine (3,4-DAP), for Lambert-Eaton myasthenic syndrome  1104 Diana v State Board of Education  1283, 1284t, e2893 Diaphragmatic breathing  1054 Diarrhea, in pediatric autonomic disorders  1174–1175 Diazepam  601t–602t, e2835t for febrile seizures  522 rectal administration of  606t for spasticity  472–473, 1251t spinal cord injury and  828 for status epilepticus  546–547 Diazoxide Parkinsonism and  e2684b toxicity  1198b Dicarboxylic acids (DCAs), in fatty acid oxidation disorders  e2554 Dichlorphenamide, for Andersen-Tawil syndrome  1155–1156 Diencephalic syndrome  e2236 see also Hypothalamic syndrome Diet approaches, for mitochondrial diseases  1139 ketogenic. see Ketogenic diets for pediatric migraine  649–650 phenylketonuria  286 Dietary vitamin A deficiency  388 Diethyltoluamide (DEET)  1195 Differential Abilities Scale II  68t–69t, e143t–e146t Differential Ability Scales  e1001t–e1004t Difficult patients, challenges and  e2818 Diffuse axonal injury  781, 784–785, e1772, e1773f abusive head trauma and  797, e1820 Diffuse cerebral swelling  784, e1772 Diffuse encephalopathies  425 Diffuse fibrillary astrocytoma  986, e2237 Diffuse intrinsic pontine glioma (DIPG)  991–994, 992f, e2244–e2250 background of  991 clinical presentation of  e2245 current treatment for  993 developmental context of  992, e2244 differential diagnosis of  e2246, e2247f emerging therapeutic strategies  994, e2247 epidemiology of  991, e2245 extent of spread  992 histopathology of  991–992 imaging and pathology studies in  e2245– e2246, e2245f molecular characteristics of  992–993, e2244–e2245 presentation and diagnosis of  991 prognosis of  991, e2248 radiation therapy for  993 surgery  992 treatment of  e2246 WHO grading system  991–992 Diffusion imaging, for encephalopathy  140 Diffusion tensor imaging (DTI)  82–83, e184–e188, e187f–e188f of abusive head trauma  e1828 of traumatic brain injury  e1795 Diffusion tensor MRI (dMRI)  97

Index Diffusion-weighted imaging (DWI)  82, e183–e184, e185f–e186f for traumatic brain injury  e1795 Diffusion-weighted magnetic resonance imaging for abusive head trauma  e1828 for encephalopathy  e324 Diffusivity, decreases in  101 Difluoromethylornithine, for T. b. rhodesiense disease  e2096 DiGeorge syndrome congenital heart defects and  1206t genetics  265 nonverbal learning disabilities and  440, e1065 Digital subtraction angiography in brain death determination  836 for measurements of cerebral perfusion  e1912 Digitalis sensorium changes  e2682b toxicity  1196b Digitoxin causing peripheral neuropathy  e2684b toxicity  1197b, 1200b tremor and  e2685b Digoxin Parkinsonism and  e2684b toxicity  1198b Dihydrofolate reductase deficiency  379–381, 482t–486t, e932 Dihydrolipoamide dehydrogenase deficiency  e1382 Dihydrolipoyl dehydrogenase-deficient maple syrup urine disease  288–290, e682 Dihydropteridine reductase deficiency  356– 357, 356t, 756, e876t, e877, e1700 Diltiazem associated with myopathies  e2683b toxicity  1197b Dinitrophenols causing peripheral neuropathy  e2684b toxicity  1197b Dipeptidyl-peptidase-like protein-6 (DPPX) potassium channel antibody encephalitis  1179, e2652 DIPG. see Diffuse intrinsic pontine glioma (DIPG) Diphenhydramine abuse in  e2693 toxicity  1201 Diphtheria  1083, 1197b, e2417 causing peripheral neuropathy  e2684b vaccines for  922, e2128 Diphyllobothriasis  e2101 Diphyllobothrium latum  e2101 Diplegia, spastic  e1655 Diplopia intracranial pressure and  816t myasthenia gravis and  1098 Dipyramidole  856 Direct current stimulation, transcranial  622 Disability Rating Scale  777–778, e1753 Disability scales, in pediatric neuromuscular disorders  1050 Disabled Persons Bill  1287, e2898 Disciple, in childhood epilepsy  640 Discontinuation, of antiseizure drug therapy  610 Discriminative measures  1289 Discussing complex outcomes  e2817b Disease stratification  1245 Disequilibrium, nonvertiginous  56–57, e122–e123

1335

Disialotransferrin  318 Disruption  e466 Disruptive behaviors tic disorders and  742 Tourette syndrome and  e1666 Disseminated intravascular coagulation  886 bacterial meningitis and  e2015 Distal hereditary motor neuropathies (dHMNs)  1077, 1078t, e2400, e2400t Distal weakness, motor neuron disease with  e2381 Disulfiram in ataxia  e2685b causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b, 1199b Diuretics sensorium changes  e2682b toxicity  1196b Divalproex sodium, for ASD  467t–468t Dizziness drug-induced  57, e123 evaluation of patients with  e116–e121 caloric testing  e119, e119f chief complaint  e116–e117 computerized dynamic platform posturography  e120–e121, e120f history  e116–e117 physical examination  e117, e118f posturography and vestibular disorders  e121 rotational testing  e119–e120 vestibular-evoked myogenic potentials  e121 videonystagmography  e117–e119, e118f–e119f migraine-related  56, e122 patients evaluation with  52–54 caloric testing  54 chief complaint  52–53 computerized dynamic platform posturography  54, 55f history  52–53 physical examination  53 posturography and vestibular disorders from medical literature results  54 rotational testing  54 vestibular-evoked myogenic potentials  54 videonystagmography  53–54 DLG3 gene mutation  421t DMD. see Duchenne muscular dystrophy (DMD) DNA (deoxyribonucleic acid)  257 noncoding  257 repetitive  261 somatic mosaicism and challenges of  262–264 DNA sequence analysis  260–262, e618–e623 DNAJC5  e951t–e952t, e962–e963 DNM gene, mutations in  515 DNM1, gene mutations in, and infantile onset epilepsies  558t–560t DNM2-related CNM  e2527–e2528 “Do not attempt resuscitation” order  1260 “Do not resuscitate” order  1260 Doctor-to-patient discussions, in internet  1295–1296 Dok-7 myasthenia  1095, e2447 DOK7 gene, mutations in  1095 Dolichocephaly  233, e568, e568f Doll’s-eye movement  e43 Domperidone, for gastro esophageal reflux  474–475

1336

Index

Donepezil, for tic disorders  745t Doose syndrome  630 Dopa-decarboxylase deficiency  357–358, e879–e880, e879f Dopa-responsive dystonia  710–711, e1606 autosomal-dominant  e878–e879 autosomal-recessive  e880–e881 Dopamine  1165, e2632 deficiency  356t metabolism, metabolite patterns in  e877t tic disorders and  744, e1669–e1670 Dopamine agonists, for tic disorders  745, 745t Dopamine B-hydroxylase, deficiency  358 Dopamine beta-hydroxylase  1181 deficiency  1181, e876t, e881, e2655, e2655f Dopamine receptor antagonists  e1181– e1184, e1181t aripiprazole  494–495 atypical antipsychotics  494–495 clozapine  495 olanzapine  494 quetiapine  494 risperidone  494 side effects of  494 typical antipsychotics  493–494 ziprasidone  494 Dopamine receptor blockade, drug-induced movement disorders associated with  728–732, e1641–e1646 acute, chronic, tardive and withdrawal emergent syndromes and  729–731 clinical features of  729–731, e1644–e1645 epidemiology of  728–729, 730t–731t, e1641–e1644, e1643t–e1644t neuroleptic malignant syndrome and  732 pathophysiology of  731, e1645 treatment of  731–732, e1645–e1646 Dopamine transporter in ADHD  450 deficiency  356t, 359, 712, e876t, e882 Dopaminergic projections, PFC and  1187–1188 Dorsal rhizotomy, selective , in spasticity  e2837 patient criteria selection  e2837b Dose-response concept  e1404 Down syndrome  271–272, 479, 479t, e57, e642–e643, e643f central hypotonia and  1055t, e2345 congenital heart defects and  1206t and developmental language disorders  432 and intellectual disability  418 treatment of  e1138t, e1139–e1140 Doxazosin  e2755b Doxepin myopathies and  e2683b toxicity  1197b Doxycycline for Lyme disease  891 for rickettsial diseases  909 for Rocky Mountain spotted fever  e2076 DPAGT1-CDG (Ij)  320, e752t–e760t, e761 DPAGT1 myasthenia  1096, e2447–e2448 DPM1-CDG (Ie)  e752t–e760t, e762–e763 DPM2-CDG  e752t–e760t, e763 DPM3-CDG (Io)  e752t–e760t, e763–e764 Dravet syndrome  516, 535, 536f, 538, 567, e977–e979, e1232–e1233, e1273–e1274 clinical features of  405–406, e977–e978 obtundation status  405

Dravet syndrome (Continued) clinical laboratory tests of  406, e978–e979 EEG findings in  567 in electroclinical syndrome, infantile onset  e1331–e1332, e1332f–e1333f etiology of  567 genetics of  406, e978, e979f ketogenic diets for  624 neuroimaging in  567 neurologic findings in  567 outcomes for  567 pathophysiology of  406, e978, e979f seizures in  567 treatment of  406–407, 567, e979 DRD1 single-nucleotide polymorphism, and ADHD  450–451 Drooling, excessive, in cerebral palsy  740 Drosophila melanogaster  114 Drowning  808–809 cardiac arrest and  e1846 children with epilepsy and  642, 645 epidemiology of  808–809 Drowsy patterns  89–90 of EEG  e221–e222, e221f Droxidopa  1181 Drug holidays  453 Drug-induced encephalopathy, in renal failure  e2766, e2766b Drug-induced lupus syndrome, in SLE  951, e2170–e2171 Drug-induced neurologic diseases  1193–1204 Drug-induced syncope  e1516 Drug information and interactions  1297 Drug-resistant epilepsy  e1132 Drugs, renal transplantation complications and  1220, e2752 Dry mouth  1179 DSM-V classification tic disorders  742b Duane retraction syndrome, CHN1-related  207 Dubowitz disease  e2357 Duchenne muscular dystrophy (DMD)  1046, 1106–1111, e2472–e2482, e2726 in boys  1162 cardiac manifestations in  1161 clinical features of  1107, e2473–e2475, e2474f dystrophin protein in  e2472 dystrophinopathy therapeutics for  e2478– e2479, e2478f genotype-phenotype correlations in  1109, e2476–e2477 interdisciplinary management of  1158f laboratory features of  1108–1109, e2475–e2476 management of  1109–1110, e2477–e2478, e2617f, e2621 cardiac  1110 contractures  1110 corticosteroids  1109–1110 medical  1109–1110, e2477–e2478 nonmedical  1110, e2478 pulmonary  1110 spine/scoliosis  1110 muscle biopsy in  1109, e2477 mutation analysis in  1108–1109, e2475–e2476 “reading frame rule” in  e2472–e2473, e2473f–e2474f serum CK levels found in  1039t weakness and  1157 see also Becker muscular dystrophy (BMD)

Duplex Doppler sonography  e163 Duplication  270, e637 analysis  260–261, e619 Dural sinus thrombosis, in CNS leukemia  1017, 1018f Duty  1264 Dwarfism, cachectic  751 Dynamic nuclear bag fibers  27 Dynamic splinting  1157 Dynamin-2 (DNM2)  1124t–1125t, 1127 DYRK1A disorders  247, e592 Dysarthria cerebellar (ataxic)  689 in dermatomyositis  1141 Dysautonomia  1250, e2832 metabolic disorders and  e667–e668 “Dysautonomic crises”  1179 Dyscognitive seizures  e1265 Dysdiadochokinesia  689 Dysembryoplastic neuroepithelial tumors (DNTs)  593, 986, e1376–e1377, e2236 Dysequilibrium syndrome  e519 DYSF gene, mutations in  1115 Dysferlin  1034, e2306–e2307 Dysferlinopathy  1115, e2492–e2493 Dyskinesia antipsychotic medications and  e1182– e1183, e1182t paroxysmal  718–723, e1606, e1627–e1635 classic phenotypes of  718–721 clinical features of  719t exertion-induced  721 generalized epilepsy and  720 genetic causes of  722f genotype-phenotype association in  721–722 historical context of  718 hypnogenic  721 kinesigenic  719–720 nonkinesigenic  720–721 terminology in  718 treatment of  722t Dyskinetic gaits  31–32 Dyslexia  435, 442–446, e1068–e1075 accommodations for  e1073–e1074 attentional mechanisms in reading and  e1073 brain imaging studies for  444 children with, tests helpful in evaluation with  445 academic achievement in  445 letter knowledge  445 phonological processing  445 clues to  444b definition of  442, e1068, e1069f diagnosis of  444–445, e1070–e1072, e1071b in adolescents and young adults, essential components of  445 epidemiology of  442–443, 443f, e1068–e1069, e1069f etiology of  442–443, e1068–e1069 evaluation of  e1072 evolution of  e1068 laboratory tests  445 learning disabilities and  e1068 neural signature of  443f, 444 neurobiological evidence supporting  443– 444, e1069–e1070, e1070f neuroimaging, fMRI  443 neurologic examination  445 outcome in  445, e1072 phonologic model of  443–444, e1069–e1070

Dyslexia (Continued) physical examination in  445 reading systems in  443, 443f treatment of  445–446, e1072–e1074 accommodation in  446 Dysmetria  689 Dysosmia  63 Dysostosis multiplex  e783, e800, e800f Dysphagia  1141, 1228, e2776 neuromuscular disorders and  1162 Dysplasias cerebellar  203–204 isolated septum pellucidum  e462, e462f pontine tegmental cap  206 retinal  e74–e75 septooptic  e461, e461f Dyspraxia motor, and ASD  465 verbal  434, 434t Dyssynergia cerebellaris myoclonica  e1617 Dystonia  27, 472, 707, 707t, 709–712, e54, e1598, e1603–e1611 associated with neurodegenerative disorders  e1607–e1609 causes of  710b, e1604b classification of  e1604t due to nonprogressive disorders  712, e1609–e1610 DYT1  710, e1605 DYT2  e1605 DYT4  e1606 DYT5  710–711, e1606 DYT6  e1606 DYT8  e1606 DYT9  e1606 DYT10  e1606 DYT11  711, e1606–e1607 DYT12  e1607 DYT16  e1607 genetic  710–711, e1603–e1607, e1605t IEMS and  282–283 medication-induced  712, e1610 metabolic disorders and  711–712, e665–e666 neurodegenerative disorders and  711 orofacial  357f tics and  741 treatment of  473, 712, 1253, e1129, e1610–e1611, e2837–e2838 Wilson’s disease and  1235 Dystonia musculorum deformans  710 Dystonic cerebral palsy  e1655–e1656 Dystonic storm  e1610 Dystroglycan  1033 α-Dystroglycan, abnormalities of  1119–1122, e2505–e2510 Bethlem myopathy  e2508 clinical presentations of  e2505–e2509 congenital muscular dystrophy with early rigid spine syndrome  e2508 with integrin α7 deficiency  e2507 Fukuyama congenital muscular dystrophy in  e2506 laminin-α2 (merosin)-negative congenital muscular dystrophy  e2508 MDC 1D  e2507 muscle biopsy features of  e2505–e2506 muscle-eye-brain disease  e2506–e2507 muscular dystrophy congenital type 1C  e2506 nonsyndromic congenital muscular dystrophies, merosin-positive  e2508 Ullrich congenital muscular dystrophy  e2508 Walker-Warburg syndrome  e2507

Index Dystroglycan complex  e2485–e2486 α-Dystroglycan glycosylation, disorders of  1114–1115, e2490–e2493 anoctaminopathy  1115, e2493 autosomal-recessive conditions in  e2493 calpainopathy  1114–1115, e2491–e2492 congenital muscular dystrophies due to  206 dysferlinopathy  1115, e2492–e2493 fukutin-related protein deficiency  1114, e2490 other α-dystroglycanopathies in  e2490–e2491 X-linked recessive conditions in  e2493–e2494 Dystroglycanopathies  1120–1121, 1161, e752t–e760t, e1704 serum CK levels found in  1039t α-Dystroglycanopathies  e478 Dystrophin  1032–1033, 1106, 1161, e2304–e2305, e2472 domains of  1106 function  1106 muscle membrane and  1106 Dystrophin-associated proteins (DAPs)  e2485 Dystrophin-glycoprotein complex  1033– 1034, e2305–e2306 Dystrophinopathies  1112, e2483 therapeutics  1110–1111 recent advances in  e2478–e2479, e2478f

E

E-mail  1296 Ear anatomy and physiology of  43, e89–e94, e91f external malformations of  45–46 Early infantile epileptic encephalopathy (EIEE)  513–514, e1227–e1228 electroclinical syndrome, in neonatal  e1310–e1313 clinical features of  e1310 diagnosis of  e1312, e1313f differential diagnosis of  e1313 etiology of  e1310–e1312, e1311t–e1312t prognosis of  e1313 treatment of  e1313 Early myoclonic encephalopathy (EME)  132, 555, e312 clinical features of  555 diagnosis of  555 differential diagnosis  555 in electroclinical syndrome  e1313–e1314 etiology of  555 management of  555 prognosis of  555 Early onset childhood occipital epilepsy  573, e1343 Early poststroke seizures  e1376 versus late poststroke seizures  e1375 Early posttraumatic seizures, versus late posttraumatic seizures  e1374 Early Start Denver Model (ESDM)  469 Eastern equine encephalitis virus  e2045 Eating disorders  1178, e2651 sleep-related  669 ECE1 gene, mutations in  1182 Echinococcosis  914–915, e2101–e2102 Echinococcus spp. E. granulosus  914, e2101–e2102 E. multilocularis  914

1337

Echolalia  434, 741 delayed  459 immediate  459 Echopraxia  741 ECMO. see Extracorporeal membrane oxygenation (ECMO) Ecstasy  1199 abuse in  e2691 renal toxicity of  1225t, e2765t Ectocranial bone deposition  e567 EDMD. see Emery-Dreifuss muscular dystrophy (EDMD) EDN3 gene, mutation in  1182 Edrophonium (Tensilon) test for autoimmune myasthenia gravis  e2455–e2457 for myasthenia gravis  1099 Education computer resources and  1298, e2916–e2917 febrile seizures and  522 Education Act  1286–1287 Education and training  e2919–e2924 of child neurologists and workforce issues  1299–1303 current approaches in  1300–1302, 1301t, e2920–e2922, e2921t–e2922t current workforce issues and  1302–1303 future workforce issues and  1303 historical aspects of  1299–1300, e2919–e2920 preceding child neurology  1302, e2922–e2923 Education for All Handicapped Children Act  1283–1285, 1287 Edwards’ syndrome. see Trisomy 18 Edwin Smith Surgical Papyrus  e1731 EEG  e237–e240 abnormal patterns of  e226–e237 assessment of prognosis  e226–e228, e226f–e228f, e227t epileptiform abnormalities  e231–e235 focal abnormalities  e228–e229, e228f–e229f focal periodic patterns  e231, e231f idiopathic focal epilepsies of childhood  e235–e236 neonatal  e226 neonatal seizures  e229–e231, e230f spike discharges associated with specific neurologic conditions  e236–e237 spikes and sharp waves  e231 for absence seizures  527, 527f–528f for acute cerebellar ataxia  704, e1588–e1589 for ADHD  452, e1083 in atonic seizures  529 autistic spectrum disorder and  465, e1107 for benign epilepsy of infancy/benign familial infantile epilepsy  565 for benign epilepsy with centrotemporal spikes  572, 573f for benign familial neonatal epilepsy  553 for benign myoclonic epilepsy of infancy (BMEI)  538 beta activity of  e220 brain death determination  831, 834–836, 836t, e238, e1909–e1910, e1909t for breath-holding spells  656 central nervous system infections  e238–e239 for childhood absence epilepsy  569, 570f for coma  777

1338

Index

EEG (Continued) conventional video  132–133, 133f, e313, e313f degenerative diseases  e239, e239f and developmental language disorders  436 for Dravet syndrome  567 drowsy patterns of  e221–e222, e221f for epilepsy and seizure  499 for epilepsy of infancy with migrating focal seizures  563, 564f in epilepsy surgery  614, e1421 for febrile seizures  520, e237 for focal seizures  531–533, 532f, 534f following cardiac arrest  810, e1848–e1849 and functional neuroimaging  e241 for generalized tonic-clonic seizures  524–525 for genetic epilepsy with febrile seizures plus (GEFS +)  568 for genetic generalized epilepsies with convulsions  578 guidelines for interpretation  e210–e211 head trauma  e237–e238 for headache  649, e238 for hemiconvulsions, hemiplegia, and epilepsy syndrome (HHE)  565–566 hyperammonemic coma and  300 hyperventilatory response  e221, e221f ictal, in infantile spasms  540 for intellectual disability  422 for juvenile myoclonic epilepsy  539, 577 lambda waves  e221 for Lennox-Gastaut syndrome  571–572, 571f maturational patterns  e210–e223 for mesial temporal lobe epilepsy resulting from hippocampal sclerosis  579 monitoring of  e313 indications for  133, e313 neonatal  132–133 mu rhythm of  e220 for myoclonic-astatic epilepsy of Doose (MAE)  539 for myoclonic encephalopathies in nonprogressive disorders  557–563 for myoclonic epilepsy in infancy  557 in myoclonic seizures  528 neurophysiological basis for  e205–e210, e206f–e208f newborn electroencephalographic patterns  e211–e212, e212f–e215f nonepileptic paroxysmal disorders  e239–e240 normal patterns, in infancy through adolescence  e219–e221 normal variation in, significance of  e210–e223 ontogeny of  e212–e219 gestational age of 28 to 31 weeks  e214f– e215f, e216–e217 gestational age of 28 weeks  e214f–e215f, e216 gestational age of 32 to 34 weeks  e217 gestational age of 34 to 37 weeks  e214f–e215f, e217–e218 gestational age of 38 to 42 weeks  e214f–e215f, e218–e219 photic stimulation  e221, e222f, e225f in PNES  632 for postischemic seizures  809–810 predictive value of, for ketogenic diets  627 prognosis after hypoxic-ischemic insults  e238

EEG (Continued) progressive encephalopathies and  428 recording of, duration of  133, e313–e314 Rett syndrome and  244 Reye syndrome  e239 for seizures  475 sleep activation procedures  e222–e223 sleep patterns  e223–e226 arousal patterns  e225 frequency distribution  e225 infant and childhood  e224 occipital sharp transients  e225, e225f ultradian rhythm  e223–e224 vertex waves and sleep spindles  e224, e224f theta and delta slowing  e220, e220f in tonic seizures  529 for traumatic brain injury  787, e1795–e1796 uncertain significance patterns of  e225– e226, e225f waking patterns of  e219–e220, e219f for West syndrome  566 of white matter injury  167, e388 Effective connectivity  e258 definitions of  99 Efferent autonomic pathways  1173, e2642–e2643, e2643f efferent neurotransmission in  e2643 parasympathetic  e2643 sympathetic  e2642–e2643 Efferent neurotransmission  1173 EFHC1, mutations in  517 EGR2 gene, mutations in  1074 Ehlers-Danlos syndrome (EDS)  e1990 postural orthostatic tachycardia syndrome and  e1518 Ehrlichia ewingii  e2073t–e2074t, e2078 Ehrlichiosis  e2077–2078 human monocytic  e2077, e2077f eIF-2B-related disorder  755, e1685f, e1696–e1697 18q Minus syndrome  e1690 Electrical impedance myography  1041, e2319 Electrical injuries  809 Electrical shock  809 cardiac arrest and  e1847 Electrical status epilepticus  475 in sleep  637 Electrocerebral silence  834–835 Electroclinical syndromes  242, 498, e1269b arranged by typical age of onset  553t defined  552 Electroclinical syndromes, adolescent onset  576–582, e1349–e1363 additional diagnostic considerations for  581–582 biomarkers in  581 chronobiology in  581 pharmacogenetics in  581–582 additional diagnostic considerations in  e1359–e1360 avoiding triggers in  576–577 behavioral issues in  576–577, e1350 classification of  576, e1349 compliance in  576–577, e1350 epidemiology of  576, e1349–e1350 focal epilepsies  579–580, e1356–e1359 autosomal-dominant nocturnal frontal lobe epilepsy  579–580 autosomal-dominant partial epilepsy with auditory features  579

Electroclinical syndromes, adolescent onset (Continued) mesial temporal lobe epilepsy resulting from hippocampal sclerosis  579, 580f treatment for  581 generalized epilepsies  577–579, e1351–e1356 genetic, with convulsions  577–578, 578f juvenile absence epilepsy  577 juvenile myoclonic epilepsy  577, 577f progressive, rare Mendelian-inherited  578–579 treatment of  580–581 nonmendelian-inherited, genetics of  578 ontogenesis of  576, e1349 psychosocial and cognitive implications of  576, e1349–e1350 treatment of  e1360–e1361 Electroclinical syndromes, childhood onset  569–575, e1336–e1348 focal epilepsy syndromes  572–573, e1342–e1344 benign epilepsy with centrotemporal spikes  572–573, e1342–e1343, e1343f early onset childhood occipital epilepsy  573, e1343 late-onset childhood occipital epilepsy  573, e1344 generalized epilepsy syndromes  569–572, e1336–e1342 childhood absence epilepsy  569–570, e1336–e1338, e1337f with eyelid myoclonia (Jeavons syndrome)  570, e1338 Lennox-Gastaut syndrome  571–572, e1339–e1342 with myoclonic absences (Tassinari syndrome)  570, e1338 with myoclonic-atonic seizures  571, e1338–e1339, e1339f undetermined  573–574 acquired epileptic aphasia  574 epileptic encephalopathy with continuous spike and wave during sleep  573–574 Electroclinical syndromes, infantile onset  557–568, e1316–e1335 Dravet syndrome in  e1331–e1332, e1332f focal syndromes  563–566, e1325–e1329 benign epilepsy of infancy/benign familial infantile epilepsy  565 epilepsy of infancy with migrating focal seizures  563–565 hemiconvulsions, hemiplegia, and epilepsy syndrome (HHE)  565–566 gene/genetic syndromes associated with  558t–560t generalized syndromes  557–563, e1316–e1335 myoclonic encephalopathies in nonprogressive disorders  557–563 myoclonic epilepsy in infancy  557 genetic epilepsy with febrile seizures plus (GEFS+)  e1332–e1333, e1333f inborn errors of metabolism associated with  560t–562t myoclonic epilepsy in infancy in  e1316–e1317

Electroclinical syndromes, infantile onset (Continued) undifferentiated syndromes  566–568, e1329–e1333 Dravet syndrome  567 genetic epilepsy with febrile seizures plus (GEFS +)  567–568 West syndrome  566–567 West syndrome in  e1329–e1333 Electroclinical syndromes, neonatal onset  552–556, e1308–e1315, e1309t benign  552–553 benign familial neonatal epilepsy  553–554, e1309–e1310, e1309t, e1310f benign neonatal seizures in  e1308, e1309t early myoclonic encephalopathy  555, e1313–e1314 Ohtahara syndrome  554–555, e1310, e1311t–e1312t Electroclinical uncoupling  549 Electrodiagnosis in CIDP  e2435 in GBS  e2431–e2432, e2432b Electroencephalogram. see EEG Electroencephalographic neonatal sleep, as ultradian rhythm  90–91 Electroencephalographic patterns abnormal  92–96 assessment of prognosis  92 beta activity  88 epileptiform abnormalities  93–96 focal abnormalities  92 focal epileptiform  95 focal periodic  93 generalized periodic discharges  95 hyperventilatory response  89 hypsarrhythmia  95 lambda waves  89 mu rhythm  87 multiple independent spike foci  95 neonatal seizures  92–93 newborn  87 normal, in infancy through adolescence  87–89 occipital spikes  95 periodic discharges  96 photic stimulation  89, 90f rolandic spikes  95 sharp-wave and slow-wave complexes  94–95 spike-and-wave patterns  94 spikes and sharp waves  93 temporal spikes and sharp waves  95 theta and delta slowing  88–89, 88f waking patterns  87, 88f Electroencephalographic sleep analyses, computer strategies for  e241–e242, e242f–e243f Electroencephalography. see EEG Electrographic data, monitoring strategies and computer analyses of  e240–e247 electroencephalography and functional neuroimaging  e241 evoked potential analysis  e242–e247 magnetoencephalography  e241 pediatric neurointensive care  e240–e241 synchronized videoelectroencephalographic recordings  e240 Electrolyte imbalance cardiac arrest and  805t in coma  776 impairment of consciousness and  e1750

Index Electromyography (EMG)  1040–1041 in acute cerebellar ataxia  704, e1588–e1589 in dermatomyositis  1142 in neuromuscular disorders  e2318–e2319 single-fiber, for myasthenia gravis  1099–1100 Electronic health record (EHR)  1296, e2912–e2913 Electrophysiologic evaluation, for spinal cord injury  822 Electrophysiologic testing for autoimmune myasthenia gravis  e2457–e2458 for myasthenia gravis  1099–1100 Electrophysiology  e111 Electroretinography  e245–e246, e246f Elementary and Secondary Education Act of 1965 (P.L. 89-10)  1285 Eletriptan  650t Embden-Meyerhof pathway  312 Embryology malformations of cortical development  218 split cord malformations  190 Embryonal tumors atypical teratoid/rhabdoid tumors (AT/ RT)  995–999 of central nervous system  e2211–e2214 clinical presentation of  e2211 medulloepithelioma  e2211–e2212, e2213f treatment and outcomes  e2212–e2213 types of  e2211–e2212, e2212f clinical presentation of  969 medulloblastoma. see Medulloblastoma outcomes  971 treatment of  971 types of  969–971 medulloepithelioma  969–970, 971f, e2211–e2212, e2213f with multilayered rosettes (ETMRs)  969, 970f not otherwise specified  970–971, 971f Embryonal tumors with abundant neuropil and true rosettes (ETANTRs)  e2211, e2212f Embryonic period, brain development  e986, e987f Embryonic stem cells, human and murine NSCs from, generation of  108, e278 Emerin  1034 Emery-Dreifuss muscular dystrophy (EDMD)  1116, e2495–e2496, e2621–e2622, e2726 approach to  e2509 approach to patient with  1122 clinical features of  1117, e2496f, e2497–e2498 diagnosis of  1117, e2498 genetics of  1117–1118 management of  1117, e2498 pathophysiology and genetics in  e2496–e2499 pathophysiology of  1117–1118 Emesis, sinovenous thrombosis and  860 EMGWhiz  e2917 EMLA  75, 1258, e153 Empathy  1240, 1240b Empty delta sign  861, 879f, e348–e349 Empty sella syndrome  1167 Enalapril  e2755b

1339

Encephalitides, autoimmune  e2137 Encephalitis  896, 933, e2141 anti-N-methyl-D-aspartate receptor  931, 934–935, e2137, e2143, e2652 autoimmune  548 basal ganglia  935 dipeptidyl-peptidase-like protein-6 (DPPX) potassium channel antibody  e2652 in disorders of excessive sleepiness  e1535 glycine receptor antibody  935 granulomatous amebic  911 limbic  930, 933, e2136–e2137 pan  933 Encephalocele  189, e438–e439 clinical characteristics of  189, e438–e439, e439f–e440f etiology of  189, e438, e439t management of  189, e439 Encephalofacial angiomatosis  e900–e902 see also Sturge-Weber syndrome Encephalomyelitis acute disseminated  759, 761f, 895, e1715–e1716, e1718f etiology, influenza virus  919 influenza virus vaccine and  e2125 multiphasic  764, e1724 recurrent  e1724 Encephalopathies chronic, without multiorgan involvement  176, e418–e419 developmental  242–248 autism spectrum disorders and  242– 243, e587–e588 biological pathways involved  243–244 definition of  242 genes and biological pathways associated with  243t neurofunctional domains commonly disordered individuals  243t relationship to disorders with prominent brain malformations  242 specific  244–247 diffuse  425 epileptic, relationship to  242 metabolic  e401–e421 specific developmental  244–247 subacute epileptic  e413–e418 Encephalopathy  e2054 acute IEMs and  278–279 metabolic disorders and  e658–e659 acute necrotizing  904 aluminum toxicity and  1218, e2747–e2748 bilirubin. see kernicterus brain imaging of newborns with  139–140, 139f, e323–e324, e323f advanced magnetic resonance techniques  e324 diffusion imaging  e324 magnetic resonance spectroscopy  e324 cat scratch disease  892 congenital uremic  1217 developmental  e521 drug -induced  1224–1225 hyperammonemic  301 hypertensive  1220, e2753–e2754 influenza  904 KCNQ2  513 milder forms of  1218–1219, e2748–e2749 neonatal  138

1340

Index

Encephalopathy (Continued) posttreatment in central nervous system posttreatment sequelae  e2289–e2290 with neurologic impairment  1022–1024 uremic  1216–1217, e2742–e2745 congenital  e2745–e2746 “Encephalopathy of prematurity”  165 Encephalopathy Scoring System  e40t Encopresis, fecal incontinence and  1191 Endocarditis, infective  852, e2720–e2721, e2721f Endocrine disorders, of hypothalamus and pituitary gland  1165–1172, e2627–e2641 Endocrinologic sequelae  968 Endocrinopathy  1219, e2751 Endoscopic third ventriculostomy, for hydrocephalus  e560 Endothelial differentiation, in cerebrovascular system  842–843, 843f, e1922–e1923, e1923f Endothelin  800 Endotracheal intubation  826 Endplate acetylcholinesterase (EP AChE) deficiency  1093–1094, e2444–e2445 Endplate choline acetyltransferase deficiency  e2443–e2444 Endplate development, defects in, congenital myasthenic syndromes caused by  e2446–e2447 Energy balance disorders of  1170–1171, 1170f hypothalamic disorders of  e2635–e2636, e2635f Energy metabolism, disorders of  131, e311 Energy production, disorders of  e2725 Energy utilization  1131 Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA)  e270 Entamoeba histolytica  e2079 Enteric infections  1231–1232, e2785–e2787 Enteric nervous system (ENS)  1228, e2775–e2776 Enteric neuropathies  e2779–e2780 Enteric rotavirus infection  e2787 Enterovirus  e2384 Enteroviruses, nonpolio  899t Enthesitis-related arthritis  e2165 Entrustable Professional Activities (EPA)  e2922 model  1301–1302 Environmental risk factors, to multiple sclerosis  763 Environmental toxins  e2686–e2689 Enzymatic assays, in fatty acid oxidation disorders  e2555, e2556t Enzyme replacement therapy, juvenile and adult GAA deficiency and  310 Eosinophilic myositis  1145 EP AChE. see Endplate acetylcholinesterase (EP AChE) deficiency Ependymal tumors, WHO classification of  974b Ependymoma  960t, 973–977, 1013t, e2215–e2225 biomarkers in  975, e2219–e2220 of cauda equina  1013t, 1014 chemotherapy for  975–976, e2220–e2221 of conus-cauda region  e2278 cytogenetics of  974–975, e2218–e2219, e2218t–e2219t epigenetic heterogeneity  974t genetic heterogeneity between spinal and intracranial  974t

Ependymoma (Continued) diagnostic evaluation of  973, e2215 imaging studies in  e2215, e2216b, e2217f prognostic factors in  e2215–e2217 tumor grade in  e2216–e2217 epidemiology of  973, e2215, e2216b epigenetic phenomena in  975, e2219 experimental therapy for  976, e2222 extradural myxopapillary  1014 genetics of  974–975, e2217–e2220 imaging  973 incidence of  973, e2215, e2216b intramedullary  1014–1015 location of  973, e2215, e2216b, e2216f ongoing issues in  977b, e2223b pathology of  973, e2215, e2216b patterns of failure in  e2222–e2223 prognostic factors  973–974 radiation therapy for  976, e2221–e2222 recurrence and patterns of failure  976–977 recurrence of  e2222–e2223 RTK1 protein family in  e2220 symptoms and signs of  974b treatment of  975–977, e2220–e2223 tumor grade  973–974 Epidermal nevus syndrome  370, e903–e904, e903t Epidermoid tumor, spinal  825, e1883 Epidermolysis bullosa  e577–e578 Epidural abscesses  e2027 spinal  825, 894, e1882–e1883 Epidural hematoma  785, e1775–e1776, e1775f abusive head trauma and  797, e1818 spinal  824, e1881–e1882 Epidural hemorrhage  157, e362 Epilambanein  e1197 Epilepsy  1232, 1272, e268–e269, e1197– e1201, e1198t, e2789 absence, physiology of  e1217–e1218, e1217f and abnormal neuronal firing  508–509, 510f with ADHD  453 age of onset  499t, e1198t ancient disease in modern times  497 antiseizure drug mechanisms in  511 arachnoid cysts and  e563 arterial ischemic stroke and  856 and ASD  465–466, e1108 associated with brain tumors  e1376–e1377 autoantibody associations with  933 autosomal dominant nocturnal frontal lobe  408 cellular electrophysiology of  506–509 abnormal neuronal firing in  508–509, 509f and epileptogenesis in developing brain  511 excitation-inhibition balance  506 ion channels in  506, 507f and regulation of ionic environment  511 structural maturation of brain and seizure susceptibility  511 synaptic physiology  507–508 voltage-dependent membrane conductance in  506–507 in cerebral palsy  739–740 channelopathies and  e977–e980, e978t

Epilepsy (Continued) childhood disorders that may mimic  e1203b scoring system for  e1204t childhood absence  104, 569–570, e268 clinical characteristics of  569 EEG findings for  569, 570f etiology of  569 genetics of  569 prognosis of  570 treatment for  569–570 classification of seizures in  e1198t clinical definition of  e1198t cognitive problems in  504 conceptual evolution of  498, e1199, e1199t defined  506, e1210 of ILAE  e1202 diagnosis of  499–501, e1199–e1200 disorders that may mimic  502b epidemiology of  498–499, e1199 focal structural. see Focal structural epilepsy frontal-lobe  104 generalized epilepsy with febrile seizures plus  407 genetics of  497–498, 513–518, e1226– e1239, e1227f, e1230t–e1231t idiopathic generalized  e1233–e1234 IEMS and  279–280 immune-mediated  933–934 inborn errors of metabolism and  486– 487, e1153 incidence of  499 interictal epileptiform discharges  e1200 intracranial arachnoid cysts and  232 intractability in  503 juvenile myoclonic  408 remission rate in  504 lissencephaly and  219, e515–e517 localization-related  e268–e269 intractable  e269 management and outcomes in, principles of  501–505 anti-epileptic drug (AED) treatment for  501–502 and routines of care  501–502 social outcomes in  504–505, 505t metabolic disorders and  e659–e662, e662t microcephaly and  209, e487 mortality in  e1482–e1489 epidemiology of  e1482–e1483 five categories of  e1483t not related to seizure, prevention of  e1487 related to seizure, prevention of  e1486–e1487 sudden unexpected death in  e1483, e1483b myoclonic, juvenile  408 neuromodulation in  e1436–e1441 deep-brain stimulation in  e1437 diagnostic transcranial magnetic stimulation  e1438–e1439 repetitive transcranial magnetic stimulation in  e1438 responsive neurostimulation in  e1437–e1438 transcranial direct current stimulation  e1439 trigeminal nerve stimulation in  e1438 vagus nerve stimulation in  e1436–e1437

Epilepsy (Continued) neurophysiology of  506–512, e1210– e1225, e1211t new conceptual and practical definitions  497–498 new lexicon for  498 with onset in childhood and adolescence  516–517 autosomal-dominant focal epilepsy with auditory features  517, e1234 autosomal-dominant nocturnal frontal lobe epilepsy  517, e1234 epilepsy-aphasia syndromes  516–517, e1233 familial focal epilepsy with variable foci and DEPDC5-related epilepsies  517, e1234–e1235 idiopathic generalized epilepsies  517, e1233–e1234 with onset in infancy  514–516, e1228–e1233 benign familial infantile epilepsy  514, e1228 Dravet syndrome and genetic epilepsy with febrile seizures plus  516, e1232–e1233 epilepsy associated with protocadherin 19 (PCDH19)  516 epilepsy of infancy with migrating focal seizures  515 epileptic encephalopathy associated with cyclin-dependent kinase-like 5 (CDKL5)  514–515, e1228–e1229 epileptic encephalopathy associated with SCN8A  516 with migrating focal seizures  e1229 West syndrome  515, e1229–e1232 with onset in neonatal period  513–514, e1226–e1228 benign familial neonatal epilepsy  513, e1226 benign familial neonatal-infantile epilepsy  514, e1228 epileptic encephalopathy associated with SCN2A  514 KCNQ2 encephalopathy in  e1226–e1227 Ohtahara syndrome  513–514, e1227–e1228 operational (practical) clinical definition of  498t overview of  497–500 perinatal arterial ischemic stroke and  e345 photosensitive, and generalized tonicclonic seizures  524 PNES and, differential diagnosis  632 polymicrogyria and  223, e533 postneonatal  e317–e318 poststroke  e1375–e1376 posttraumatic  791, 796, e1373–e1375, e1374t, e1798 abusive head injury and  e1814 prevention of  e1789 in Prader-Willi syndrome  247 and predication of seizure outcome  502–504 prevalence of  499 pyridoxine-dependent  e923–e924 remission of  502–503, 503t remote symptomatic, arterial ischemic stroke and  e1947 Rolandic  104, 501, e268 smooth sailing  502 status epilepticus  e1292–e1307 stigma from  504

Index Epilepsy (Continued) structural correlates of  e1210–e1225, e1213f structural-metabolic  497–498 subcortical band heterotopia and  219 unknown  497–498 vision loss and  37, e77 Epilepsy-aphasia syndromes  516–517, e1233 Epilepsy of infancy with migrating focal seizures  515, 563–565, e1229, e1325, e1326f differential diagnosis for  563 EEG findings in  563, 564f etiology of  563 laboratory studies in  563 neuroimaging for  563 neurologic findings in  563 outcomes for  565 seizures in  563 treatment for  563 Epilepsy surgery  592, 612–618 future trends of  617 goals of  617 historical background of  612 indications for  612–613 invasive intracranial electroencephalography monitoring  616–617 in pediatric population  e1417–e1435 goals of  e1431 historical background of  e1418 indications for  e1418–e1420, e1419f–e1420f invasive intracranial electroencephalography monitoring in  e1429 preoperative evaluation in  e1420–e1429 concept of congruence in  e1428–e1429 seizure semiology in  e1420–e1428 types of  e1429–e1431 preoperative evaluations for  613–616 concept of congruence  616 electroencephalography  614 functional mapping  616 magnetic resonance imaging  614–615, 614f magnetic resonance spectroscopy  615 magnetoencephalography  615–616 physical examination  614 positron emission tomography  615 seizure semiology  613–614 single-photon emission computed tomography  615 techniques and technologies  613–616 research issues of  617 types of  617 Epilepsy syndromes  132, 405–408, e311–e312 childhood absence epilepsy  408 developmental delay, epilepsy and neonatal diabetes  407–408 diagnosis of  e1202, e1203b early onset, treatment of  135–136, e317 outcome of  e1205 postneonatal  137 Epilepsy syndromes, with prominent myoclonic seizures  538, e1273, e1274t benign myoclonic epilepsy of infancy  538 EEG for  538 treatment and outcome for  538 benign myoclonic epilepsy of infancy in  e1273 Dravet syndrome  538, e1273–e1274

1341

Epilepsy syndromes, with prominent myoclonic seizures (Continued) infantile spasms as  539 classification of  540 course and prognosis  541 diagnostic evaluation of  540–541 electroclinical features of  539–540 etiologic factors in  540 treatment for  541 juvenile myoclonic epilepsy  539, e1275 EEG for  539 outcomes for  539 semiology of  539 treatment for  539 Lafora disease (LD) in  e1277 myoclonic-astatic epilepsy of Doose  538, e1274 EEG for  539 etiology of  538 semiology of  538–539 treatment for  539 myoclonic epilepsy with ragged-red fibers (MERFF) in  e1277 neuronal ceroid lipofuscinoses (NCL) in  e1277–e1278 progressive myoclonic epilepsies in  e1276–e1277, e1277t Unverricht-Lundborg disease (ULD) in  e1277 Epilepsy with myoclonic-atonic seizures (EMAS)  571 Epileptic encephalopathies  501 associated with cyclin-dependent kinase-like 5 (CDKL5)  514–515 cognitive and behavioral outcome of  637, e1472 with continuous spike and wave during sleep  573–574, e1344 cyclin-dependent kinase-like 5 and  e1228–e1229 developmental encephalopathies and  242, e587 early infantile  513–514 of infancy  637 of infancy, cognitive and behavioral outcome of  e1473 progressive encephalopathies and  428 Protocadherin 19 (PCDH 19) and  e1233 SCN2A and  514, e1228 SCN8A and  516, e1233 subacute  175–176 Epileptic spasms  e1273–e1291 with asymmetric features  e1265 late onset  542 and myoclonic seizures  538–542 Epileptiform patterns, generalized  e232–e234 generalized periodic discharges  e234 hypsarrhythmia  e233–e234, e234f secondary bilateral synchrony  e234 sharp-wave and slow-wave complexes  e233, e233f spike-and-wave patterns  e232–e233, e233f Epileptogenesis  506 in developing brain  511 Epileptogenicity, modulation of, glial mechanisms for  508 Episodic ataxias  698, 698t–699t, e982–e983, e1563t, e1578 Episodic gastrointestinal diseases  1229, e2776–e2778 Episodic outbursts, Tourette syndrome and  742, e1666

1342

Index

Epstein-Barr virus  901–902, e2042, e2043f clinical manifestations of  901 diagnosis of  899t, 901–902 treatment and outcome of  901–902 EquiTest system  54, e120f Ergot alkaloids for migraine  651 sensorium changes  e2682b toxicity  1196b Erythermalgia  955, e2184 Erythromelalgia  955, e2184 inherited  408 primary  408 Erythromycin for gastroesophageal reflux  1161 in myasthenia gravis  1103b Erythropoietin (EPO)  145, e332 sensorium changes  e2682b for spinal cord injury  e1886 toxicity  1196b Eschar, in scrub typhus  e2076, e2077f Escherichia coli  e2785 in pyomyositis  1146 Escitalopram  e1168, e1168t Eslicarbazepine, for antiseizure drug therapy in children  e1399 Eslicarbazepine acetate (ESL), pharmacokinetics of  604t–605t Established Status Epilepticus Treatment Trial (ESETT)  e1300 Esthesioneuroblastoma  1019 Estrogen associated with Parkinsonism  e2684b toxicity  1198b Ethambutol, for tuberculous meningitis  890 Ethanol abuse in  e2691 associated with myopathies  e2683b in ataxia  e2685b causing peripheral neuropathy  e2684b neuroteratology  1203t toxicity  1197b, 1199b Ethical issues  1263–1269, e2859–e2870 care-based ethics  1265–1266 casuistry  1266 deontology  1264–1267 ethical problems in  e2865–e2868 euthanasia in  e2866–e2867 neuroethics in  e2867–e2868 organ donation in  e2867 personhood in  e2865–e2866 ethical responsibilities in  e2863–e2865 duties as a neurologist in  e2865 duties as a pediatrician in  e2864–e2865 duties as a physician in  e2863–e2864 research in  e2865 morality, common  1264 natural law  1264 neurologist and  1268–1269 pediatrician and  1268 physician and  1267–1268 principlism  1264–1265 research and  1269 responsibilities and  1267–1269 spirituality  1266–1267 synthesis  1269 theoretical approaches to ethics  1263, e2859–e2863 casuistry in  e2862 common morality in  e2860 deontology in  e2860 ethics of care in  e2862 natural law in  e2860 spirituality in  e2862–e2863

Ethical issues (Continued) utilitarianism in  e2859–e2860 virtue or character ethics in  e2861–e2862 utilitarianism  1263–1264 virtue/character  1265 Ethics, in practice guidelines, in pediatric neurology  1281 Ethionamide causing peripheral neuropathy  e2684b toxicity  1197b for tuberculous meningitis  890 Ethnicity, and ASD  463 Ethosuximide  601t–602t for childhood absence epilepsy  569–570 for genetic generalized epilepsies  581 pharmacokinetics of  604t–605t in renal failure  1226, e2767 Ethotoin  601t–602t Ethylene glycol renal toxicity of  1225t, e2765t toxicity  1199b Ethylene glycol, in ataxia  e2685b Ethylene oxide causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b Ethylmalonic acidemia  e1382 inherited metabolic epilepsies and  595 Ethylmalonic encephalopathy  482t–486t Etoposide-carboplatin chemotherapy  1003 Etretinate associated with myopathies  e2683b toxicity  1197b Euchromatin  e613 Eutectic mixture of topical anesthetics. see EMLA Euthanasia, in ethical problems  e2866–e2867 Euvolemia  e2638 Evans ratio  229 Event-related potentials (ERPs)  768, e247 Everolimus  479–480 Evidence-based medicine (EBM)  1276 Evoked potentials (EPs)  768 analysis  e242–e247 auditory-evoked potentials  e243–e244, e244f electroretinography  e245–e246, e246f event-related potentials  e247 somatosensory-evoked potentials  e246– e247, e246f visual-evoked responses  e244–e245, e245f auditory. see Auditory-evoked potentials in brain death determination  836 sensory  777 Ewing’s sarcoma  1019–1020, e2285 Excessive daytime sleepiness  672 Excessive sleepiness, disorders of  672–677, e1529–e1538 assessment of  672–674, 673f, e1529–e1531 clinical assessment in  e1529 objective evaluation tools in  e1529–e1531 subjective evaluation tools in  e1529 clinical assessment of  672 etiologies of  673t, e1530t history of  672 idiopathic hypersomnia (IH) in  e1534 Kleine-Levin syndrome (KLS)  676–677, e1534

Excessive sleepiness, disorders of (Continued) narcolepsy type 1  674–675, e1531–e1533, e1531f narcolepsy type 2  676, e1533–e1534 objective evaluation tools for  672–674 physical examination for  672 subjective evaluation tools for  672 treatment of  675–676, e1533 Excitation-contraction coupling  e2311– e2312, e2311f–e2312f Excitation-inhibition balance  e1210 Excitatory postsynaptic potential  e205–e206 Excitatory synaptic transmission  e1214 Excitotoxic injury brain injury and  806 glutamate in  806 Excitotoxicity  143–144, e329–e330 Executive Control Network (ECN)  769, e1736 Executive function, and ADHD  449 Executive functioning, nonverbal learning disabilities and  438–439, e1062 Exercise bioenergetic substrates in  1131–1132 for congenital myopathies  e2533 forearm ischemic exercise test  1139 for pediatric migraine  649–650 second-wind phenomenon  1133 Exercise-induced dystonia  357 Exercise-induced paroxysmal dystonia  283 Exertion-induced dyskinesia, paroxysmal  e1630–e1631 Exome  1244, e613 Exome/genome sequencing  1245t, e2822t Exome sequencing  2 Exon 7 inclusion, promoting  1062–1063 Exon skipping  1110 Experimental autoimmune encephalitis (EAE)  1232, e2788 Experimental therapy, for ependymomas  e2222 Exploding head syndrome  669, e1525 Explosive outbursts, Tourette syndrome and  742 Expressive fluency disorder  e1054–e1055 Expressive language, disorders of  e1055 External ear  e91 External ear malformations  45–46, e99 reconstructive surgery for  50 External force  590 External ophthalmoplegia  e14 External trigeminal nerve stimulation. see Trigeminal nerve, stimulation External urethral sphincters (EUS)  1185, 1185f Extraaxial fluid collections  886 Extracellular matrix proteins, abnormalities of  1121 Bethlem myopathy  1121 congenital muscular dystrophy, with early rigid spine syndrome  1121 laminin-α2 (merosin)-negative congenital muscular dystrophy  1121 Ullrich congenital muscular dystrophy  1121 Extracorporeal membrane oxygenationcardiopulmonary resuscitation  812 Extracorporeal membrane oxygenation (ECMO)  1211, e2722–e2725 for hypoxic-ischemic encephalopathy  e1852–e1853 Extramedullary spinal cord tumors (EMSCTs)  1013, e2277 operative technique for  e2280

Extraocular muscle dysfunction of  9, e14 paralysis of  9, 11f–12f, 11t–12t Extraocular muscle paralysis  e14 Extrapyramidal cerebral palsy  e1655–e1656 Extrapyramidal gait  31, e64 Extrapyramidal signs, progressive encephalopathy and  e1041t Extrapyramidal symptoms, antipsychotic medications and  e1182, e1182t Extratemporal cortical resection  617, e1429 Extremely low birth weight  22, e43 Extrinsic nervous system (ENS)  1190, e2673 Eye, deviations of  8–9 Eye contact, lack of  459 Eye deviation  e14 Eye movements, in spasms  540 “Eye of the tiger” sign  711 Eyelid, abnormalities  38, e78 Eyelid myoclonia  e1252 generalized epilepsy with  570 Ezogabine  601t–602t for antiseizure drug therapy in children  e1401 pharmacokinetics of  604t–605t

F

Fabry disease  283–284, 326, 1182, e772t–e773t, e783–e785, e784f, e2655, e2726 arterial ischemic stroke and  854 Facial hemiatrophy  370, e904, e904f Facial nerve  9, e15, e15f Facial nerve injury  157–158, e363–e364, e364f, e364t Facial nerve paralysis  e2409–e2412, e2411f clinical features of  e2409–e2410, e2410t, e2411b laboratory findings of  e2410–e2412 treatment and prognosis of  e2412 Facioscapulohumeral muscular dystrophy (FSHD)  1117–1118, e2495–e2496, e2499 approach to  1122, e2509 clinical features of  1118–1119, e2498f, e2499–e2500 diagnosis of  1119, e2501f, e2503–e2504 laboratory findings in  1119, e2500–e2503 management of  e2504 molecular genetics in  1118–1119, e2499–e2504 serum CK levels found in  1039t treatment for  1119 FACL4 gene mutation  421t Factor V Leiden, arterial ischemic stroke and  853 Fahr syndrome  e1602 Falls  798 abusive head trauma and  e1824–e1825, e1824f down stairs  798 from heights  798 short  798 walker and stroller  798 Falx cerebri  775 Familial dysautonomia  e2349, e2652–e2654 Familial episodic ataxia, vertigo and  56, e122 Familial essential tremor  e1612 Familial focal epilepsy with variable foci (FFEVF)  e1234–e1235 and DEPDC5-related epilepsies  517

Index Familial hemiplegic migraines  409, e982 clinical features of  409 clinical laboratory tests of  409 genetics/pathophysiology of  409 treatment of  409 Familial hemophagocytic lymphohistiocytosis  757, e1700 Familial isolated vitamin E deficiency  378 Familial Mediterranean fever  947, e2166 “Familial megalencephaly”  e500–e501 Familial mild microcephaly  e491 Familial pain syndromes  408–409 clinical features of  408 congenital indifference to pain  408–409 erythromelalgia  408 genetics/pathophysiology of  408 inherited erythromelalgia, primary erythermalgia  408 paroxysmal extreme pain disorder  408 primary erythermalgia  408 treatment of  408–409 Family discord  1242, e2817 Family Education Rights and Privacy Act (1974)  1285, e2895 Family history  2, e3 Family members, brain death and  838–839 Fanconi’s pancytopenia, with kidney malformation  1224t, e2764t Fanconi’s syndrome  e2762 Farber disease  326, e772t–e773t, e791–e792, e792f Fast-acting electrical synapses  510 Fast-channel myasthenia  1094, e2446 Fastigial nuclei, lesions of  689 Fatigue ketogenic diets  629 in SMA  e2370 Fatigue, spinal muscular atrophy and  1064 Fats  1134 Fatty acid oxidation (FAO)  279t, 337, 625–626, 1131, 1132b branched-chain fatty acids  348f defects  174–175, e411f, e412–e413 monounsaturated  353 normal pathway of  1134, e2548 Fatty acid oxidation (FAO) disorders  1133– 1137, e659t, e1383, e2547–e2559 clinical and biochemical features of  1134–1135, e2549t alterations, in concentrations of carnitine  1134 hypoketotic hypoglycemia  1134 individual genetic defects  1135, 1135t involvement of fatty acid oxidationdependent tissues  1134 laboratory findings  1134–1135 diagnostic approaches and screening methods for  1135–1136, e2554–e2555 carnitine uptake, investigations in  1136 enzymatic assay  1136 urinary organic acids  1136 epilepsies and  596 fasting adaptation in  1134, e2547–e2548 fasting studies in  e2555 genetics in  1137, e2557 historical background in  1133–1134, e2547 history and physical examination in  1135–1136, e2554 laboratory features of  1135 differentiating  e2553, e2553t

1343

Fatty acid oxidation (FAO) disorders (Continued) other studies in  e2555 presymptomatic recognition in  1137, e2557 susceptibility of  1134 total carnitine measurement in  e2554 treatment for  1136–1137, e2555–e2559 avoidance of precipitating factors  1136 carnitine  1136 clinical monitoring  1136–1137 high-carbohydrate, low-fat diet  1136 medium-chain triglyceride (MCT) oil  1136 PPAR agonists  1136 riboflavin  1136 triheptanoin  1136 uncooked cornstarch  1136 urinary organic acids in  e2554 Fatty aldehydes, and inborn errors of metabolism  482t–486t Fazio-Londe (FL) disease  374, 1066t–1068t, 1068, e2380–e2381 Fazio-Londe syndrome  482t–486t FDA-approved drug hydroxyurea  e2368 Febrile infection-related epilepsy syndrome (FIRES)  566, 590, e1373 Febrile seizures  519–523, e1240–e1246 classification of  519 cognitive abilities of children with  520 counseling and education for  522, e1244–e1245 definitions of  519, e1240 EEG and  e237 electroencephalograms in  520 epidemiology of  519, e1240 family history of  521 genetics of  522, e1243 guidelines for therapy in  e1244 initial evaluation of  519–520, e1240–e1241 meningitis and  520 and mesial temporal sclerosis  521–522 pathophysiology of  520, e1241 preventing  e1244 prolonged episodes of  522 recurrent  520–521, 520t, e1242 related morbidity and mortality in  520, e1241–e1242 and subsequent epilepsy  521, e1242– e1243, e1242t and temporal lobe epilepsy  521–522 terminating of  e1244 treatment of  522, e1243–e1244 Federal Child Abuse Prevention and Treatment Act (CAPTA)  802 Federal legislation  1284–1285 special education law and  e2895 Feedback inhibition  507 Feedforward inhibition  507 Feeding, neurodevelopmental disorders and  e1130–e1131, e1130t Feeding and gastrointestinal issues  474–475 assessment of feeding and nutrition  474, 474t investigations in  474 management of  474–475 Feeding habits, in ASD  465 Felbamate  511, 601t–602t, e1475 for antiseizure drug therapy in children  e1399–e1400 behavioral and cognitive effects of  639 for Lennox-Gastaut syndrome  572 pharmacokinetics of  604t–605t

1344

Index

Felodipine  e2755b “Fencer’s posture”  17, e35–e36 Fenfluramine associated with tremor  e2685b in ataxia  e2685b toxicity  1199b–1200b Fenobam  480 Fentanyl, for pain management  1257, 1257t Ferritin, serum  680 Fertility problems  271 Fetal akinesia  1036–1037 Fetal alcohol syndrome (FAS)  196, 1202–1203 microcephaly and  e488–e491 Fetal circulation  1205–1207, 1208f, e2713–e2716, e2716f assessment of  e2716–e2717 Fetal development  100 environmental perturbations  100 fetal functional imaging  100 microstructural studies  100 Fetal period, brain development in  e986– e987, e988f Fever  1249–1250 Feverfew  e1501 FGF8 gene, mutation in  1166–1167 FGFR1 gene, mutation in  1166–1167 Fibrofatty filum terminale  190, e443, e443f Fibromuscular dysplasia in central nervous system vasculitis  e1992–e1993 cerebral arteriopathies and  875 Filamin A mutations  252 Filum terminale, fibrofatty  e443, e443f Finnish-type (type V) amyloidosis  e2760 Fish, as animal model, of SMA  e2365 Fistulas, arteriovenous  866–868 FKRP gene, mutations in  1114, 1120 FKTN gene, mutations in  1120 Flaccidity  775 Flagellates  e2080t Flash suppression  767–768, e1733 Flatworms  e2105 Flaviviruses  896b, 902, e2047–e2049 Flavoprotein disorder  e921t Flavor  58–59, e124–125 definition of  59 ontogeny of  e132–e135 fetus  e132 infants  e133–e134 newborns  e132 young children  e134–e135 perception of, ontogeny of  62t, 63–64 Flea-borne typhus  e2076 Flemming, Walther  257 “Flippase”  317 Floppy infant  1051–1056, e2341–e2354 see also Hypotonia Flow-metabolism coupling  845, e1925 Flowcharts  1297 “Floxed” alleles  117–118, e290–e292 Flp-Frt system  117–118, e290–e292 Fluconazole for blastomycosis  908 for candidiasis  908 for coccidioidomycosis  908 Fludrocortisone, for postural orthostatic tachycardia syndrome  665 Fluid-attenuated inversion recovery (FLAIR)  79, e305 in neonatal brain  127 Fluid-attenuated inversion recovery imaging  e1421 Fluid therapy, for acute bacterial meningitis  888

Flumazenil coma and  776 for hepatic encephalopathy  e2796 sensorium changes  e2682b toxicity  1196b Flunarizine for infantile spasms  e1286 for migraine  652t Fluorescence in situ hybridization (FISH)  259–262, 268, 269f, e616–e623, e617f, e618t, e2822t in genetic diagnosis  1245t locus-specific probes  268–269 progressive encephalopathies and  428 Fluoride associated with tremor  e2685b toxicity  1200b Fluoroquinolones, in myasthenia gravis  1103b Fluoxetine  e1168 for ADHD  455t–457t for ASD  467t–468t Fluphenazine, for tic disorders  745t Fluvoxamine  e1168–e1169, e1168t for ADHD  455t–457t for ASD  467t–468t Fly, as animal model, of SMA  e2365 FMR1 gene  420–421 FMRI1 promoter region of, repeats in  480 FMRP  480 Focal cerebral arteriopathy  849–850, 871, e1986, e1987f Focal cortical dysplasia (FCD)  223–224, 583–584, 586t, e534–e539, e536t, e1364–e1365 brain imaging of  e536–e538, e536f–e537f clinical features of  583, e538 etiology of  583, e538–e539 genetic and molecular basis of  e538–e539 imaging features of  583 management of  583–584 pathology of  583, e534–e536, e536f–e537f presurgical evaluation for  584 treatment of  e539 Focal disease, autonomic dysfunction secondary to  1178, e2651 Focal epilepsies  521 Focal epileptiform pattern  e234–e235 occipital spikes  e234–e235, e235f Rolandic spikes  e234, e235f Focal epileptiform patterns, of EEG  95 Focal/generalized condition  e2–e3 Focal nodular myositis  1145 Focal seizures  497, 521, 524, 531–537, e1197, e1262–e1272, e1263f and alteration of consciousness  531 auras in  533, e1264–e1265 automotor in  533, e1265 autonomic  533, e1265 behavioral arrest  533, e1265, e1266f clonus  533, e1265 dialeptic  533–535, e1265 dyscognitive  533–535, e1265 electroencephalogram for  531–533, 532f, 534f evaluation and management of  535 gelastic  e1265 hypermotor  e1265 hypomotor  533, e1265 management of  e1267–e1269, e1268f, e1269b, e1269t–e1271t, e1270f, e1272f

Focal seizures (Continued) migrating, epilepsy of infancy with  515, 563–565 differential diagnosis for  563 EEG findings in  563, 564f etiology of  563 laboratory studies in  563 neuroimaging for  563 neurologic findings in  563 outcomes for  565 seizures in  563 treatment for  563 myoclonus  533, e1265 ontogeny of  535, e1267 semiologic classification of  e1263–e1264, e1264t tonic  535, e1266 types of  531–535, e1262–e1267, e1264b versive  e1266–e1267 Focal structural epilepsy  583–589, e1364– e1372, e1367t with focal malformations of cortical development  583–585, 586f, e1364–e1366, e1367f disorders associated with  586t and focal cortical dysplasia  583–585 and hemimegalencephaly  584–585 with neurocutaneous syndromes  585– 588, e1366–e1368 megalencephaly capillary malformation syndrome  587, e1368 STRADA (LYK5)-related megalencephaly  587–588, e1368 Sturge-Weber syndrome  587, e1366–e1368 tuberous sclerosis complex  585–587, e1366 with other lesions  588–589, e1368–e1370 gelastic seizures with hypothalamic hamartoma  588–589 mesial temporal lobe epilepsy with hippocampal sclerosis  588 Rasmussen encephalitis  589 Folate  379, 387, e918t–e919t, e930, e931f deficiency  e930–e931, e932t nutritional  379 developing brain and  e946 malabsorption, hereditary  e935 metabolic pathways  379f metabolism, disorders of  379–381 and pregnancy  e932 transport, disorders of  381 Folic acid dependency disorders, epilepsies  597 metabolism of  e431 mood disorders and  638 Folinic acid-responsive neonatal epileptic encephalopathy (FARNE)  175 Folinic acid responsive seizures, and infantile onset epilepsies  560t–562t Follicle-stimulating hormone (FSH)  1165 Fontanels  233, e567, e568f anomalies of  236–237, e574–e575 sagittal  e575 Food preference, in ASD  465 Foodborne botulism  1104–1105, 1194–1195, e2467 Foramen/foramina magnum  775 anomalies  240, e582 parietal  237, 237f Foramina, parietal  e576–e577, e576f Forbes disease  310–311, e735–e736 Forearm ischemic exercise test  1139

Forebrain development, disorders of  192– 197, e449–e465 Forkhead box G1 (FOXG1) gene, mutations  515 Formaldehyde in ataxia  e2685b sensorium changes  e2682b toxicity  1196b, 1199b “Formes fruste”  e424–e425 Formiminotransferase deficiency  381, e934–e935 Forward flexion, spinal cord injury and  820 Fosinopril  e2755b Fosphenytoin  601t–602t for antiseizure drug therapy in children  e1401 causing peripheral neuropathy  e2684b for posttraumatic seizures  789 for status epilepticus  545, 547 toxicity  1197b Fossa, posterior, normal development of, prenatal assessment of  249–250 FOUR Score Coma Scale  772, 773t Four-step climb, in motor function scales  e2337 4H syndrome  749f, 750, e1685f, e1686– e1687, e1687f FOXG1, gene mutations in, and infantile onset epilepsies  558t–560t FOXG1 disorders  244–245, e589–e590 Foxglove  1196b sensorium changes  e2682b FOXP2 mutation  432 Fractional anisotropy (FA)  83, 97, 462 Fractured somatotopy, of cerebellum  e1554, e1557f Fractures, skull  786 Fragile X, progressive encephalopathies and  428 Fragile X-associated tremor/ataxia syndrome (FXTAS)  420–421, 695–698, e1579 Fragile X syndrome  466, 479t, 480 and developmental language disorders  432, 434 intellectual disability and  420–421, e1007 treatment of  e1138t, e1141–e1145, e1141f–e1142f, e1143t–e1144t Fragility fractures (osteoporosis)  476 Franceschetti-Klein syndrome  e103 Fraser’s syndrome, with kidney malformation  1224t, e2764t Frataxin  690–692, e1564 Free fatty acids, phospholipase release of  806 Free fatty acids (FFA)  1131 Frequency distribution, during sleep  e225 Freud, Sigmund  e1650 Friedreich ataxia  690–699, 1078, e1559–e1565 clinical manifestations of  e1559–e1564, e1564f genetics of  e1564–e1565 pathology of  e1564 treatment of  e1565 Friedreich ataxia 2  e1565 “Frogleg” position  27, e55–e56 Froin’s syndrome  e158 Front-loaded approach, for OMS treatment  940 Frontal-lobe epilepsy  104 Frontal Mesocircuit Network (FMN)  769, e1736 Frontoparietal Cobblestone malformation  e521t, e525 Frovatriptan  650t

Index Fructose-1,6-biphosphatase deficiency  174, e412 Fructose-1,6-diphosphatase deficiency  307, e727 Fructose intolerance  424 Fructose metabolism, abnormalities/ disorders of  e660t, e726–e727 fructose-1,6-diphosphatase deficiency  307, e727 hereditary fructose intolerance  306–307, e726–e727 FSHD. see Facioscapulohumeral muscular dystrophy (FSHD) FTE, mean clinical  1302 FTSJ1 gene mutation  421t Fucosidosis  328–329, 750, e772t–e773t, e777f–e778f, e808–e809, e1689 MRI findings in  330f Fukutin-related protein deficiency (FKRP)  e2490, e2506 in congenital muscular dystrophy  1120 in limb-girdle muscular dystrophy  1114 Fukutin-related protein (FKRP) gene  1161 Fukuyama congenital muscular dystrophy (FCMD)  1120, e525, e1386, e2506 serum CK levels found in  1039t Full Individual Evaluation (FIE) , and ASD  464 Full Outline of Unresponsiveness (FOUR) Score Coma Scale  e1742, e1742t Fulminant liver failure  1234 Fumarase deficiency  337 Fumaric aciduria  596, e1382 Functional connectivity  98, e257–e258, e257f assessment strategies for  97–99, 98t current clinical applications  105, 105f in developing brain  97–106, e256–e276 overview of  98f Functional disorders, of unknown origin  1176–1178 Functional electrical stimulation (FES)  828 for spinal cord injury  e1891 Functional hypogonadotropic hypogonadism  e2631 Functional Independence Measure  778 Functional magnetic resonance imaging (fMRI)  84, e190–e191, e1428, e1428f for ADHD  449–450 for disorders of consciousness  768, 768f and dyslexia  443 in nonverbal learning disabilities  440 of spinal cord injury  e1879 Functional mapping, for epilepsy surgery  616, e1426–e1428 Functional MRI (fMRI)  97 Functional recovery  e2829–e2831 plasticity. see Plasticity reorganization of neuronal connections  e2830 resolution of temporary dysfunction  e2830 through adaptation  e2830–e2831 Functors  433b, e1054b Fungal diseases  907–916, e2065–e2072, e2066t actinomycosis  908, e2069 aspergillosis  908–909, e2069–e2070, e2069f blastomycosis North American  908 South American  908 candidiasis  909, e2070, e2071f coccidioidomycosis  907–908, e2065–e2067

1345

Fungal diseases (Continued) cryptococcosis  907, e2065, e2066f histoplasmosis  908, e2068 Nocardia  908, e2068–e2069 North American blastomycosis in  e2067 Scedosporium spp. infection  909 South American blastomycosis in  e2067–e2068 zygomycosis  909, e2070–e2072 Fungal myositides  1146, e2592 Furosemide  e2755b for intracranial hypertension  819 for Reye’s syndrome  e2797

G

GAA deficiency, infantile, late  310 GABA. see Gamma-aminobutyric acid (GABA) GABAA receptor  507 activation of  507 subunit genes  407 subunits of, during brain maturation  510 GABAAR  934t GABAB receptor, metabotropic  507–508 GABABR  934t Gabapentin  601t–602t, 1063, e1176t, e1180, e1400, e1476 behavioral and cognitive effects of  640 for headache in children  e1500 for migraine  652t pharmacokinetics of  604t–605t porphyria and  e2791 in renal failure  1226, e2767–e2768 for restless legs syndrome  681b, e1543 GABRA1 gene mutations  517, 578 Gait of child and adolescent  1049 in motor function testing  e2334–e2335 Gait apraxia  32, e64–e65 Gait ataxia  1181 Gait disturbances  27–32 Gait disturbances/gait impairment  28–30, e54–67 differential diagnosis of  30–32, e62–e65 antalgic gait (painful gait)  32, e65 cerebellar gait  31, e63–e64 conversion disorder  32, e65 dyskinetic gait  31–32, e64–e65 extrapyramidal gait  31, e64 gait apraxia  32, e64–e65 hip weakness gait  32, e64 spastic diplegic gait  30–31, e62–e63 spastic hemiplegic gait  30, e62 steppage gait  32, e64 evaluation of patient  e61–e62 motor, and ASD  465 patient evaluation  30, 30f physiologic considerations  28–30, e60–e61, e60f–e61f Gait training  828 for spinal cord injury  e1891 Galactokinase deficiency  306, e726 Galactose-1-phosphate uridyltransferase deficiency  305–306, e723–e725 biochemistry of  305, e723–e724, e724f, e724t clinical characteristics of  305–306, e724–e725 clinical laboratory tests for  306, e725 management of  306, e725 pathology of  305, e723

1346

Index

Galactose metabolism abnormalities/disorders of  e660t, e723–e726 pathway of  306f Galactose mutarotase  305 Galactosemia  305–306, 424, e723–e726, e724f, e724t galactose-1-phosphate uridyltransferase deficiency  305–306 phenotypes of  306t uridine diphosphogalactose epimerase deficiency  306 Galactosialidosis  330, e811–e812 α-Galactosidase deficiency  326 Galactosylceramidase deficiency  327 Galea  781 Galea aponeurotica  e1764 Galeazzi’s sign  16, e61 GALK1 genes  306 Gallium, renal toxicity of  1225t, e2765t Galloway-Mowat syndrome  e2746 Gamma-aminobutyric acid (GABA)  129, 507, e308, e1212, e1220f, e1292 analogs, for antiseizure drug therapy in children  e1400 channel mutations, and febrile seizures  522 metabolism of, disorders of  597 tic disorders and  744 transaminase deficiency  359, e882, e883f and infantile onset epilepsies  560t–562t Gamma-aminobutyric acidergic agents, for ASD  468, e1112 Gamma efferent system  e2312–e2313, e2313f Gamma-hydroxybutyrate abuse  1198, e2690 Gamma knife  617 GAMT deficiency  482t–486t Ganaxolone  e1286 Ganciclovir, for cytomegalovirus  901 Ganglioglioma  985–990, e2236 Ganglionopathy, autoimmune autonomic  1179, e2652 Gangliosidoses  e772t–e773t, e778–e780, e1387 GM1  323, e777f, e779–e780, e780f GM2  323–325, e780–e783 Gasoline  1196b, 1199b associated with myoclonus  e2685b in ataxia  e2685b sensorium changes  e2682b Gastaut syndrome  573, e1344 Gastric irritation, antiseizure drug therapy and  609 Gastric lavage  1193 Gastro esophageal reflux (GER)  474–475, e1131 Gastroenteritis, and febrile seizures  520 Gastroenterologic manifestations, mucopolysaccharidoses and  328 Gastroesophageal reflux (GER)  1229 anatomic gastrointestinal disorders of  e2778–e2779 Sandifer syndrome and  671 Gastrointestinal causes, of spinal muscular atrophy  1064 Gastrointestinal diseases  1233 anatomic  1229–1231, e2778–e2782 gastroesophageal reflux  1229 Hirschsprung disease  1230 intestinal pseudoobstruction  1229– 1230, 1230b intussusception  1231 mitochondrial neurogastrointestinal encephalomyopathy  1230

Gastrointestinal diseases (Continued) neurocristopathy syndromes  1230 pseudoobstruction syndromes  1230 disorders associated with  1228–1233, e2775–e2791 dysphagia and  1228 enteric infections  1231–1232, e2785–e2787 episodic  1229, e2776–e2778 cyclic vomiting syndrome and  1229 infantile colic and  1229 irritable bowel syndrome and  1229 recurrent abdominal pain and  1229 hepatic encephalopathy and  1233–1235 hepatitis and  1233 irritable bowel syndrome and  1229 malabsorption syndromes  1231, e2782–e2785 celiac disease  1231 inflammatory bowel disease  1231 short bowel syndrome  1231 neurologic disorders associated with  1228–1237, e2775–e2812 hepatobiliary diseases  1233–1236 microbiome and  1232 other  e2789–e2791 porphyria and  1233, e2790–e2791 pseudoobstruction syndromes  e2782 Turcot’s syndrome and  1233, e2790 Whipple’s disease and  1233, e2789 Gastrointestinal dysmotility, management of, in congenital myopathies  e2533 Gastrointestinal motility, abnormal, and orthostatic intolerance  e2646 Gastrointestinal tract, and nervous system  1228 Gastrostomy feeding tubes  475, e1131 Gaucher disease  326, e772t–e773t, e785–e788, e786f, e1387 Gaucher disease type III  482t–486t GBS. see Guillain-Barré syndrome (GBS) GDAP1 gene, mutations in  1077 GDDI. see Guideline Development, Dissemination, and Implementation (GDDI) GDG. see Guideline development group (GDG) GDI1 gene mutation  421t GDNF gene, mutation in  1182 Gelastic seizures  535, e1265 Gelastic seizures, with hypothalamic hamartoma  588–589, e1369 clinical management of  588–589 etiology of  588 neuroimaging of  588 neurologic features of  588 nonneurologic features of  588 Gemini bodies  1061 Gender, cerebral palsy and  736 Gene testing, in neuromuscular disorders  e2320, e2320b Gene therapy for CNS tumors  961 for lysosomal storage diseases  323 for mitochondrial diseases  1139 for SMA  e2369 for spinal muscular atrophy  1063 for tumors  e2198 for urea cycle disorders  303, e719 Gene transfer  1111 General examination, preterm infant  22, 22t General motor function scales, in neuromuscular disorders  e2336 General Movement Assessment  e2900

General mutation detection, methods of  260–262 General screening instruments  e9t Generalized epilepsy, surgical indications for  e1419–e1420 Generalized epilepsy and paroxysmal dyskinesia (GEPD)  720, e1630 Generalized epilepsy with febrile seizures plus  407, e979–e980 clinical features of  407 genetics/pathophysiology of  407 treatment of  407 Generalized seizures  524–529, e1247–e1261 absence  e1251–e1256 atonic  e1257–e1258 classification of  e1248t Lennox-Gastaut syndrome in  e1258– e1259, e1258f, e1259b myoclonic  e1256 tonic  e1257, e1257f tonic-clonic  e1247–e1251 Generalized tonic-clonic seizures  524–525, 570, e1247–e1251 clinical features of  e1247 comorbidities associated with  e1249 differential diagnosis of  e1247, e1248t electroencephalographic findings of  e1248–e1249, e1248f etiology of  e1249 initial evaluation of  e1249 medical treatment of  e1249–e1251 Genes  268 Genetic autonomic disorders  1179–1183 Allgrove syndrome  1182 with autonomic dysfunction  1182–1183 congenital central hypoventilation syndrome (CCHS)  1182 hereditary sensory and autonomic neuropathies  1179–1181, 1180t Hirschsprung disease  1182 metabolism, inborn errors of  1181–1182 Genetic chorea  709 Genetic counseling  286, e626–e627, e626f–e627f for brain malformation  181–182 in NCL  404 Genetic epilepsy with febrile seizures plus (GEFS +)  567–568, e1332–e1333 EEG findings in  568 etiology of  568 neuroimaging of  568 neurologic findings in  568 outcomes for  568 seizures in  568 treatment of  568 Genetic hearing loss  e100–e104 Genetic linkage analysis  e2822t in genetic diagnosis  1245t Genetic peripheral neuropathies  e2390–e2408 CMT in, specific forms of  e2396–e2405 definition of  e2390 genetic testing and diagnostic strategies in  e2394–e2396, e2395f–e2396f inherited neuropathy and, clinical sequelae of  e2390–e2393 neurophysiology of  e2393–e2394 pathophysiology of  e2393, e2394f prevalence and classification of  e2390, e2391t–e2393t Genetic syndromes, associated with pediatric brain tumors  e2194t Genetic testing  1042 Genetic Testing Registry  1297

Genetics of disease autistic spectrum disorder  e1101–e1102 breath-holding spells  e1508 epilepsy  513–518 febrile seizures  522 microcephaly  212 multiple sclerosis  763 phosphofructokinase deficiency  314 heredity  257 in proposed mechanisms for sudden unexpected death in epilepsy  e1486 Genome, human  257–262 Genome era, neurogenetics in  257–266 Genome sequencing  1246, e2822, e2826–e2827 major approaches to  e2822t Genome-wide association studies (GWAS)  2 for dyslexia  442 Genomic care, standards of  264 Genomic diagnosis  1244, 1245t, e2821–e2823 Genomic disorders, in central hypotonia  e2347 Genomic microarray  420, e1000–e1005 Genomic testing  1244 online tools involved analysis of  263t resources for interpreting  262–264, 262t Genomic variation  257, e613, e614t glossary of  258t Genotype-phenotype correlations, of DMD and BMD  e2476–e2477 Gentamicin for DMD  1110 for fatty acid oxidation disorders  e2563 GER. see Gastroesophageal reflux (GER) Germ cell tumors (GCTs) of central nervous system  e2257–e2263 epidemiology of  1000 etiology of  1000 pathology of  1000 tumor markers  1001 Germinal matrix hemorrhage (GMH)  e377 Germinoma  1001–1004, e2258–e2261 chemotherapy  1002 role of  1002–1003 clinical presentation of  1001, e2258 prognosis of  1004, e2261 radiation therapy  1002 role of  1002–1003 radiology in  1001, e2258 s-kit in  1001, e2259 staging of  1001–1002, e2259 surgery for  1003, e2260–e2261 treatment of  1002–1003, e2259–e2261 chemotherapy for  e2259–e2260 combined chemotherapy and radiation therapy  1002–1003 radiation therapy for  e2259 tumor markers in  1001, e2258–e2259 Germline therapy, for mitochondrial diseases  1139 Geste antagoniste  e1598, e1603 GFPT1 myasthenia  1096, e2447 GH1 gene, mutation in  1169 Ghrelin  1170f GHRHR gene, mutation in  1169 Giant axonal neuropathy  e2403 Giant cell arteritis  954–955, e2181–e2182 Takayasu’s arteritis  947t, 954–955 temporal arteritis  947t, 954 Giant depolarizing potentials (GDPs)  510–511

Index Giemsa stain  268 Gilles de la Tourette syndrome-quality of life scale (GTS-QOL)  e1664 Gilliam Autism Rating Scale™  e1105 Gingival hyperplasia, antiseizure drug therapy and  609 Ginkgo nuts  1196b, e2682b GJβ1 gene, mutations in  1076 GLA gene, mutation in  1182 Glasgow Coma Scale (GCS)  772, 772t, 782, 782t, 795, e1740–e1741, e1741t, e1770, e1770t for cerebral unresponsivity  833 for posttraumatic epilepsy  e1373 Glasgow Coma Scale-Modified, for children  e1741, e1741t Glasgow Outcome Scale  777, 815, e1753 Glatiramer acetate, for multiple sclerosis  763, 763t Glaucoma, congenital  e74 Glia in epilepsy  508 hypoxic-ischemic encephalopathy and  807–808 Glial-astrocytic tumors, ependymoma. see Ependymoma Glial cells, modulating epileptogenicity for  e1216–e1217 Glial fibrillary acidic protein (GFAP) gene mutations  1182, e1691 Glial scar-associated inhibitors, for spinal cord injury  e1887 Glial tumors  1014, e2278 spinal, malignant  1016 Glioblastoma, Turcot’s syndrome  e2790 Gliomas  979, 1013t cortical high-grade  959t low-grade  959t diencephalic low-grade  959t high grade. see High-grade glioma low-grade. see Low-grade glioma Global cerebellar hypoplasia, with involvement of vermis and hemispheres  e472, e472t Global CH, with involvement of both vermis and hemispheres  203 Global developmental delay  413, 418–423, 426, e997–e1018 coexisting conditions in, management of  422–423 de novo dominant  421, e1008 definition of  418, e997–e998 diagnosis of  414, 418–420, e999–e1006, e1001t–1004t, e1005f definitions and testing  418 diagnostic testing advances  418–420, 419f genomic microarray  420 imaging advances  420 epidemiology of  418, e997–e998 ethics and  e998–e999 etiology of  420–421, e1006–e1008, e1006t–e1007t general considerations in  420 genetic causes in  420–421 other considerations in  421 other X-linked ID conditions  421 evaluation of patient  422, e1008–e1012, e1009b–e1013b consultation in  422 history in  422 laboratory and other diagnostic testing in  422 physical examination in  422

1347

Global developmental delay (Continued) health outcome measures for  e2904t history of  e998–e999 medical management of coexisting conditions in  e1012 outcome of  423, e1012–e1014 prognosis of  423, e1012–e1014 testing for  416 Globoid cell leukodystrophy (GCL)  112, 754, e282, e792–e795, e1692f, e1695, e2415–e2416 see also Krabbe disease Globotriaosylceramide (Gb3)  1182 “Glomeruli”  208, e484 Glossopharyngeal nerve  10, e16 Glucocerebrosidase  326 Glucocorticoid production disorders  1168– 1169, e2632–e2633 adrenocorticotropic hormone (ACTH) deficiency  1168–1169, e2632–e2633 adrenocorticotropic hormone (ACTH) excess  1168, e2632, e2633f Gluconeogenesis, disorders of  e660t Glucose balance, correctable disturbances of  171 in brain metabolism  625–626 in coma  776 correctable disturbances of  e402–e405 in CSF  76, e157 for impairment of consciousness  e1750 metabolism, in urea cycle disorders  301 molecules  307 transport , and inborn errors of metabolism  482t–486t Glucose-6-phosphatase deficiency  307–309, e728–e732 biochemistry of  e728–e730 clinical characteristics of  e731 clinical laboratory tests for  e731 management of  e731–e732 pathology of  e728 Glucose homeostasis  811 disorders of  e1384–e1385 epilepsies and  597 hypoxic-ischemic encephalopathy and  e1851–e1852 Glucose transporters  306–307 defects  e416–e417 Glucose transporter deficiency, and infantile onset epilepsies  560t–562t Glucose transporter 1 deficiency  e1385 epilepsies and  597 β−D-Glucosidase  326 GLUT1  e1630–e1631 GLUT1 transporter deficiency syndrome  482t–486t Glutamate  359, 405, 508, e308, e329 in excitotoxic injury  806 posttraumatic release of  781 tic disorders and  744 Glutamic acid decarboxylase (GAD)  934t antibody  e1588 ataxia and  703 Glutamine, elevated levels  301 Glutamine synthetase deficiency  174, e412, e412f Glutaminergic agents, for ASD  468 Glutaric acidemia magnetic resonance imaging in  296f type I  482t–486t, e1382 and infantile onset epilepsies  560t–562t inherited metabolic epilepsies  595 type II  482t–486t, e2552

1348

Index

Glutaric aciduria  176, e418–e419 type I  295–296, e698–e699, e698f Glutathione synthetase deficiency  e699 Glutethimide sensorium changes  e2682b toxicity  1196b Glycans  317 Glyceryl trierucate  353 Glycine  359 Glycine cleavage defects  175, e413–e414, e414f Glycine cleavage system  291f, e683f Glycine encephalopathy  290–292, 359, 597, e683–e685, e683f, e884, e1385, e1386f and infantile onset epilepsies  560t–562t Glycine receptor (GlyR)  934t Glycine receptor antibody encephalitis  935, e2143–e2144 Glycogen  1131 formation, defects impairing  315 lysosomal storage diseases and  e772t–e773t storage  315 synthesis  307, 309f Glycogen storage diseases  308t, e727–e741, e728t, e729f–e730f, e2725 clinical manifestations of  307 type I  307–309, e728–e732 type II  309–310, e732–e733, e772t–e773t, e815–e817 type III  310–311, e735–e736 type IV  311–312, e736–e737 type V  e737–e739 type VI  312–314, e739 type VII  314, e739–e740 type IX  314 Glycogenin  315 Glycogenoses  1132–1133, 1133t, e2538– e2547, e2539f, e2540t glycolytic/glycogenolytic defects in  1133, e2539–e2547 acid maltase deficiency  e2539–e2542 aldolase a deficiency  e2547 branching enzyme deficiency  e2546–e2547 Debrancher deficiency  e2544–e2545 lactate dehydrogenase deficiency  e2546 phosphofructokinase deficiency  e2545 phosphoglycerate kinase deficiency  e2545–e2546 phosphoglycerate mutase deficiency  e2546 phosphorylase B kinase deficiency  e2542–e2543 phosphorylase deficiency  e2543–e2544 pathophysiology of  1133, e2539, e2541b type XII  e2547 Glycolysis  1131 Glycolytic/glycogenolytic defects  e2539–e2547 acid maltase deficiency  e2539–e2542 aldolase a deficiency  e2547 branching enzyme deficiency  e2546–e2547 Debrancher deficiency  e2544–e2545 lactate dehydrogenase deficiency  e2546 phosphofructokinase deficiency  e2545 phosphoglycerate kinase deficiency  e2545–e2546 phosphoglycerate mutase deficiency  e2546 phosphorylase B kinase deficiency  e2542–e2543 phosphorylase deficiency  e2543–e2544 Glycopeptides, lysosomal storage diseases and  e772t–e773t

Glycoprotein IIb-IIIa antagonists  856 Glycoproteinoses  e807–e812 Glycosaminoglycans  327 lysosomal storage diseases and  e772t–e773t Glycosphingolipids, defects of  e762, e763f Glycosylation  315 defining types of  317 N-linked  317–318 biosynthesis  317–318, 318f Glycosylation disorders/defects  317–322, e749–e770, e1386 congenital  176–177, 318–319, e419, e659t, e750–e751 clinical features of  319 congenital myasthenic syndromes associated with  1096, e2447–e2448 diagnosis of  318–319 glycosphingolipids  320–321 glycosylphosphatidylinositol  321 multiple defects  321 peripheral hypotonia and  1055t–1056t protein N-glycosylation defects  319–320 protein O-glycosylation defects  320 suspect and test  321–322 inherited metabolic epilepsies  598 specific  e751–e765 Glycosylphosphatidylinositol glycosylation  e762, e764f GM1 disease  749f GM1 ganglioside, for spinal cord injury  e1885 GM1 gangliosidosis  e1685f, e1706–e1707 GM2 gangliosidoses  e1707 GMPPA gene, mutation in  1182 GNAO1, mutations in  514 Gnathostoma spinigerum  914, e2100 Gnathostomiasis  914 GnRH agonist  1166 GnRH pulse generator  1165–1166, e2628 Goal Attainment Scaling (GAS)  e2901 Golgi tendon organs  e54–e55 Gómez-López-Hernández syndrome (GLH)  e477–e478 Gomitoli  1165 Gonadotropin-releasing hormone (GnRH)  1165 Gonadotropins, in GCT  1000 Gorlin’s syndrome  240, 958t, e2201 Gottron sign  1141 Gowers maneuver  1049, 1107, e25f, e62 in motor function testing  e2335–e2336 GPR54 gene mutation  1166 Grading of Recommendations Assessment, Development and Evaluation (GRADE) process  1280 rating system  e2887, e2888t Grainy-head-like 3 (Grhl3)  e430 Granisetron sensorium changes  e2682b toxicity  1196b Granular osmophilic deposits  e955f Granulomatosis with polyangiitis  947t, 953–954, e2179 Granulomatous amebic encephalitis  e2083– e2085, e2084f–e2085f Acanthamoeba spp.  910–911 Balamuthia mandrillaris  911 Granulomatous angiitis  953–954, e2179–e2181 Churg-Strauss syndrome  947t, 953 necrotizing sarcoid granulomatosis  954 primary angiitis of the central nervous system  947t, 954 sarcoidosis  947t, 954

Grasp reflex  e50 in preterm infants  24 Gray matter disorders  390–404 clinical description and characterization of  390–393 CLN1  397 CLN2  397–398 CLN3  398 CLN4  398–399 CLN5  399 CLN6  399–400 CLN7  400 CLN8  400–401 CLN10  401 CLN11  401–402 CLN12  402 CLN13  402–403 CLN14  403–404 degenerative  e950–e976 diagnosis  396–397 FTLD biology/pathology of  401–402 genetics and pathology  397 historical clinical characterization of  390–397 molecular genetics of  393, 395f NCL-FTLD overlap  402 NCL models and clinical trials  396 nomenclature of  390 pathobiology of  393–396 pathology of  393 Gray Oral Reading Test-Fifth Edition (GORT-5)  445 Gray Oral Tests of Reading IV  68t–69t, e143t–e146t Green fluorescent protein (GFP)  115 Greig cephalopolysyndactyly syndrome (GCPS)  e504 GRIN2A, mutations in  516–517 Grip strength  68t–69t, e143t–e146t GRN  e951t–e952t, e966–e967 Grooved Pegboard  68t–69t, e143t–e146t Gross Motor Function Classification Level I (GMFC I)  1290–1291 Gross Motor Function Classification System (GMFCS)  472, 473t, e1127, e1128t, e1656, e1657f for cerebral palsy  737–738, 737f Gross Motor Function Measure-66 (GMFM-66)  1290–1291 Gross total resection, in AT/RT  997–998 “Growing fontanelle”  157 “Growing skull fractures”  157 Growth hormone (GH)  1165 deficiency  1169, e2634 medulloblastoma  968 excess in  1169, e2634 Growth-hormone-releasing hormone (GHRH)  1165 Growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACE)  340 Growth suppression, in ADHD  453 GSKJ4, in diffuse intrinsic pontine glioma  e2247 GTP cyclohydrolase, deficiency  356t GTPCH1 deficiency  482t–486t GTPCH1-deficient dopa-responsive dystonia (GTPCH1-DRD)  487 Guaifenesin sensorium changes  e2682b toxicity  1196b

Guanfacine  490 for ADHD  454–455, 455t–457t, e1086– e1087, e1087t–e1089t side effects of  490–491 for tic disorders  745t Guanidine hydrochloride, for LEMS  e2466–e2467 Guanine  260 Guanine nucleotide binding protein Q polypeptide (GNAQ) gene, mutation in, and Sturge-Weber syndrome  587 Guanosine triphosphate cyclohydrolase deficiency, autosomal-recessive  e878 Guideline Development, Dissemination, and Implementation (GDDI)  1276 Guideline development group (GDG)  1280 Guideline execution engines  e2915 Guillain-Barré syndrome (GBS)  896, 1086–1090, 1178, 1232, e2348–e2349, e2426–e2434, e2427f, e2427t, e2651– e2652, e2788 antecedent events in  1086–1087, e2427–e2428, e2428b childhood, outcome  1089–1090 classic, presentation  1087b clinical features of  1087, e2428, e2429b corticosteroids in  1089 diagnostic challenges of  1087, e2430 diagnostic criteria for  1087, 1088b, e2430, e2431b differential diagnosis of  1088, 1088b, e2430, e2431b epidemiology of  1086, e2426–e2427 etiology, influenza virus  919 hepatitis and  e2791 immunotherapy  1089 influenza virus vaccine and  e2123–e2124 laboratory findings supportive of  1088– 1089, e2430–e2432 cerebrospinal fluid  1088, e2430–e2431, e2432b electrodiagnosis  1088, e2431–e2432 magnetic resonance imaging  1089, e2432 Miller Fisher variant of  702, 705 other subtypes of  e2429–e2430 acute motor axonal neuropathy  e2429, e2429f, e2430t acute motor sensory axonal neuropathy  e2429–e2430 Miller Fisher syndrome  e2430 outcome of  e2434 pathogenesis of  1089, e2432–e2433, e2433f potential, therapies  1089 rare, variants of  e2427t, e2430 serum CK levels found in  1039t subtypes and variants of  1087, 1087t supportive care for  1089 treatment of  1089, e2433–e2434 corticosteroids for  e2434 immunotherapy for  e2433–e2434 potential GBS therapies in  e2434 supportive care for  e2433 Gut, central nervous system (CNS) and  1190 Gyrate atrophy  e926 Gyration, bandlike intracranial calcification with simplified  756 Gyrencephalic brain  794 Gyri (of cortex)  249

Index

H

H protein  290–291 H2 receptor antagonists, for gastroesophageal reflux  1161 Haemophilus influenzae meningitis  883 type b vaccines  922, e2127–e2128 Hair abnormalities, intellectual disability and  e1012b Hallucinations  769, e1737 hypnogogic, in narcolepsy  674 sleep-related  669 Hallucinogens  1199 abuse in  e2690 sensorium changes  e2682b toxicity  1196b Haloperidol  1226, e1181t, e1183 for ASD  466 for tic disorders  745t Hamartoma hypothalamic, with gelastic seizures  e1369 of tuber cinereum  e841, e842f Handicapped Children’s Early Education Assistance Act of 1968  1285, e2895 Hangman’s fracture  820, 822 Hansen’s disease  892–893 see also Leprosy Haploinsufficiency  514 of FOXG1  515 Hardware  e2917 Harley-Rand-Ritter (HRR) test plates  34, e69 Hartmannella  e2085 Hartnup’s disease  292, 374, e687–e688, e922 Hashimoto encephalopathy  427, 936–937, e2145–e2146 HCN1, gene mutations in, and infantile onset epilepsies  558t–560t Head banging  670, e1526 Head circumference charts  e41f Head drops, nonepileptic and epileptic  529 Head injury, sinovenous thrombosis and  860 Head nodding  725t, 726, e1638 Head shape  233–234, e568–e571 Head size, intracranial pressure and  816t Head trauma abusive. see Abusive head trauma (AHT) EEG and  e237–e238 vertigo and  56, e121 Head ultrasonography (HUS)  e305 neonatal  127 Headache  647–655, 1258, e1490–e1505 arterial ischemic stroke and  856, e1947 channelopathies and  e978t classification of  647–648, e1490–e1491 chronic migraine  647–648 migraine variants  648 migraine with aura  647 migraine without aura  647 tension-type headache  648 trigeminal autonomic cephalalgia  648 EEG and  e238 epidemiology of  648, e1491–e1492 evaluation of  648–649, e1492–e1493 clinical laboratory testing  649 electroencephalogram  649 lumbar puncture  649 neuroimaging  648–649 hypnic  670 intracranial pressure and  816t management of  e1493–e1500

1349

Headache (Continued) migraine management of  649–653 pathophysiology of  648 nonpharmacologic treatment for  650, e1494–e1495 pain management in  e2851 pathophysiology of  e1492 pharmacologic therapies for  650–652, e1494–e1500, e1494t, e1497t acute therapy/outpatient abortive therapy  653 emergency room management of  653 preventive treatment  652t posttraumatic  791–792 in traumatic brain injury  e1799 in SLE  950, e2169 specific secondary headache syndromes  650–651, e1495–e1496 Health 2.0  1296, e2912 Health Insurance Portability and Accountability Act (HIPAA)  1286, e2896–e2897 Health literacy, low  1242 Health outcomes, measurement of, in neurologic disorders  1289–1294, e2900–e2907 child’s age and stage as determinant for  e2903–e2905 ICF framework for  e2901–e2903, e2902f, e2902t–e2904t new directions for  e2905–e2906 outcome measures in  e2900–e2901 Hearing abnormalities, intellectual disability and  e1011b autistic spectrum disorder and  e1107 chronic kidney disease and  1219 definitive evaluation of, in ASD  465 Hearing impairment (HI)  43–51, e89–e115, e90f classification of  e94–e95 auditory neuropathy spectrum disorder  e94 central  e94 conductive  e94 by definition of impairment site  e94 sensorineural  e94 by severity and profile of thresholds elevation  e94–e95, e95t clinical examples of  e106, e107f–e109f consequences of  49, e104–e105 diagnostic evaluation of  e105–e106 audiological evaluation  e106 clinical evaluation and specialized testing  e105–e106 patient and family histories  e105 future developments for  e111 conventional hearing aids  e111 electrophysiology  e111 hearing restoration therapies  e111 imaging  e111 management of  e106–e111 severe to profound, communication mode for  e109–e110 Hearing loss (HL)  43–44, 44f, e89 acute bacterial meningitis and  888 assistive devices for  50 audiological evaluation  50 bacterial meningitis and  e2018 central  44 classification of  43–44 by definition of impairment site  43–44 by severity and profile of thresholds elevation  44, 44t

1350

Index

Hearing loss (HL) (Continued) clinical evaluation and specialized testing of  49–50 CNS tumor posttreatment sequelae  1025 conductive  43, 45–46, e99 evaluation of auditory function  44–45 behavioral methods  44–45 cross-check principles  44 objective methods  45 future developments for  51 genetic  46–49, e100–e104 imaging  45 management of  50–51 in neurosensory deficits  e2295 nonsyndromic  46–47, e101–e102 autosomal dominant inheritance  46, e101 autosomal recessive inheritance  46, e101–e102 genetic diagnostics for  47, 47t, e101–e102, e102t X-linked and mitochondrial inheritance  46, e101 patient and family histories  49 in pediatric population  45–46 sensorineural  43, 46, e94, e99–e100 severe to profound, choice of communication mode for  50 syndromic  47–49, 48t, e102–e104 genetic  e102–e104, e103t traumatic  e100 Hearing restoration therapies  e111 Heart, inherited disorders of  e2723 Heart disease acquired  e2714t, e2723, e2724t cardiac defects in, genetic disorders with  e2723 energy production, disorders of  e2725 inborn errors of metabolism  e2723–e2725 inherited neuromuscular disorders with cardiac complications  e2726 storage disorders  e2725–e2726 congenital. see Congenital heart defects (CHDs) neurologic disorders with  1205–1214, e2713–e2737. see also Congenital heart defects (CHDs) Heart failure, neurologic sequelae of  1211, e2721 Heart surgeries  1207–1208 in CHD  e2718, e2718f Heavy metal neuropathy  1084, e2418–e2419 Heavy metals causing peripheral neuropathy  e2684b metabolism, disorders of  e660t sensorium changes  e2682b toxicity  1196b–1197b Heel-shin test  e37 Helminths  913–916, e2097–e2107 gnathostomiasis in  e2100–e2101 toxocariasis  e2097–e2098 trichinellosis  e2098–e2100 Hemangioblastoma  1013t Hematological disorders, arterial ischemic stroke and  853 Hemianopia, homonymous  796 Hemiconvulsions, hemiplegia, and epilepsy syndrome (HHE)  565–566, e1327– e1329, e1328f differential diagnosis of  566 EEG findings in  565–566 etiology of  565 laboratory studies for  566 neuroimaging of  566

Hemiconvulsions, hemiplegia, and epilepsy syndrome (HHE) (Continued) neurologic findings in  565 outcome for  566 seizures in  565 treatment of  566 Hemicraniectomy, for increased intracranial pressure  865, e1969 Hemimegalencephaly  223–224, 584–585, 586t, e534–e539, e536t, e1365–e1366, e1366f brain imaging of  e536–e538, e536f–e537f clinical features of  e538 etiology of  584–585, e538–e539 genetic and molecular basis of  e538–e539 neuroimaging of  584, 585f neurologic features of  584 nonneurologic features of  584 pathology of  e534–e536, e536f–e537f treatment of  e539 Hemiparesis, arterial ischemic stroke and  856, e1946 Hemiplegia, spastic  e1654–e1655 Hemiplegic migraines, familial  409 Hemispherectomy  613, 617, e1430 Hemispheres, global CH with involvement of  203 Hemispheric swelling, abusive head trauma and  797, e1819 Hemlock, poison  1196b, 1198b–1199b Hemodialysis, urea cycle disorders and  303, e717–e718 Hemolytic-uremic syndrome (HUS)  1222, e2757–e2758, e2758b, e2758t, e2785 treatment of  e2758 Hemophilia  e2004 Hemorrhages anatomic factors for  161–162 epidural. see Epidural hemorrhage intracranial. see Intracranial hemorrhage intraparenchymal. see Intraparenchymal hemorrhages optic nerve sheath  797 differential diagnosis of  798–799 retinal, posttraumatic  797 differential diagnosis of  798–799 subarachnoid. see Subarachnoid hemorrhage subdural. see Subdural hemorrhage Hemorrhagic stroke, coagulation disorders in  881–882, e1999f, e2004–e2005 Hemotympanum  799 Henoch-Schönlein purpura  851, 947t, 953, e2178–e2179 Heparin low-molecular-weight  855–856 unfractionated  855–856 Hepatic encephalopathy (HE)  1233–1235 cognitive and behavioral abnormalities in  1234, e2793 fulminant liver failure in  1234, e2792–e2793 grade I  1234 grade II  1234 grade III  1234 grade IV  1234 laboratory tests for  1234, e2793–e2794 minimal  1234, e2793 neurologic abnormalities in  1234, e2792 neuropathology and pathophysiology of  e2794–e2795 prognosis of  1235, e2796 treatment of  1234, e2795–e2796 Hepatic fructose-1-phosphate aldolase B deficiency  306–307

Hepatic phosphorylase kinase deficiency  314, e740 Hepatitis  1233, e2791–e2792 Hepatitis A neurologic disorders  e2791 vaccines  919, e2125 Hepatitis B neurologic disorders  e2791 vaccines  922, e2128 Hepatitis C, neurologic disorders  e2791–e2792 Hepatobiliary diseases  1233–1236 neurologic disorders associated with  e2791–e2802 progressive hepatocerebral disease  e2800 Hepatocyte transfer  303 urea cycle disorders and  e719 Hepatolenticular degeneration  e2797–e2800 Hepatomegaly Pompe disease and  310 von Gierke disease and  307 Hepatophosphorylase deficiency  312–314, e728t, e739 Hepatorenal glycogenosis  307–309, e728–e732 Hepatorenal syndrome (HRS)  1222, e2758–e2759 clinical features of  e2759 pathophysiology of  e2759 therapy for  e2759 Hepatorenal tyrosinemia  e678–e679, e679f Hepatosplenomegaly  427 intellectual disability and  e1012b lysosomal storage diseases and  e783 Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome (HANAC)  1221 Hereditary ataxias  690–699, 690t, e1554– 1584, e1559t autosomal dominant  e1561t–e1562t autosomal recessive  e1559–e1578, e1560t diagnostic approach to  e1580 spastic  699, 699t Hereditary folate malabsorption  381, e935 Hereditary fructose intolerance  e726–e727 Hereditary hemorrhagic telangiectasia (HHT)  154 Hereditary neuropathy with liability to pressure palsy (HNPP)  1075–1076 Hereditary sensory and autonomic neuropathies  1179–1181, 1180t, e2652–e2655, e2653t type 1  1179, e2652 type 2  1179, e2652 type 3 (familial dysautonomia)  1179– 1181, e2652–e2654 type 4 (congenital insensitivity to pain with anhidrosis)  1181, e2654 type 5  1181, e2654 type 6  1181, e2654 type 7  1181, e2654 Hereditary sensory neuropathies (HSNs)  1077, e2401, e2401t Hereditary spastic ataxia  e1563t, e1578–e1579 Heredopathia atactica polyneuritiformis  e2416 see also Refsum disease Herniation  784, e1766f, e1771–e1772 cerebellar tonsillar herniation  784 lateral transtentorial (uncal) herniation  784 syndromes, brain, intracranial pressure and  817t

Heroin myopathies and  e2683b Parkinsonism and  e2684b toxicity  1197b–1198b Herpes simplex viruses (HSVs)  900–901, e2038–e2040 clinical manifestations of  900, e2038–e2039 diagnosis of  900, e2039, e2039f treatment and outcome of  900–901, e2039–e2040, e2040f type 1  899t, 900–901 type 2  899t, 900–901 Herpesvirus-6 infections, and febrile seizures  520 Herpesvirus-7 infections, and febrile seizures  520 Herpesviruses  896b, 900, e2038–e2045 human, types 6 and 7  e2042–e2043 Hers disease  312–314, e739 HESX1 gene, mutation in  1170 Heterochromatin  257, e613 Heteroplasmy  e613, e614t Hexachlorophene sensorium changes  e2682b toxicity  1196b Hexosaminidase  323–325 Hexosaminidase A deficiency, spinal muscular atrophies and  e2362–e2363 HHH syndrome  482t–486t High-carbohydrate, low-fat diet, for fatty acid oxidation disorders  e2557 High-dose chemotherapy (HDC), for AT/ RT  998, e2255 High-grade glioma (HGG)  979–984, e2226–e2234 classification of  e2227t clinical presentation of  979, e2226 CNS-directed delivery strategies in  983 convection-enhanced delivery for  983, e2231 diagnosis of  979–982, e2226–e2229 diffuse intrinsic pontine glioma and  e2244 future directions for  982–983, e2230–e2231 histopathology of  979–980, e2226–e2228 imaging of  980–982, e2228–e2229 metabolic  e2228, e2229f perfusion magnetic resonance  e2228–e2229 initial management of  979–982, e2226–e2229 intranasal delivery for  983, e2231 metabolic imaging  981–982, 981f molecular pathology of  979–980, e2226–e2228 perfusion MR  982 therapy for  982, e2229–e2230 current  e2229–e2230 targeted  982–983 WHO classification of  980t High-level (level A) recommendations, writing  1279t, 1280 “High-throughput sequencing”  e622–e623 Higher-order language disorders  e1055–e1056 Hill, Leonard  e1747 Hip dislocation, in children with physical disabilities  474 Hip weakness gait  32, e64 Hippocampal sclerosis, mesial temporal lobe epilepsy resulting from  579, 580f, e1356–e1357, e1357f–e1358f

Index Hippocampus in epilepsy  e1210–e1211, e1213f neuronal synchronization  508 Hirayama disease  e2363 Hirschsprung, Harald  e2780 Hirschsprung disease  751, 1182, 1230, e556, e2656 anatomic gastrointestinal disorders of  e2780–e2781 Histidinemia  292, e688 Histiocytosis  1018–1019, e2283–e2284 Histocompatibility antigen (HLA) subtypes, in excessive sleepiness  674 Histone deacetylase inhibitors (HDACIs)  1062, e2367 Histones  e2367 Histoplasma spp. H. capsulatum  908, e2066t, e2068 H. duboisii  908 Histoplasmosis  908, e2068 HIV-encephalopathy  427 HLA alleles, and developmental language disorders  432 HMG-CoA lyase deficiency  482t–486t HMPDC syndrome  482t–486t HNPP  e2397 Hobson v Hanson  1283, 1284t, e2893 Holmes (rubral) tremor  713, e1612 Holocarboxylase synthetase deficiency  295, 482t–486t, e695 Holoprosencephaly (HPE)  192–194, e449–e453 alobar  192, e450 clinical manifestations and outcomes of  193–194, e452–e453 definition and subtypes of  192–193, e450, e451f epidemiology of  192, e449 etiology of  193, e452 genetic counseling and testing of  194, e453 historical background of  e449 lobar  192, e450 management of  194, e453 neuropathological findings of  e450 prenatal diagnosis and imaging of  194, 195f, e453, e454f semilobar  192, e450 Home management, of febrile seizures  e1244 Homocysteine  292 Homocystinuria  292, 482t–486t, e685–e687 arterial ischemic stroke and  854 classical  e926 Homology-directed repair (HDR)  118–119 Homonymous hemianopia  796 Homovanillic acid, cerebrospinal fluid concentration of  358 Horizontal gaze palsy  206–207, e480 Hormonal therapy for infantile spasms  541 for West syndrome  567 Horner’s syndrome  e42f lightning and  809 HRS. see Hepatorenal syndrome (HRS) HSN IA-IF  e2401–e2402 HSN II  e2402 HSN III  e2402 HSN IV  e2402 HSN V  e2402 HSN VI  e2402 HSN VII  e2402–e2405 5-HT serotonin  1190 Human chorionic gonadotropin (hCG), as tumor marker in germinoma  1001

1351

Human chorionic gonadotropin (hCG)secreting tumors  1166 Human embryonic stem cells (hESCs)  107, e277, e295 Human genome  257–262 Human immunodeficiency virus (HIV)  904– 905, e2055–e2057 clinical features of  904, e2055–e2056, e2055f diagnosis of  904–905, e2056, e2056f inflammatory myopathy and  1145 treatment and outcome of  905, e2056–e2057 Human microbiota, development and role of  e2787–e2788 Human mitochondrial genome  e2564f Human models, neuronal ceroid lipofuscinosis and  e957 Human monocytic ehrlichiosis  e2077, e2077f Human mtDNA, morbidity map of  339f Human papillomavirus vaccines  922, e2128 Human T-cell lymphotropic virus type 1  e2057 Humor comprehension, and nonverbal learning disabilities  439 Hunter serotonin toxicity  1194 Hunter syndrome  482t–486t, e772t–e773t, e803–e804, e803f Huntington disease-like 4  e1574–e1575 Huntington’s disease  e1615 Hurler syndrome  e801, e801f HUS. see Hemolytic-uremic syndrome (HUS) Hutchinson’s teeth  890–891 Hydantoins, for antiseizure drug therapy in children  e1400 Hydatid cysts  914 Hydatid disease  914 Hydatid sand  915 Hydralazine  e2755b causing peripheral neuropathy  e2684b Hydralazine toxicity  1197b Hydranencephaly  770–771 Hydrocarbon abuse  1198–1199, e2690 Hydrocephalus  36–37, 226–232, e77, e434, e551–e566 abusive head trauma and  795 acquired causes of  227, e555 acute bacterial meningitis and  886 arrested  226 bacterial meningitis and  e2014 benign extracranial  229 causes of  e554t classification of  226, e551 clinical characteristics of  227–228, 228f, e555–e556, e555f compensated  226, e551 complications of  e560–e561 congenital causes of  227, e554–e555 in congenital toxoplasmosis  e2087–e2088, e2087f CSF production, circulation, and absorption  226–227, e552–e553, e552f definition of  226, e551 diagnosis of  229, e558 differential diagnosis of  229, e553b, e558–e559 epidemiology of  226, e551–e552 etiology and pathophysiology of  227, 227f, e553–e555, e554f extraventricular obstructive  226, e551 genetics of  228, e556–e557, e556t

1352

Index

Hydrocephalus (Continued) in infants acquired causes of  227, e555 congenital causes of  227, e554–e555 symptoms and signs  228, e555–e556 management of  230, 230f, e559–e560 neuroimaging of  228–229, e557–e558 computed tomography  229 cranial ultrasound  228–229 magnetic resonance imaging  229 pathology of  229–230, e559 posthemorrhagic  e381–e382, e381f, e555 posttraumatic  791 in traumatic brain injury  e1797–e1798 prognosis of  230, e561–e562 shunted, as risk factor for neurocognitive deficit  1025 in spinal cord tumor  1012 symptoms and signs  228, e556, e556t uncompensated  e551 Hydrochlorothiazide  e2755b for hyperkalemic periodic paralysis  1154 Hydrogen nuclei (protons)  e170 Hydrogen peroxide associated with myopathies  e2683b sensorium changes  e2682b toxicity  1196b–1197b Hydrolethalus syndrome  240 Hydromorphone, for pain management  1257t Hydrops fetalis, nonimmune, lysosomal storage diseases and  e782 Hydroxamic acid  e2368 3-Hydroxy-3-methylglutaric acidemia  e1382 inherited metabolic epilepsies  595 Hydroxychloroquine associated with myopathies  e2683b causing peripheral neuropathy  e2684b in dermatomyositis  1143 neuroteratology  1203t toxicity  1197b D-2-Hydroxyglutaric aciduria  e1382 L-2-Hydroxyglutaric aciduria  e1382 Hydroxyglutaric aciduria, inherited metabolic epilepsies  595 3-Hydroxyisobutyric aciduria  296, e699 27-Hydroxylase deficiency  757, e1700 5-Hydroxytryptamine system, in sudden infant death syndrome  686, e1549 Hydroxyurea  1062–1063 Hygromas intracranial arachnoid cysts and  232 subdural  797 Hyoscyamine  1199b–1200b associated with tremor  e2685b in ataxia  e2685b Hyoscyamus niger  1196b sensorium changes  e2682b Hyper-IgE syndrome  e752t–e760t Hyper-IgG syndrome  948, e2166 Hyperactivity, medications to treat  468 Hyperammonemia diagnosis of  302f differential diagnosis of  e717f with insufficient ketosis  278 ketoacidosis with  278 without metabolic acidosis  278 Hyperammonemic coma, EEG and  300 Hyperammonemic crises, management of  303 Hyperammonemic encephalopathy  301 Hyperbaric oxygen therapy (HBOT) , for ASD  469 Hyperbilirubinemia  1236 pathophysiology of  e2800–e2801

Hyperbradykininism  1183, e2656 Hypercalcemia  1217b Hypercalciuria  e579–e581 Hypercapnic vasodilatation  845, e1925 Hyperekplexia  359, 716, e1617–e1618 Hyperglycemia, hypoxic-ischemic encephalopathy and  811 Hyperglycinemia, nonketotic  131 Hyperglycolysis  e1767 Hyperhidrosis  e2646 in pediatric autonomic disorders  1175 Hyperhomocysteinemia  163, 596, e1383 and inborn errors of metabolism  482t–486t Hyperhomocystinuria  1218, e2748 Hyperinsulinemia  1167 Hyperinsulinism-hyperammonemia syndrome  482t–486t, 597, e1384 Hyperkalemia  1216t, e2741t Hyperkalemic periodic paralysis  1153–1154, 1153t clinical features of  1153 genetics  1153 laboratory tests for  1153–1154 pathophysiology of  1153 treatment for  1154 Hyperkinetic disorders  706 Hyperkinetic movement disorders arterial ischemic stroke and  e1946–e1947 treatment of  1253 Hypermagnesemia  1216, 1217b, e2741b, e2742 Hypermotor seizures  535, e1265 Hypernatremia  131, e2740t AKI and  1216t sodium balance disturbances  171 Hyperornithinemia-hyperammonemiahomocitrullinuria (HHH) syndrome  298, 300, e714 Hyperosmia  63 Hyperosmolar therapy  789 for traumatic brain injury  e1785 Hyperostosis, of skull  e579–e581 Hyperphagia  1171 Hyperphenylalaninemia  176, e418, e418f, e875–e878 mild  287 monoaminergic neurotransmitter deficiency states with  355–357, 356t Hyperphosphatasia intellectual disability syndrome  e752t–e760t Hyperphosphatemia  1132 Hyperpigmentation, in neurofibromatoses  362 Hyperplasia, cerebellar  204 Hyperpolarization-activated cation (HCN) channel  509 Hyperpolarizing conductances  506–507, e1212 Hyperprolactinemia, clinical features and management of  e2632 Hyperprolinemia type II  377, e926 Hypersensitivity angiitis  953, e2179 Hypersomnolence  676–677 Hypertelorism  274 Hypertension  1220, e2753–e2756 Hypertensive encephalopathy  1220, e2753–e2754 clinical features of  1220, e2753 diagnostic considerations in  1220, e2754 outcomes from  1220–1221, e2754 pathophysiology of  1220, e2753–e2754 SLE-associated  950, e2170 Hyperthermia, neuroteratology  1203t

Hyperthyroidism  1178 central  1170, e2635 chorea-associated  709 Hypertonia  472–473, e1127–e1129, e2332 assessment of  472, 473t, e1127, e1128t interventions for  472, e1127, e1128t Hypertonia Assessment Scale  e59f Hypertonia Assessment Tool (HAT)  472 Hyperuricemia myoglobinuria and  1132 von Gierke disease and  308 Hyperventilation  e2646 and absence seizures  527 EEG of  89f for intracranial pressure  818 in pediatric autonomic disorders  1175 for traumatic brain injury  789, e1785 Hyperventilation syncope  662, e1516 Hyperventilatory response, in EEG  e221, e221f Hypervitaminoses  373 Hypnic headaches  670, e1526 Hypnic jerks  670 Hypnogenic paroxysmal dyskinesia  721, e1631 Hypnogogic hallucinations, in narcolepsy  674 Hypoalbuminemia, early onset ataxia with  e1567 Hypocalcemia  1217b myoglobinuria and  1132 seizures and  e311 Hypocretin-1 levels, cerebrospinal fluid  674 Hypodontia, 4H syndrome and  e1687, e1687f Hypoglossal nerve  10, e16–e17, e16f Hypoglycemia  131 galactose-1-phosphate uridyltransferase deficiency  305 glucose balance disturbances  171 ketogenic diets and  629b metabolic encephalopathies and  e402– e404, e404t, e405f seizures and  e311 Hypogonadism, ataxia-telangiectasia and  e1566 Hypogonadotropic hypogonadism associated with multiple hypothalamic/ pituitary hormone deficiencies  e2630–e2631, e2631f functional  1167, e2631 isolated. see Isolated hypogonadotropic hypogonadism (IHH) with multiple hypothalamic/pituitary hormone deficiencies  1167 see also Delayed puberty Hypohidrosis, in pediatric autonomic disorders  1175 Hypokalemia  1216t, e2741t enteric infections cause by  e2785 Hypokalemic periodic paralysis  1153t, 1154, e2607t, e2609 clinical features of  1154 genetics  1154 laboratory tests for  1155 pathophysiology of  1155 treatment for  1155 Hypoketotic hypoglycemia  1134, e2549 Hypokinesia  713–714 Hypomagnesemia  1216, 1217b, e2741– e2742, e2741b Hypomelanosis of Ito  371, 586t, e906 Hypomelanotic macules  427

Hypomyelinating white matter disorders  747–751, e1680–e1691, e1684f with atrophy of basal ganglia and cerebellum  750, e1688–e1689 Cockayne syndrome and trichothiodystrophy  e1690 with congenital cataract  749f, 750, e1685f, e1688 cytoplasmatic tRNA synthetase defects and  e1687–e1688 18q minus syndrome in  e1690 4H syndrome in  e1685f, e1686–e1687, e1687f fucosidosis in  e1689 oculodentodigital dysplasia in  e1688 Pelizaeus-Merzbacher disease in  e1683– e1686, e1685f Pelizaeus-Merzbacher-like disease in  e1685f, e1686 serine synthesis defects in  e1689–e1690 sialic acid storage disorders in  e1685f, e1689 SOX10-associated disorders in  e1690–e1691 Hyponatremia  131, e2738, e2740t AKI and  1215, 1216t bacterial meningitis and  e2013–e2014 causes of, postmeningitis  885–886 enteric infections cause by  e2785 metabolic encephalopathies and  e404– e405, e406b sodium balance disturbances  171 Hypophosphatasia, congenital  377, e926 Hypophysial stalk  1165 Hypoplasia, optic nerve  e75, e75f Hypoplastic left heart (HLHS)  1205, 1207f, e2713, e2715f fetal circulation in  1206–1207, 1208f, e2714–e2716, e2716f white matter injury in  e2719 Hyporeflexia  e22–e23 Hyposmia  63 Hypotension, trauma-induced  794–795 Hypothalamic dysfunction, in craniopharyngioma  1007–1008 Hypothalamic hamartoma, gelastic seizures with  e1369 Hypothalamic-pituitary-adrenal (HPA) axis  799, 1168, e2632 Hypothalamic/pituitary disorders appetite regulation and energy balance  1170–1171, 1170f, e2635f disorders of appetite regulation and energy balance  e2635–e2636, e2635f glucocorticoid production  1168–1169, e2632–e2633 adrenocorticotropic hormone (ACTH) deficiency  1168–1169, e2632–e2633 adrenocorticotropic hormone (ACTH) excess  1168, e2632, e2633f hormone deficiencies, hypogonadotropic hypogonadism associated with  e2630–e2631, e2631f organogenesis of  e2627 prolactin secretion  1168, e2631–e2632 pubertal development  1165–1168, e2628–e2631 age of onset  1166 delayed/arrested puberty  1166–1168 normal physiology  1165–1166 sexual precocity  1166

Index Hypothalamic/pituitary disorders (Continued) statural growth  1169, e2633–e2634 growth hormone deficiency  1169, e2634 growth hormone excess  1169, e2634 thyroid function  1169–1170, e2634–e2635 central hyperthyroidism  1170, e2635 central hypothyroidism  1170, e2635 physiology  1169–1170 water balance  1171–1172, e2636–e2638 diabetes insipidus  1171–1172, e2637 syndrome of inappropriate antidiuretic hormone secretion  1172, e2637–e2638 Hypothalamic-pituitary-gonadal (HPG) axis  1165–1166 Hypothalamic-pituitary-portal system  1165 Hypothalamic syndrome  986, e2236 Hypothalamus  e2627 anatomic and physiologic aspects of  1165, e2627–e2628, e2628f development of  1165 Hypothermia coma and  776 intracranial pressure and  789, 818 for refractory status epilepticus  549t spinal cord injury and  823, e1886 therapeutic  811 outcome and  141 traumatic brain injury and  e1787 Hypothyroidism  427, 1178 central  1170, e2635 congenital  487, e1154–e1155 Hypotonia  689, e1556, e2332 algorithm  1051, 1053f and ASD  465 central  1054, 1055t definition of  1051, e2341 examination for  1052–1054, e2342–e2344 history of  1051–1052, e2341–e2342 localization of  1051, 1052t, e2341, e2342t, e2343f muscle tone in  e2341 onset and progression of  1052 peripheral  1054–1056, 1055t–1056t popliteal angle in, measurement of  1052–1054 pull-to-sit test for  1052 scarf-sign in  1052 selected conditions associated with  e58b shoulder suspension test for  1054 ventral suspension test for  1054 Hypotonic (atonic) cerebral palsy  e1656 Hypoxemia, in drowning  808–809 Hypoxia cerebrovascular system and  845–846 trauma-induced  794–795 Hypoxia-ischemia, abusive head trauma and  794–795 Hypoxic-ischemic brain injury  112, 1052, e282 cell death and  e331 cerebral blood flow and  e327–e329 clinical syndromes  e321–e322 and natural history  e321–e325 energy metabolism and  e327–e329 etiology of  e321 future directions of  e333 neuroinflammation in  e331 neuroprotection strategies in  e331–e332 neurotrophic factors of  e332

1353

Hypoxic-ischemic brain injury (Continued) outcomes of  e325–e327, e326t cognition  e326 motor function  e325 prediction of  e327, e328f and therapeutic hypothermia  e326–e327 vision and hearing  e326 oxidative stress and  e330–e331 pathophysiology of, and neuroprotection  e327–e331, e329f in preterm infant  e333 scope of problem  e321 stem cells and  e332–e333 in term newborn  138–146, e321–e338 cell death and  145 cerebral blood flow and energy metabolism  143 clinical syndromes of  138–140 cognition of  141 etiology of  138 future directions for  146 inflammation in  143f, 144–145 motor function of  140–141 natural history of  138–140 and neuroprotection  143–145, 143f neurotropic factors  145 outcomes of  140–141, 141t, 142f oxidative stress and  144 pathophysiology of  143–145, 143f patterns of  140 progression of  140 scope of problem  138 stem cells in  145 therapeutic hypothermia and  141 vision and hearing of  141 Hypoxic-ischemic encephalopathy  130, e310, e321 current treatment options for  e302–e303 neonates with, treatment options for  124–125 Hypoxic-ischemic encephalopathy, in infants and older children  804–812, e1839–e1857 cardiac arrest and  804, 805t, e1839, e1845–e1847 abusive head trauma  808, e1845 drowning (submersion injury)  808– 809, e1846 electrical shock  809, e1847 lightning and electrical injuries  809, e1846–e1847 neurologic complications after  809–810, e1847–e1848 neurologic prognosis after  810–811, e1848–e1850 strangulation injury  809, e1846 sudden, in children and adolescents  809, e1847 sudden infant death syndrome  808, e1845–e1846 cardiopulmonary resuscitation for  e1852–e1853 cardiovascular support for  e1852 cerebral blood flow and metabolism after resuscitation in  e1844–e1845 clinical pathophysiology of  808, e1844–e1845 cerebral blood flow and metabolism after resuscitation  808 dilemma of neurologic morbidity  812 extracorporeal membrane oxygenation for  e1852–e1853

1354

Index

Hypoxic-ischemic encephalopathy, in infants and older children (Continued) mechanisms of brain injury  804–808, e1840–e1844 activation of intracellular enzymes  806, e1841 activation of nitric oxide synthesis  806– 807, 807f, e1842–e1843, e1843f, e1843t autophagy  808, e1844 brain energy failure  804–806, 805f, e1840–e1841, e1841f calcium-mediated injury  806, 806f, e1841, e1842f excitotoxic injury  806, e1841 formation of oxygen radicals  807, e1843–e1844, e1844f genetic damage and regulation  808, e1844, e1846b neuroinflammation, glia, and neurovascular unit  807–808, e1844 phospholipase release of free fatty acids  806, e1842, e1842f neuroimaging, injury and outcome assessment of  e1849–e1850, e1851f neurologic morbidity of  e1854 postcardiac-arrest syndrome and  804, e1839–e1840 temperature control for  e1853 treatment of  811–812, e1850–e1854, e1852t cardiovascular support  811 extracorporeal membrane oxygenationcardiopulmonary resuscitation  812 glucose homeostasis  811 intracranial pressure monitoring and control  811 postcardiac-arrest brain injury  812, e1853–e1854 postresuscitation interventions as  e1851–e1853 resuscitation  811–812, e1850 temperature control  811 Hypoxic-ischemic insults, prognosis after, EEG and  e238 Hypoxic vasodilatation  845–846, e1925 Hypsarrhythmia  95, e233–e234, e234f, e1229, e1278–e1284, e1279f in infantile spasms  540, 540f

I

I-cell disease  331, e752t–e760t, e772t–e773t, e813–e814, e813f–e814f I-k B kinase-associated protein (IKAP)  1179 Iatrogenic movement disorders  e1641 Iatrogenic neurotrauma, during newborn period  160 Iatrogenic trauma  e367 IBD. see Inflammatory bowel disease (IBD) IBS. see Irritable bowel syndrome (IBS) Ibuprofen, for pain management  1257t ICF. see International Classification of Functioning, Disability and Health (ICF) Idiopathic focal epilepsies of childhood  e235–e236 multiple independent spike foci  e235– e236, e236f temporal spikes and sharp waves  e235, e235f Idiopathic generalized epilepsies  e1233–e1234 Idiopathic generalized glycogenosis  309– 310, e732–e733

Idiopathic hypersomnia (IH)  e1534 Idiopathic inflammatory myopathies  e2585–e2590 dermatomyositis in  e2585–e2589 polymyositis in  e2589–e2590 Idiosyncratic reactions laboratory tests for  608 managing  610 Ifosfamide  e2696 toxicity  1202 Ifosfamide-based chemotherapy  1003 IL1RAPL1 gene mutation  421t ILAE. see International League Against Epilepsy (ILAE) Illusions  769 Imaging genetics  104, e269–e270 Imerslund-Gräsbeck syndrome  482t–486t Imipramine, for ADHD  455t–457t IMM lipid milieu, defects of  e848 Immature neuraxis, abusive head trauma and  794, 795b Immune activation  e2140 definition of  932 Immune dysregulation, in opsoclonus myoclonus syndrome  940, e2153 Immune-mediated epilepsy  933–934, e2141–e2143 autoantibody associations with epilepsy in  e2141–e2142, e2142t autoimmune encephalitis syndromes in  e2141 autoimmune epilepsy in, guidelines for identification of  e2142–e2143, e2143b Immune-mediated nervous system disorders  e2788 microbiota and  1232 Immune mediation  e2140 definition of  932 Immune therapies, for autoimmune status epilepticus  548 Immunization for bacterial meningitis  889, e2018–e2019 of healthy infants and children  919t neurologic complications of  918–923, e2122–e2131, e2123t assessing causality in  e2122 combination vaccines and additives in  e2128 Immunoglobulin for acute demyelination  760–761 for ASD  469 for dermatomyositis  1143 Immunomodulators sensorium changes  e2682b toxicity  1196b Immunomodulatory therapy drug-induced movement disorders associated with  733, e1647 for low-grade glioma  990, e2241 for multiple sclerosis  763–764, 763t, e1722–e1723, e1723t Immunosuppressive agents, for nocturnal sleep fragmentation  676 Immunotherapy brain inflammation and  e2153 for CIDP  e2437 in CNS tumors  961 effect of, on brain inflammation  940 for GBS  e2433–e2434 for opsoclonus myoclonus syndrome  941–943, 942t, e2154– e2157, e2156t side effects and safety monitoring  943 for tumors  e2197–e2198

Impaired upgaze, intracranial pressure and  816t Imprinting  261 Impulsivity and ADHD  451 in childhood epilepsy  636 In-hospital management, of febrile seizures  e1244 Inadequate response  e2157, e2158f Inborn errors, presenting in the neonatal period  e1029t–e1030t Inborn errors of metabolism (IEMs)  131, 171–177, 172b, 277, 286, 424, 481–487, e402t–e403t, e405–e419, e406t–e408t, e657, e660t, e2655–e2656, e2723–e2725 acute fulminant metabolic diseases  172–175 fatty acid oxidation defects  174–175 fructose-1, 6-biphosphatase deficiency  174 glutamine synthetase deficiency  174 maple syrup urine disease  172 organic acidopathies  172–174 primary lactic acidosis, resulting from defects in oxidative phosphorylation  174 urea cycle disorders  175 arterial ischemic stroke and  854 as cause of neonatal seizures  e311 chronic encephalopathies, with multiorgan involvement  176–177 cholesterol biosynthesis defects  177 congenital disorders of glycosylation  176–177 peroxisomal disorders  177 chronic encephalopathies, without multiorgan involvement  176 glutaric aciduria  176 hyperphenylalaninemia  176 succinic semialdehyde dehydrogenase deficiency  176 classification of  277–278 by pathway and organelle  e659t clinical presentation of  278–282 abnormal development associated with congenital anomalies and dysmorphic physical features  280–281 acute encephalopathy  278–279 in childhood  282–284 epilepsy  279–280 neuromuscular weakness  282 inheritance of  277 intellectual developmental disabilities  481–486, 482t–486t laboratory evaluation of  277 nonneurologic features of  e661t by pathway and organelle  279t secondary leukoencephalopathies to  758 subacute epileptic encephalopathies  175–176 asparagine synthetase deficiency  176 glycine cleavage defects  175 L-amino acid decarboxylase deficiency (L-ADD)  176 purine biosynthesis defects  176 pyridoxine-dependent and pyridoxal phosphate dependent  175 serine biosynthesis defects  175–176 sulfite oxidase and molybdenum cofactor deficiency  175

Inborn errors of metabolism (IEMs) (Continued) treatable diagnostic approach to  481, 481b presenting with other neurodevelopmental disorder phenotypes  486–487 treatment of  e1145–e1154, e1146t–e1150t, e1151f, e1152b outcomes, and evidence  481–486 with x-linked and autosomal dominant inheritance  e658t Inborn errors of thiamine metabolism  e920 Inborn errors of urea synthesis  298–304, e710–e722 Incomplete spinal cord injuries  823 Incontinentia pigmenti  371, 427, e905–e906 Incontinentia pigmenti achromians  371, e906 Incoordination, progressive encephalopathy and  e1037t–e1039t Indels  259, e614t, e617 Independent component analysis (ICA)  97– 99, e258 India, special education in  1287, e2898 Indian tobacco  1196b, 1200b associated with tremor  e2685b sensorium changes  e2682b Indium, renal toxicity of  1225t, e2765t Individual Education Plan (IEP)  1162, 1285–1286 Individual genetic defects, specific features of  e2549–e2553, e2549t Individualized Family Service Plan (IFSP)  1286 Individuals with Disabilities Education Act (IDEA)  1285–1286, 1285b, e2895– e2896, e2895b service, evaluation for, and ASD  463–464 Indoleamine, synthesis and catabolism of  e876f Indomethacin  e383–e384 Induced pluripotent stem cells (iPSCs)  107, 120–121, e277, e295 current limitations of, as disease modeling approach  e295–e296 for drug screening  e296 generation of NSCs from  e278–e279, e278f to model neurodevelopmental disorders  121, e296 Infancy benign idiopathic dystonia of  e1639 benign myoclonus of  e1636 congenital myopathies  e2519–e2523, e2522f epilepsies with onset in  e1228–e1233 benign familial infantile epilepsy  e1228 Dravet syndrome in  e1232–e1233 epileptic encephalopathy associated with cyclin-dependent kinase-like 5  e1228–e1229 with migrating focal seizures  e1229 West syndrome in  e1229–e1232 epilepsy in myoclonic  e1198t West syndrome in  e1198t health outcome measurement and  e2905 movement disorders of  724–727, 725t, e1636–e1640, e1637t outcome measurement in  1292 paroxysmal tonic upgaze of  e1637–e1638 progressive encephalopathy in  e1030t–e1035t

Index Infant Development Inventory  e1001t–e1004t Infant/infantile antiseizure drug therapy in  603 bilateral striatal necrosis (IBSN)  711–712 botulism  1104, 1195, e2349, e2467, e2786 colic  1229 episodic gastrointestinal disease and  e2778 convulsions with choreoathetosis (ICCA)  514, e1228 diagnostic evaluation of, with poor vision  e76f, e77 with Dravet syndrome  535, 536f floppy  1051–1056 motor function testing in  1048, e2333– e2334, e2335t neuroaxonal dystrophy (IND)  e2349 neuronal ceroid lipofuscinosis  749f nystagmus in  40, 41t, e81–e83 olfaction, clinical significance of  61b, 62t, 63–64 Parkinson’s disease  358 with poor vision, diagnostic evaluation of  37 progressive myoclonus epilepsy  403 Refsum disease  48, 349–350, e103, e863–e866 clinical features of  e864 laboratory of  e864–e865 prenatal diagnosis of  e865 routine immunization, schedule of  919t sleep  91 taste, clinical significance of  60–62, 60b, 62t vision assessment in  33, e68–e69, e69f vision loss in  35–37, e71–e77 with visual problems  e73 see also Preterm infant Infant-Toddler Checklist (ITC)  e1103 Infant toddler social emotional assessment  4, e5 Infantile spasms  539, e1278 in childhood epilepsy  637 classification of  540, e1279 cognitive and behavioral outcome of  e1472–e1473 corticosteroids for  e1284–e1286 course and prognosis of  541, e1281–e1282 diagnostic evaluation of  540–541, e1280–e1281, e1280f electroclinical features of  539–540, e1278 hypsarrhythmia and ictal EEG in  540, 540f spasms in  539–540 emerging therapies for  e1286–e1287 etiologic factors of  540, e1279–e1280 hormonal therapy for  e1284 pathophysiology of  e1282 surgical therapy for  e1285–e1286 symptomatic, surgical indications for  e1419 treatment of  541, e1282–e1284, e1283f, e1283t–e1284t ACTH  541–542, 541t corticosteroids for  541t, 542 hormonal therapy in  541 surgical therapy  542 vigabatrin  541t, 542 vigabatrin for  e1285 Infantile spasms syndrome (ISSX)  515

1355

Infarction  849 arterial ischemic stroke and  e1933 cerebral  797 migrainous  854 Infections in arterial ischemic stroke  849, e1934 bacterial. see Bacterial infections in coma  776 impairment of consciousness and  e1750 of implantable devices  884 inflammatory myopathy associated with  e2590–e2592 bacterial  e2592 cysticercosis in  e2592 fungal myositides  e2592 influenza myositis in  e2590–e2591 toxoplasmosis in  e2591–e2592 trichinosis in  e2591 viral myositides in  e2591 intrauterine viral  897 in motor neuron diseases  e2383–e2384 enterovirus  e2384 poliovirus  e2383–e2384 West Nile virus  e2384 PANDAS, Tourette syndrome and  743 renal transplantation complications and  1219–1220, e2751–e2752 sinovenous thrombosis and  860, e1956, e1958f in sudden infant death syndrome  687, e1549 Infectious endocarditis (IE)  e2720–e2721, e2721f Inflammatory bowel disease (IBD)  851, 1231, e2784–e2785 von Gierke disease and  308 Inflammatory cerebellitis  701–703, e1585–e1587 demyelinating  702, e1585–e1586 infectious/postinfectious  701–702, 702t, e1585, e1586t paraneoplastic  702 Inflammatory myopathies  926t, 1044, 1045t–1046t, 1141–1147, 1142b, e2585–e2594, e2586b associated with infections  1145–1146, e2590–e2592 bacterial infections  1146, e2592 cysticercosis  1146, e2592 fungal myositides  1146, e2592 influenza myositis  1145, e2590–e2591 other viral myositides  e2591 toxoplasmosis  1146, e2591–e2592 trichinosis  1145–1146, e2591 viral myositides  1145 congenital  1145, e2590 idiopathic  1141–1145, e2585–e2590 dermatomyositis  1141–1144, e2585–e2589 polymyositis  1144–1145, e2589–e2590 steroid-sparing immunosuppressive therapy for  1144t Inflammatory neuropathies  1086–1091, e2426–e2440 causes of  e2427t chronic inflammatory demyelinating polyradiculoneuropathy  e2434–e2438 etiologies of  e2427t Guillain-Barré syndrome  e2426–e2434, e2427f immune-mediated neuropathies, other causes of  e2438 Inflammatory proteins, in opsoclonus myoclonus syndrome  940, e2153

1356

Index

Influenza A viruses  e2054 Influenza myositis  1145, e2590–e2591 clinical features of  1145 laboratory features of  1145 pathogenesis of  1145 treatment for  1145 Influenza viruses  899t, 904 vaccines  918–919, e2123–e2125 Infratentorial (cerebellar) herniation syndromes  775–776, e1748–e1749 Infratentorial tumors  e2196t differential diagnosis of  960t Infundibular stalk  e2627 Infundibulum  e2627 Inhalational anesthetics sensorium changes  e2682b toxicity  1196b Inheritance of inborn error of metabolism  277 mitochondrial  334 Inherited erythromelalgia  e981 Inherited metabolic disease, neuropathies associated with  1077–1078, 1079t, e2402–e2403, e2404t Inherited metabolic epilepsies  594–599, e1380–e1390 based on age at onset  595b general principles of  594, e1380, e1381b–e1382b, e1381t large molecule disorders  598 disorders of glycosylation  598 leukodystrophies  598 lysosomal storage disorders  598 peroxisomal diseases  598 large molecule disorders in  e1386–e1387 disorders of glycosylation in  e1386 leukodystrophies in  e1387 lysosomal storage disorders in  e1386–e1387 peroxisomal diseases in  e1387 pathophysiologic mechanisms invoked in  595b small molecule disorders  594–598 amino and organic acid disorders  594–596 disorders of glucose homeostasis  597 fatty acid oxidation disorders  596 mitochondrial diseases  596 neurotransmitter disorders  597 purine and pyrimidine defects  597–598 urea cycle disorders  596–597 vitamin dependency states  597 small molecule disorders in  e1380–e1386 disorders of glucose homeostasis  e1384–e1385 fatty acid oxidation disorders in  e1383 mitochondrial diseases in  e1383–e1384 neurotransmitter disorders in  e1385 purine and pyrimidine defects in  e1385–e1386 urea cycle disorders in  e1384 vitamin dependency states in  e1385 Inherited neuromuscular disorders, with cardiac complications  e2726 Inherited neuropathy, sequelae of  1073, e2390–e2393 Inhibitory synaptic transmission  e1214 Injury, to developing preterm brain  161–170 Inner ear  e91–e92 Inner mitochondrial membrane, lipid milieu of, alterations of  e2566 Inositol triphosphate (IP3) receptors, cerebrovascular system and  844 Insect repellents  1195, e2688

Insecticides  1195, e2687 Insertions  259, e638 Inspection, of neuromuscular disorders  e2332 Institute of Medicine (IOM)  1276–1278 standards for developing “trustworthy” guidelines  1278b Insufficient sleep syndrome (ISS)  677, e1536 Insula  e2666 Insulin  1170 for hyperkalemic periodic paralysis  1154 Insulin growth factor 1 (IGF1)  121 Insulin-like growth factors (IGFs)  1169 Integrated Visual and Auditory Continuous Performance Test  e143t–e146t Integration and Education of Disabled Children (IEDC) law, India’s  1287, e2898 Integrin α7 deficiency  1121 congenital muscular dystrophy with  e2507 Intellectual developmental disabilities  481– 486, 482t–486t treatment of  e1145–e1154 Intellectual disability  209, 269, 415–416, 418–423, 426, 1232, e638–e640, e997–e1018, e2789 birth history of  415 causes of  418, e1006t coexisting conditions in, management of  422–423 de novo dominant  421, e1008 definition of  418, e997–e998 developmental history of  415 diagnosis of  418–420, e999–e1006, e1001t–1004t, e1005f advances in diagnostic testing  418–420, 419f advances in imaging  420 definitions and testing  418 genomic microarray  420 epidemiology of  418, e997–e998 ethics of  e998–e999 etiology of  420–421, e1006–e1008, e1007t general considerations in  420 genetic causes in  420–421 other considerations in  421 other X-linked ID conditions  421 evaluation of patient  422, e1008–e1012, e1009b–e1013b consultation in  422 history in  422 laboratory and other diagnostic testing in  422 physical examination in  422 family history of  416 health outcome measures for  e2903t history of  e998–e999 life expectancy of  423 medical management of coexisting conditions in  e1012 microcephaly and  e486 outcome of  423, e1012–e1014 physical examination of  416 prognosis of  423, e1012–e1014 social history of  415–416 social outcome for  504–505 X-linked, genes implicated in  421t Intelligence decline in medulloblastoma  968 dyslexia and  e1068 measure of, in dyslexia  445 Intention tremor  689, e1557 Interferon-alpha, in craniopharyngioma  1007

Interferons causing peripheral neuropathy  e2684b for CIDP  e2437 intracystic  1007–1008 for craniopharyngioma  e2268 for multiple sclerosis  763, 763t toxicity  1197b Intergenomic signaling, defects of  e2565–e2566 Interleukin-1β (Il-1β)  163 Intermediate CMT  e2399–e2400 Intermediate filaments  1034, e2307 Intermediate hemisphere disease  689, e1557 Intermediate maple syrup urine disease  288, e680 Intermittent catheterization, of bladder  827 Intermittent maple syrup urine disease  288, e680 Internal medicine/pediatric subspecialist, referral to  1274 Internal ophthalmoplegia  e14 International Classification of Functioning, Disability and Health (ICF) framework, outcome measurement and  1290–1292, 1291f, 1291t, e2901–e2903, e2902f, e2902t International Classification of Headache Disorders (ICHD)  647 International League Against Epilepsy (ILAE)  497, e1197 classification of seizures of  e1198t International Medical Society of Paraplegia (IMSOP)  821, 821b International Restless Legs Syndrome Study Group (IRLSSG)  678, 679b, e1540b International special education  1286–1287 Internet-based support group  1274 Internuclear ophthalmoplegia  e14 Interoperability, of computer resources  e2916 Intestinal pseudoobstruction  1229–1230, 1230b, e2779–e2780, e2779b Intoxication, in acute cerebellar ataxia  e1587, e1587b Intracavitary irradiation  1007 for craniopharyngioma  e2267 Intracellular DAPs  e2485 Intracellular enzymes, activation of, hypoxic-ischemic encephalopathy and  806 Intracerebral hemorrhage  e339 perinatal clinical presentation and diagnosis of  e351–e352, e351f–e352f definitions and epidemiology of  e350–e351 management of  e352 outcomes of  e352 pathophysiology and risk factors of  e351 Intracranial arachnoid cysts  230–232 clinical characteristics of  231 posterior fossa  231 sellar region  231 sylvian fissure/middle cranial fossa  231 complications of  231–232 definition of  230–231, 231f management of  232 Intracranial calcification, associated with calcifying leukoencephalopathies  e1700 Intracranial electroencephalography monitoring, invasive  616–617

Intracranial ependymoma  e2215, e2216b, e2218t epigenetic heterogeneity of  974t genetic heterogeneity of  974t symptoms and signs of  974b Intracranial hemorrhage  130–131, 157, 158f, 865–870, 1210, e362, e1968– e1985, e2004, e2720, e2748 acute medical and surgical monitoring and management of  e1969–e1970 AKI and  1218 differential diagnosis of  e1968 epidemiology of  865, e1968 high flow lesions  866–868, e1970–e1976 arteriovenous fistulas  866–868, e1973–e1975 arteriovenous malformations  866, 867f, e1970–e1973 vein of Galen malformations  868, e1975–e1976, e1975f initial management of  865, e1969 initial studies of  e1968–e1969 low flow lesions  868–870, e1976–e1980 aneurysms  869–870, e1979 cavernous malformations  868–869, e1976–e1978, e1977f developmental venous anomalies  e1978–e1979 outcomes of  866, e1970 presentation of  e1968 recurrent  866, e1970 seizures and  865–866 Intracranial hypertension autoregulation and  e1859, e1860f, e1863 bacterial meningitis and  e2014 on cerebral autoregulation  813–814 cerebral perfusion and  e1858 chronic  e1868 idiopathic  818–819, e1868, e1868b lumbar punctures for  819 related to compromise of autoregulation  815–816 autoregulation-directed therapy in pediatric neurotrauma  815 calculation of cerebrovascular reactivity  815 linking intracranial pressure and cerebral metabolism  815–816 utility of measurement of intracranial pressure  816 see also Intracranial pressure Intracranial hypotension spontaneous  818, 818t, e1866t, e1867–e1868 Intracranial pressure A waves  814 B waves  814 C waves  814 cerebral metabolism and  e1863–e1864 cerebral perfusion pressure insults and  e1862 combining high-frequency data collection with calculation of  e1863 control  811 disorders of  813–819, e1858–e1871 evidence supporting age-dependent physiologic thresholds of  e1862–e1863 gender and  e1864 hypoxic-ischemic encephalopathy and  e1851 impairment of consciousness and  e1750 intracranial hemorrhage and  e1969

Index Intracranial pressure (Continued) management of  788–789 barbiturates  789 cerebrospinal fluid drainage  789 hyperosmolar therapy  789 hyperventilation  789 monitoring  789 sedation and neuromuscular blockade  789 surgical  789 temperature control and hypothermia  789 management of acutely elevated  816–818, 817f evidence in support of guideline-directed  818 general principles of medical management  816–817 initial assessment, imaging, and surgical intervention  816 monitoring  811, 814, e1860–e1862 history  814, e1860 indications for  e1860, e1861b, e1861t methods of  814, e1860–e1861 noninvasive approaches to  814, e1861–e1862 Monroe-Kellie doctrine  813 normal  e1858 physiologic measurements of  e1794 pressure reactivity index for  815 raised/increased  e1858–e1860, e1859f acute bacterial meningitis and  886 age and  e1858, e1859f application of receiver operating characteristic curves to determining thresholds of  e1862 cerebral autoregulation and  813, 814f, e1858, e1860f clinical manifestations of  816, e1864, e1865t compliance and cerebral blood flow changes with age  813 duration of physiologic derangement and outcome in  e1862 effects of intracranial hypertension on autoregulation  813–814 guideline-directed management of  e1867 herniation syndromes and  e1864, e1865t initial assessment, imaging and surgical intervention for  e1865–e1866 intracranial pressure-directed therapy for  e1867 lumbar puncture in patients with  e1864–e1865, e1866t management of  e1865–e1867, e1866f medical management for  865, e1866–e1867 monitoring of  865 pathophysiology of  813–814 physical examination findings for  816, 816t–817t, e1864 reduction, in coma  776 sinovenous thrombosis and  863 surgical management for  865 thresholds and doses of  814–815, e1862 sinovenous thrombosis and  e1964 surgical management of  e1787–e1788 thresholds affect outcomes in severe brain injury  e1863 traumatic brain injury and  e1785–e1786 treatment algorithm for  e1789, e1790f–e1791f

1357

Intracranial pressure (Continued) utility of measurement of  816, e1864 see also Intracranial hypertension Intractability definition of  e1205–e1206 ILAE  e1205 Nova Scotia  e1205 in epilepsy  503 Intractable localization-related epilepsy  e269 Intracystic therapy, for craniopharyngioma  e2267–e2268 Intradural spinal cord tumors  e2276–e2281 diagnosis of  e2276–e2277, e2277t epidemiology of  e2276 presentation of  e2276, e2277b subtypes of  e2277–e2279 ependymomas, of conus-cauda region  e2278 extramedullary spinal cord tumors  e2277 intramedullary spinal cord tumors  e2278–e2279, e2279f peripheral nerve tumors  e2278 spinal meningiomas  e2277–e2278 surgery for  e2279–e2281, e2280b operative technique in  e2280 risks of, complications and  e2280– e2281, e2281b Intrafusal muscle fibers  e54 Intramedullary ependymomas  e2278–e2279 Intramedullary spinal cord tumors (IMSCTs)  1014–1016, e2278–e2279, e2279f operative technique for  e2280 Intramitochondrial β-oxidation defects  e2551 Intramuscular administration, of antiseizure drug  e1406 Intramyelinic edema, white matter disorders with  e1696–e1698 Intranasal administration, of antiseizure drug  e1406–e1407 Intranasal delivery, for high-grade glioma  983, e2231 Intranuclear ophthalmoplegia  759 Intraparenchymal echodensities intraventricular hemorrhage and  163 neuroimaging of  e379, e379f Intraparenchymal hemorrhages  157, 1210, e2720 evacuation of  865, e1969 Intraspinal extramedullary injuries  824–826 catastrophic spinal cord injuries  825–826 cauda equina injuries  825 herniation of nucleus pulposus  825 spinal arachnoid cysts  825 spinal epidermoid tumor  825 spinal epidural abscess  825 spinal epidural hematoma  824 spinal subarachnoid hemorrhage  825 spinal subdural hematoma  824–825 supraspinal changes  826 Intraspinal intramedullary injuries  823–824 anterior spinal cord syndrome  824 Brown-Séquard syndrome  824 central spinal cord syndrome  824 cervical cord neuropraxia  823 cervical nerve root/brachial plexus neuropraxia  823 cervicomedullary syndrome  823–824 complete spinal cord injuries  823 conus medullaris syndrome  824 incomplete spinal cord injuries  823 posterior spinal cord syndrome  824

1358

Index

Intrathecal baclofen therapy  1252 in spasticity  e2836–e2837 complications  e2837b patient selection  e2836b Intrauterine growth, cerebral palsy and  735–736 Intrauterine trauma  156, e359 Intravenous administration, of antiseizure drug  e1406 Intravenous immunoglobulin (IVIg) for chronic inflammatory demyelinating polyradiculoneuropathy  1090 for CIDP  e2436 for dermatomyositis  1144t for GBS  1178 for juvenile myasthenia gravis  e2464–e2465 for myasthenia gravis  1103 for opsoclonus myoclonus syndrome  941, 942t, e2154–e2155 Intraventricular hemorrhage (IVH)  131, 161–170, 162t, e372–e400, e373f, e373t anatomic factors in  161–162, e373–e375, e374f, e374t antenatal corticosteroid exposure in  e383 candidate genes for  162–163, e375–e377 clinical studies implicate candidate genes in coagulation, inflammatory and vascular pathways  e376–e377 preclinical studies suggest variants in microvascular proteins  e375–e376, e376t cerebral blood flow alterations contributing  162, e375, e375b cerebrospinal fluid studies for  e380 clinical findings of  164, e379–e380 clinical manifestations of  e380 clinical risk factors of  161, 162b, e373, e374b coagulation candidates of  e376, e376t cognitive outcomes in neonates with  e382, e382f as complex disorder  161, e372–e373, e373f gene-by-environment interactions  e377 incidence of  e379–e380 inflammatory factors of  e376–e377 long term outcome of  164, e382–e383 alterations in brain development  e382–e383 cerebral palsy  e382 maternal race and healthcare disparities influence risk for  e373 neonatal outcome  164, e380–e381 neuroimaging of  163, e378, e378f neuropathology of  163, e377–e378, e377f pathophysiology of  161–163, e372–e377 prevention of  164–165, 164t, e383–e384, e383t environmental strategies  e383–e384 pharmacologic  e383–384 timing of  e380 vascular genes and  e377 white matter injury and  166, e387 Intrinsic connectivity networks (ICNs)  97, 100, e259–e260, e259t Intrinsic nervous system  1190, e2672–e2673 Intussusception  1231, e2782 Invasive intracranial electroencephalography monitoring  616–617 for epilepsy surgery, in pediatric population  e1429 Inversion-duplication 15 syndrome, and infantile onset epilepsies  558t–560t

Inversions  e637–e638 paracentric  270 pericentric  270 “Inverted comma” position  27, e56 Iodinated contrast agents, in myasthenia gravis  1103b Iodine  386 deficiency  386 developing brain and  e943t, e945 as nutrient  384t Ion channels  405, e1211, e1211t, e1213f in cerebrovascular system  844, e1924 development of, and membrane properties  509–510 ligand-gated  405 in seizures and epilepsy  506, 507f voltage-gated  405 Ion pumps, in cerebrovascular system  844 Ionizing radiation, neuroteratology  1203t Ipecac syrup  1193 IQ  418 and ASD  461 decline in, neurocognitive deficits  1024 in DMD  1107 and reading ability  442 Irbesartan  e2755b Iridocyclitis, in pauciarticular juvenile idiopathic arthritis  e2165 Iris, anomalies of  e78 Iris coloboma, trisomy 13 and  271 Iron  385–386 for breath-holding spells  658–659 deficiency, restless legs syndrome and  680 developing brain and  e943t, e944–e945 and neuroimaging  680 as nutrient  384t Iron deficiency anemia  854 arterial ischemic stroke and  e1941 sinovenous thrombosis and  860, 861f Irritable bowel syndrome (IBS)  1229 episodic gastrointestinal disease and  e2776–e2778 Ischemia, trauma-induced  794–795 Ishihara color plates  e69 Isobutyryl-CoA dehydrogenase deficiency  296, e699 Isochromosomes  271, e638 Isolated congenital microcephaly  210, e491 Isolated hypogonadotropic hypogonadism (IHH)  1166–1167 congenital  1166–1167, e2630 normosmic  1167, e2630 Isolated lissencephaly sequence  e516f–e517f, e517–e518 Isolated septum pellucidum dysplasias  e462, e462f Isolated sulfite oxidase deficiency  131, e311 Isoniazid side effects, hepatic encephalopathy  e2792 for tuberculous meningitis  890 Isotretinoin sensorium changes  e2682b toxicity  1196b, 1203 Isotropic diffusion  82 Isovaleric acidemia  295, 482t–486t, e692–e693 Isradipine  e2755b Israel, special education in  1287, e2898 Italy, special education in  1287, e2898 Itraconazole for aspergillosis  909 for blastomycosis  908 for coccidioidomycosis  908 for histoplasmosis  908 Ivermectin, for gnathostomiasis  914

J

Jackson, Johns Hughlings  497 Jackson-Weiss syndrome  235 Jacobsen syndrome  274, e650–e651 Jactatio capitis nocturna  670, e1526 James, William  e1731 Janeway lesions  852 Japan, special education in  1287, e2898 Japanese encephalitis virus  e2047 Jeavons syndrome  570, e1338 Jefferson fracture  820, e1874–e1875, e1875f Jervell-Lange-Nielsen syndromes  e104 Jimson weed  1196b sensorium changes  e2682b Jitteriness  725, 725t, e1636–e1637 Jo-1  1141–1142 Johanson-Blizzard syndrome, with kidney malformation  1224t, e2764t Joint attention  459–460 Joint Attention, Symbolic Play, and Regulation (JASPER) program  469 Joint contractures  1054, e2332 for congenital myopathies  e2533 Joint mobility and tone, of neuromuscular disorders  e2332 Joint pediatric/adult transition clinic  1274 Joints, Clutton’s  890–891 Joubert syndrome (JS)  202–203, e470–e472, e471f with kidney malformation  1224t, e2764t Jump gait  30–31, e62 Justice, as precepts of natural law  1265 Juvenile absence epilepsy  517, 577, e1252, e1353–e1354, e1354f genetics of  578 Juvenile dermatomyositis  1141, 1142f serum CK levels found in  1039t Juvenile idiopathic arthritis  945–946, e2162–e2165, e2163b, e2164t management of  945–946, e2165 neurologic manifestations of  945, e2162–e2165 pauciarticular  945 polyarticular  945, e2164–e2165 psoriatic, enthesitis-related, and undifferentiated syndromes  945 systemic  945, 947t, e2162–e2164 neuropathology of  945, e2165 Juvenile muscular atrophy of distal upper extremity (JMADUE)  e2363 Juvenile myasthenia gravis serum CK levels found in  1039t treatment of  e2460–e2467, e2465b Juvenile myoclonic epilepsy  539, 577, 577f, e981, e1252, e1275, e1351–e1353, e1351f–e1353f EEG for  539 genetics of  578 outcomes for  539 remission rate in  504 semiology of  539 treatment for  539 Juvenile myoclonic seizures  e1198t Juvenile Parkinson disease  714 Juvenile polymyositis, serum CK levels found in  1039t Juvenile xanthogranuloma  362

K

K27M mutation  992–993 Kainate  405 Kainate (KA) receptors  508 KAL1 gene, mutations in  1166–1167, e2630 Kallmann syndrome  1166–1167, e2630

Karyotype  266f, 268, e616, e616f, e618t female  271 male  271 Katayama fever  915 Kaufman Assessment Battery for Children II  68t–69t, e143t–e146t Kawasaki disease  851, 947t, 953, e2178 KCC2  510 KCNQ, gene mutations in, and infantile onset epilepsies  558t–560t KCNQ2  513 encephalopathy  407, 513, e980–e981, e1226–e1227 mutation of  513 and benign familial neonatal epilepsy  553 KCNQ3  513 mutation of  513 and benign familial neonatal epilepsy  553 KCNT1, mutations in  515, 517 KCTD7  e951t–e952t, e968–e970 Kearns-Sayre syndrome  344–345, 1161, e843f, e850–e851, e2559, e2622, e2725 Kennedy’s disease  1066t–1068t, 1068–1069, e2381 Keratan sulfate  323 Kernicterus  712, 1236, e1609–e1610, e2800–e2802 Kernig’s sign  883, 896 Ketamine associated with Parkinsonism  e2684b for glycine encephalopathy  292 for refractory status epilepticus  549t sensorium changes  e2682b toxicity  1196b, 1198b Ketoacidosis, with hyperammonemia  278 Ketogenesis  625–626 in oxidation of fatty acids  e1449–e1450, e1449f–e1450f Ketogenic diets  624–630, e1442–e1464 advantages of  629, e1456 contraindications to  627b, e1452b disadvantages of  629–630, e1456–e1457 for Dravet syndrome  406 efficacy of  624–625, e1442–e1448 in adults  625, e1446–e1447, e1447t alternative  625, e1447–e1448, e1447f, e1448t classic  624–625, e1442–e1446, e1443t–e1445t experimental studies, in animal models  e1451 history of  624, e1442, e1443t hospitalization and  627–628, e1453– e1454, e1453b initiation of  627–628, 627b–628b, e1453–e1454, e1453b for Lennox-Gastaut syndrome  572 maintenance of  627–628, 627b–628b, e1453–e1454, e1454b mechanisms of action  625–626, e1448–e1451 animal models in  626 clinical studies of ketosis  626 experimental studies of  626 ketogenesis  625–626 oxidation of fatty acids  625–626 predictive value of EEG  627 for myoclonic-astatic epilepsy of Doose (MAE)  539 prehospital evaluation and  627, e1453 randomized controlled trial of  625 for refractory status epilepticus  549t

Index Ketogenic diets (Continued) selection of candidates for  626–627, e1451–e1453, e1452b, e1452f side effects of  628–629, 629b, e1454– e1456, e1454b–e1455b specific conditions treated with  627b in 21st century  630, e1457 α-Ketoglutarate dehydrogenase, deficiency  301 Ketone bodies  336–337 Ketorolac  651 for pain management  1257t Ketosis clinical studies of  626, e1450–e1451 organic acidemias  294–295 Kidney stones  1226, e2768 Kinesigenic paroxysmal dyskinesia  719–720, e1628–e1629 Kinetic defects, in acetylcholine receptor  1094 King’s Outcome Scale for Childhood Head Injury (KOSCHI)  777, 778t, e1753, e1754t Kinky-hair disease. see Menkes disease Kissing bug  912, e2093 Kisspeptin  1165–1166, e2628 Kisspeptin receptor  e2628 Kleine-Levin syndrome (KLS)  676–677, e1534 Klinefelter syndrome  272, e645, e645f and developmental language disorders  432 Klippel-Feil syndrome, with kidney malformation  1224t, e2764t Klippel-Trénaunay-Weber syndrome  370– 371, e905 Klüver-Bucy syndrome  e2786 Knee-ankle-foot orthoses (KAFOs)  1157 Knock-in mice  115–118, 117f Knock-out mice  116–118, 117f–118f Krabbe disease  327, 752f, 754, e772t–e773t, e792–e795, e793f, e1692f, e1695 diagnosis of  754 Krabbe leukodystrophy  112, e282 Krabbe’s disease  1083, e2415–e2416 Krebs cycle  334 defects of  337, e845 Kufor-Rakeb syndrome  e1614 Kugelberg-Welander disease  1058t, 1059, e2357

L

L-Asparaginase  e2695 L-DOPA  360 associated with myoclonus  e2685b associated with Parkinsonism  e2684b for dystonia  e1610 indications  358 sepiapterin reductase deficiency  358 for parkinsonism  e1615 sensorium changes  e2682b toxicity  1196b, 1198b–1199b L protein  290–291 L-selectin  800 L-tyrosine, in nemaline myopathies  1128 L2-hydroxyglutaric aciduria  e1702f, e1704 La Crosse encephalitis virus  895 La Crosse virus  e2049 Labetalol  e2755b Lacosamide  511, 601t–602t, e1476–e1477 for antiseizure drug therapy in children  e1401 behavioral and cognitive effects of  640 pharmacokinetics of  604t–605t

1359

β-Lactams toxicity  1199b Lactate dehydrogenase deficiency  1132b, e2546 genes encoding  1132–1133 M subunit deficiency  315 Lactate elevation, leukoencephalopathy with  757 brainstem and spinal cord involvement and  e1701, e1702f Lactic acid  336–337 Lactic acidemia, differential diagnosis of  e2567 Lactic acidosis  336–337 congenital  301 Lafora body disease (LBD)  311, 579, e1355 Lafora disease  e1277 Lambda waves  89, e221 Lambert-Eaton myasthenic syndrome (LEMS)  926t, 927, 1098, 1103, 1179, e2133–e2135, e2465, e2466f, e2652 clinical features of  1103–1104 diagnostic tests for  1104 treatment for  1104 Lamictal. see Lamotrigine Lamin A/C  e2399 Lamin A/C-associated congenital muscular dystrophy  1121, e2509 Lamin B1  758 Laminin-α2  1034, e2307 Laminin α2 deficiency, partial  1115 Laminin-α2 (merosin)-negative congenital muscular dystrophy  e2508 β2-Laminin deficiency, congenital myasthenic syndrome associated with  1094, e2445 Lamininopathies  e525 Laminopathies  1116, 1161, e2495 Lamins  1034–1035 Lamotrigine  493, 511, 601t–602t, e1176t, e1179–e1180, e1475 for antiseizure drug therapy in children  e1401–e1402 for ASD  467t–468t, 468 behavioral and cognitive effects of  639 for focal epilepsy  501 for generalized tonic-clonic seizures  e1250 for genetic generalized epilepsies  580–581 for juvenile myoclonic epilepsy  e1276 for Lennox-Gastaut syndrome  572 mood disorders in  638 pharmacokinetics of  604t–605t porphyria and  e2791 rectal administration of  606t for renal diseases  1223–1224, e2764– e2765, e2767 in renal failure  1226 Landau-Kleffner syndrome  461t, 516–517, 574, e1198t, e1345 continuous spike-waves during slow-wave sleep  e1097t and developmental language disorders  432, 435 electrical status epilepticus in  637 Landau reflex  17, e36 Langer-Giedion syndrome  e650 Langerhans cell histiocytosis (LCH)  1018, e2283 Language development, in CHD  e2730 disorders, developmental  e1051–e1059 milestones, normal  e1052b milestones of  432b nonverbal learning disabilities and  438, e1061

1360

Index

Language impairment arterial ischemic stroke and  e1947 in cerebral palsy  740 Language screening instruments  e9t Lansoprazole, for gastroesophageal reflux  1161 Large deformation diffeomorphic mapping, for ADHD  450 LARGE gene  1120–1121 Large intestine, functional anatomy of  e2672, e2673f Large molecule disorders  e657 of inborn error of metabolism  277 metabolic epilepsies and  598 Large neutral amino acids (LNAAs)  287 Larry P. v Riles  1283, 1284t Larva migrans, cutaneous  914 Laser-induced thermal therapy (LITT), in epilepsy surgery  617 Late effects  1021 Late infantile GAA deficiency  e733–e734, e734f Late-onset childhood occipital epilepsy  573, e1344 Late-onset epileptic spasms  e1287 Late poststroke seizures, versus early poststroke seizures  e1375 Lathyrus  1197b causing peripheral neuropathy  e2684b Lau v Nichols  1283, 1284t, e2893 Law, practice guidelines, in pediatric neurology  1281 LC-PUFAs, as nutrient  384t LCH RELN-type  e519 LCHAD/TFP deficiency, specific therapies for  e2563 Lead  e2688 level autistic spectrum disorder and  e1107 testing for, in ASD  465 neuroteratology  1203t poisoning  1195–1197 renal toxicity of  1225t, e2765t Learning disability, in childhood epilepsy  636–637 Learning Experiences: Alternative Programs for Preschoolers and Parents (LEAP)  469 “Least restrictive environment”  1285–1286 Leber hereditary optic neuropathy (LHON)  342, 344 Leber hereditary optic neuroretinopathy  e2561–e2562 Leber’s congenital amaurosis  36, e75–e76, e76f Legionella organisms, in pyomyositis  1146 Legius syndrome  e504 Leigh syndrome  340, 596, e843f, e1384 Leiter International Intelligence Scale  e143t–e146t Leiter International Intelligence Scale-3  68t–69t Leiter International Performance Scale  e1001t–e1004t Lennox-Gastaut syndrome (LGS)  406, 513, 529, 571–572, 637, e515–e517, e1198t, e1258–e1259, e1258f, e1259b clinical characteristics  571 cognitive and behavioral outcome of  e1473 EEG findings in  571–572, 571f in electroclinical syndromes, childhood onset  e1339–e1342 clinical characteristics of  e1339–e1340 EEG findings of  e1340, e1340f–e1341f

Lennox-Gastaut syndrome (LGS) (Continued) etiology of  e1340–e1341 prognosis of  e1342 treatment of  e1341–e1342 etiology of  572 prognosis for  572 treatment of  572 Leprosy  892–893, e2024–e2025 Leptin  1167 deficiency  1171, e2636 Leptin receptor  1167, 1171 Leptomeningeal cyst  157, 792 Leptospira spp., in leptospirosis  891–892 Leptospirosis  891–892, e2022 Lesch-Nyhan disease  711, e1608 Lesionectomy, stereotactic  617 Lethal arthrogryposis with anterior horn cell disease (LAAHD)  e2381 Lethargy  e302 Letter knowledge, dyslexia and  445, e1072 Leukemia acute promyelocytic  1018 central nervous system  1017–1018, e2282–e2283 Leukemic lymphocytes  1017 Leukocytoclastic vasculitis  953, e2178–e2179 Henoch-Schönlein purpura  947t, 953 hypersensitivity angiitis  953 Leukodystrophies  425, e1387 autosomal dominant, with autonomic disease  758, e1702f, e1703 inherited metabolic epilepsies and  598 primary demyelinating  751–754 Leukoencephalopathies  1017 adult-onset  758, e1703–e1704 autosomal recessive spastic ataxia with  e1579 bilateral occipital calcifications with  757 with brainstem, cerebellum, and spinal cord involvement  757–758, e1701–e1703, e1702f and lactate elevation  757 with calcifications and cysts  756 calcifying  755–757, e1698–e1700 cerebral autosomal dominant arteriopathy with subcortical infarcts and  756 chronic  1024 cystic  757, e1700 due to mutations in AARS2  e1704 genetic  e1706t–e1707t intracranial calcification associated with  756 mitochondrial  e1685f, e1707–e1708 secondary, to inborn errors of metabolism  758 with vanishing white matter  e884 Levetiracetam  511, 601t–602t, e1476 for antiseizure drug therapy in children  e1402 for ASD  467t–468t, 468 behavioral and cognitive effects of  639 for breath-holding spells  658–659 Dravet syndrome  406 for generalized tonic-clonic seizures  e1250–e1251 for genetic generalized epilepsies  580–581 for juvenile myoclonic epilepsy  e1276 for migraine  652t pharmacokinetics of  604t–605t for posttraumatic seizures  789 in renal failure  1226, e2767 for status epilepticus  545, 547–548 for tic disorders  745t

Levothyroxine associated with tremor  e2685b sensorium changes  e2682b toxicity  1196b, 1200b Lexical syntactic syndrome  435, e1055–e1056 Lexicon  433b, e1054b LGI1, mutations in  517 LGMDs. see Limb-girdle muscular dystrophies (LGMDs) L’Hermitte’s symptom  759 Lhx2 gene, mutations in  e2630, e2632–e2633 Lhx3 gene, mutation in  1167 Li Fraumeni syndrome  958t, e2201 medulloblastoma and  963 Licorice associated with myopathies  e2683b toxicity  1197b Lidocaine associated with myoclonus  e2685b associated with tremor  e2685b familial pain syndromes  408 in myasthenia gravis  1103b for refractory status epilepticus  549t toxicity  1199b–1200b Lifespan Developmental Neuropsychology  e140 Ligaments, anatomy of  e1873 Ligand-gated channels  405, 506 Lightning injuries  809 Limb-girdle muscular dystrophies (LGMDs)  1112–1116, e2483–e2496, e2621 approach to  1122, e2509 autosomal-dominant  1115–1116, e2494–e2496 with cardiac involvement  e2494 caveolinopathy  e2494 laminopathy  e2495 without cardiac involvement  e2494 autosomal-recessive  1112–1115, e2484–e2490 conditions  1115 sarcoglycanopathies in  e2485–e2490 clinical features of  1117–1118 definition of  1112 diagnostic algorithm in  1117 α-dystroglycan glycosylation, disorders of  1114–1115, e2490–e2493 anoctaminopathy in  e2493 autosomal-recessive conditions in  e2493 calpainopathy in  e2491–e2492 dysferlinopathy in  e2492–e2493 fukutin-related protein deficiency in  e2490 other α-dystroglycanopathies in  e2490–e2491 x-linked recessive conditions in  e2493–e2494 historical background and definition of  e2483–e2484, e2486t–e2487t molecular and genetic testing in  1117 muscle biopsy and protein studies in  1117, 1118t serum CK levels found in  1039t summary and approach to  1117, e2497f, e2498, e2500t type 1A (myotilinopathy)  1115–1116, 1118t type 1B (laminopathy)  1116, 1118t type 1C (caveolinopathy)  1116, 1118t type 2A (calpainopathy)  1114–1115, 1118t type 2B (dysferlinopathy)  1115, 1118t

Limb-girdle muscular dystrophies (LGMDs) (Continued) type 2C-F (sarcoglycanopathies)  1113– 1114, 1118t type 2G (telethoninopathy)  1115, 1118t type 2H  1118t type 2I (fukutin-related protein deficiency)  1114, 1118t type 2J (titinopathy)  1115 type 2L (anoctaminopathy)  1115, 1118t X-linked recessive conditions in  1115 Limbic encephalitis  926t, 933, e2136–e2137, e2141, e2141f Limbic system tracts  e260 Limit dextrinosis  310–311, e735–e736 Lincomycin, in myasthenia gravis  1103b Lindane  e2687–e2688 sensorium changes  e2682b toxicity  1196b Lipid milieu, IMM  341–342 Lipids, lysosomal storage diseases and  e772t–e773t Lipoamide dehydrogenase  290–291 Lipoate, metabolic disorders  290–291 Lipofuscinosis, neuronal ceroid disorders, management and treatment of  403–404 juvenile form of  398 masqueraders  394t–395t models and clinical trials  396 protein localization  396f Lipogranulomatosis  e791–e792, e792f Lipoprotein, arterial ischemic stroke and  853 Lisch nodules  362 Lisdexamfetamine for ADHD  455t–457t for excessive daytime sleepiness  675 Lisinopril  e2755b Lissencephaly  180–181, 218–219, e512–e520 brain imaging for  e514–e515, e514t, e516f–e517f with cerebellar hypoplasia  e518–e520 clinical features of  e515 epilepsy and  e515–e517 genetic counseling of  e514t, e518t, e519 neuropathology of  e512–e514 survival of  e517 syndromes, genetics, and molecular basis  e517–e519 type I prenatal diagnosis of  252 syndromes, Miller-Dieker syndrome  252 variants  e519 X-linked, with abnormal genitalia  e519 Listening in spatialized noise (LISN) test  e96–e97 Listeria monocytogenes, meningitis  883 LITAF gene, mutations in  1074 Lithium  480, 492–493, e1175–e1177, e1176t abuse in  e2692 associated with myoclonus  e2685b associated with Parkinsonism  e2684b associated with tremor  e2685b in ataxia  e2685b in myasthenia gravis  1103b renal toxicity of  1225t, e2765t sensorium changes  e2682b for spinal cord injury  e1885 toxicity  1196b, 1198b–1200b, 1201 Liver disease, Wilson’s disease  e2798 Liver failure, fulminant, hepatic encephalopathy  e2792–e2793

Index Liver transplantation neurologic abnormalities with  1235 urea cycle disorders and  303, e718 LMNA gene, mutations in  1121 Locked-in syndrome  769f, 770t, 771, e1737t, e1740 Loeys-Dietz syndrome  e2351 Long-chain acyl-CoA dehydrogenase (LCAD)  e2725 Long-chain polyunsaturated fatty acids  388–389 developing brain and  e943t, e947–e948 Long QT syndrome  656, 809 Look-up tables  1297 Lorazepam  601t–602t associated with myoclonus  e2685b for cyclic vomiting syndrome  1229 for febrile seizures  522 rectal administration of  606t for status epilepticus  545, e1298–e1299 as first-line drug  546 toxicity  1199b Losartan  e2755b Lovastatin associated with myopathies  e2683b sensorium changes  e2682b toxicity  1196b–1197b Low birth weight  22 Low glycemic index diet  625 Low-grade astrocytomas  e2279, e2280f Low-grade glioma  985–990, e2235–e2243 classification and histologic features of  985–987, 986t, e2235–e2237, e2236t diffuse fibrillary astrocytoma  e2237 dysembryoplastic neuroepithelial tumor  e2236 ganglioglioma  e2236 not otherwise specified  986–987 pilocytic astrocytoma in  e2236 pilomyxoid astrocytoma in  e2236 pleomorphic xanthoastrocytoma  e2236–e2237 clinical presentation of  985, 986t, e2235, e2236t current clinical trials in  e2240–e2241 antiangiogenic therapy  e2241 immunomodulatory therapy  e2241 mTOR pathway inhibition  e2240–e2241 RAS/MAP-kinase pathway  e2240 differential diagnosis of  987, e2237 evaluation and diagnosis of  987, e2237 genetic features of  989, e2240 management of  987 neurofibromatosis type 1 and  e2241, e2241f outcome of  990, e2241–e2242 pathogenesis of  987, e2237–e2238 progression  989 relapse  989 supportive care for  989, e2240 treatment of  987–989, e2238–e2240 chemotherapy for  988–989, 988f, e2238–e2240, e2239f radiation therapy for  989, e2240 surgery for  987, e2238 Low health literacy  e2817, e2817b Low-level (level C) recommendations, writing  1279t, 1280 Low-molecular-weight heparin (LMWH)  855–856 for arterial ischemic stroke  e1945

1361

Lower urinary tract (LUT) afferent mechanisms of  e2662, e2662f–e2664f anatomy of  1185, 1185f, e2661–e2670 anterior cingulate cortex in  e2666, e2667f cortex in  e2665 efferent mechanisms in central  e2669–e2670 peripheral  e2668–e2669, e2669f–e2670f insula in  e2666 other brain areas and  e2666–e2668 periaqueductal gray in  e2664–e2665, e2665f pontine micturition center in  e2664– e2665, e2665f prefrontal cortex in  e2666, e2668f Lowest-level recommendation (level U), writing  1279t, 1280 LRP4 myasthenia  1095, e2447 Luckenschadel  238, e578–e579 Luft disease  344, e850 Lujan syndrome  e504 Lumbar puncture for acute bacterial meningitis  884 contraindications, brain abscess and  893 for headache  649 for headache in children  e1493 impaired consciousness and  776 for intracranial hypertension  819 in neonates with infection  131 for spinal cord injury  823 Lupine  1196b, 1199b associated with myoclonus  e2685b sensorium changes  e2682b Lupus aseptic meningitis  950 in systemic lupus erythematosus  e2170 Luteinizing hormone (LH)  1165 Lyme disease  891, 947t, 949, e2022, e2167–e2168 clinical characteristics of  891 diagnosis of  891 treatment and outcome of  891 Lyme neuroborreliosis  891, e2022 Lymphocytes, leukemic  1017 Lymphocytic choriomeningitis virus  897, 899t, 904, e2053, e2054f Lymphoma  1018, e2283, e2283f radiation therapy  1018, 1018f Lysergic acid diethylamide (LSD) in ataxia  e2685b toxicity  1199, 1199b Lysine degradation pathway  e925f Lysinuric protein intolerance  301 Lysosomal and peroxisomal storage diseases  e2725–e2726 Lysosomal disorders  279t, e659t Lysosomal enzyme, soluble  397 Lysosomal storage diseases/disorders  107, 110–112, 323–333, e277, e280–e282, e771–e838, e772t–773t, e1386–e1387 algorithm for diagnosis of  325f bystander effects of NSCs in  110–111, 110f–111f, e281, e281f cell replacement of NSCs in  111–112, e281–e282 classification according to relevant substrate involved  324t–325t clinical manifestations of  e782b–e783b diagnosis and therapeutic options for  e774t, e776f–e778f GM1 gangliosidoses  323 GM2 gangliosidoses  323–325 inherited metabolic epilepsies and  598 metachromatic leukodystrophy  327 neuronal ceroid lipofuscinoses  331–333

1362

Index

Lysosomal storage diseases/disorders (Continued) oligosaccharidoses and mucolipidoses  328–330 sphingolipidoses  323–327 Lysosomes  323 and inborn errors of metabolism  482t–486t

M

M-current  513 MacArthur-Bates Communicative Development Inventory  432 Machado-Joseph disease  e1571–e1572 Macrocephaly  212–216, 234 causes of  e495b definition of  e493–e495 lysosomal storage diseases and  e782 Macrocephaly autism syndrome  e502 Macroglossia  282 Macroprolactinomas  e2632 Maffucci syndrome  370, e902–e903, e902f Magnesium abnormalities  1215–1216, 1217b, e2740–e2742 for gastroesophageal reflux  1161 Magnesium ions, voltage-dependent block by  508 Magnesium pemoline, for ADHD  455t–457t Magnetic resonance angiography  e1912 in brain death determination  835–836 Magnetic resonance imaging (MRI)  79–80, e169–e176, e173f–e178f of abusive head trauma  e1828 in acute cerebellar ataxia  704, e1588 in acute demyelination  760, 761f in arterial ischemic stroke  854, e1943 for ASD  462, 465 in brain death determination  835–836 for cavernous malformations  868 for cerebral palsy  735 chronology of sulcation according to  250t in CIDP  e2436 for epilepsy and seizure  499–500 in epilepsy surgery  614–615, 614f, e1421, e1422f–e1423f fetal  e2716f–e2717f, e2717 for focal cortical dysplasia  583 functional  84 in GBS  e2432 of generalized tonic-clonic seizures  525 of hemimegalencephaly  584 for high-grade glioma  980–981, e2228 for hydrocephalus  229, e558 for impaired consciousness  779 for measurements of cerebral perfusion  e1912 in multiple sclerosis  763 for neonatal brain  127 in neuromyelitis optica  765, 766f in Pelizaeus-Merzbacher disease  e1685f, e1686 perfusion  83 in progressive encephalopathies  428 for sinovenous thrombosis  861–862, e1960f, e1961–e1962, e1962f in spinal cord injury  829 of spinal cord injury  e1878 for traumatic brain injury  787, e1782, e1782t, e1783f, e1795 for viral infections  898, 898f–899f for white matter injury  167–168, 167f

Magnetic resonance spectroscopy (MRS)  80– 81, e176–e183 of abusive head trauma  e1828 in brain death determination  836 for diffuse intrinsic pontine glioma  e2246 for encephalopathy  140, e324 for epilepsy surgery  615, e1425 for high grade glioma  981–982, 981f for measurements of cerebral perfusion  e1913 for traumatic brain injury  e1795 Magnetic source imaging  84, e191–e192 Magnetoencephalography (MEG)  84, e191–e192, e241 for epilepsy surgery  615–616, e1425– e1426, e1426f–e1427f for specific language impairment  431 Maintenance of Wakefulness Test (MWT)  673 Maintenance of wakefulness test (MWT), in disorders of excessive sleepiness  e1530 Malabsorption syndromes  1231, e2782–e2785 Malaria  912, e2088–e2092 clinical characteristics, clinical laboratory tests and diagnosis of  e2089–e2091 epidemiology, microbiology and pathology of  e2088–e2089, e2089f management of  e2091 prevention of  e2092 supportive care for  e2091–e2092 Malformations of cortical development (MCD)  218–225, e510–e550 biologic pathways  218, e512, e513t Cobblestone malformations  220–221 brain imaging of  220–221 clinical features of  221 prognosis and management of  221 embryology of  218, e510–e512, e511f classic studies  e510–e511 cortical organization  e512 neurogenesis  e511 neuronal migration  e511–e512 focal cortical dysplasia and hemimegalencephaly  223–224 brain imaging of  224 clinical features of  224 etiology, genetic, molecular basis of  224 summary of  224–225 treatment of  224 lissencephaly and subcortical band heterotopia  218–219 brain imaging  218–219 clinical features of  219 epilepsy and  219 survival of  219 neuronal heterotopia  221–222 brain imaging of  221–222 clinical features of  222 polymicrogyria and schizencephaly  222–223 brain imaging of  222–223 clinical features of  223 patterns of  223 tubulinopathies  219–220 brain imaging of  220 clinical features of  220 Malignancy, renal transplantation complications and  1220, e2752 Malignant spinal gliomas  e2279 Malignant Tourette syndrome  e1663 Malnutrition chronic kidney disease and  1219, e2751 protein-calorie  383–385

Malondialdehyde  658 Mammalian target of rapamycin (mTOR)  214, e500 MAN1B1-CDG  e762 Manganese associated with Parkinsonism  e2684b in ataxia  e2685b sensorium changes  e2682b toxicity  1196b, 1198b–1199b Mania, Wilson’s disease  e2798 Mannitol  789 for intracranial pressure  818 for Reye’s syndrome  e2797 Mannosidosis  328, e772t–e773t, e777f, e807–e808 α-Mannosidosis  482t–486t Mantle radiation therapy, for lymphoma  1018 Manual ability  e1656 Manual Ability Classification System (MACS)  e1656, e1658f for cerebral palsy  738, 738f Manual muscle testing (MMT)  e2333 Maple syrup urine disease (MSUD)  172, 287–290, 289f, 424, 482t–486t, e405–e409, e409f, e679–e683, e1382, e1383f classic  288 clinical manifestations of  288–290, e680–e682, e681f genetics of  290, e682 inherited metabolic epilepsies  596 laboratory tests of  290, e682 treatment of  290, e682–e683 Marfan syndrome  e1990, e2351 Marie, Pierre  e1747 Marijuana  1196b chronic  1204 sensorium changes  e2682b Marinesco-Sjögren syndrome  695, e2352 Marinesco-Sjögren syndrome, peripheral hypotonia and  1055t–1056t Marker chromosome  e638 Maroteaux-Lamy syndrome  e772t–e773t, e806 Marshall-Stickler spectrum  49, e104 Mass lesions, in acute cerebellar ataxia  e1587 Masturbation, posturing during  725t, 727, e1639 Maternal 15Q11Q13, duplication of  247 Maternal duplication, of 15q11.2q13.1 region  e652 Maternal phenylketonuria syndrome  e674 Maternal protein-calorie malnutrition  383 Maternal syphilis  e2021 Maturation, cerebral  781 Mayapple  1196b, 1199b in ataxia  e2685b sensorium changes  e2682b MC4R gene, mutation in  1170 McArdle disease  312, e728t, e737–e739, e737f biochemistry of  312 clinical characteristics of  312 clinical laboratory tests of  312 genetics of  312 management of  312 pathology of  312 McCune-Albright syndrome  e581f McEwen’s sign  e555 McLeod syndrome  e2726 MDS. see mtDNA depletion syndromes (MDS) MDs. see Muscular dystrophies (MDs)

Meadow syndrome  662, e1516 Mean diffusivity (MD)  97–98, e257 Mean length of utterance (MLU)  433b, 434, e1054–e1055, e1054b Measles inclusion body encephalitis  e2050–e2051 Measles-mumps-rubella (MMR) vaccination, and ASD  461–462 Measles vaccines  920–921, e2125–e2126 Measles virus  902–903, e2050–e2052 clinical features of  902, e2050–e2051 diagnosis of  899t, 902, 903f, e2051, e2051f treatment and outcome of  902–903, e2052 Mebendazole, for trichinellosis  e2099–e2100 Mebendazole, for trichinosis  1146 Mechanical circulatory support devices  1211 in CHD  e2722 Mechanoelectrical transduction (MET)  e92–e93 Meckel-Gruber syndrome, with kidney malformation  1224t, e2764t MECP2 gene  478 loss of function of  e651–e652 mutations in  421t, 478 MECP2 gene/duplication of the MECP2 region (Xq28) loss of function of  275 MeCP2-related disorders, central hypotonia and  1055t, e2347 Medical history  2, e3 Medication-induced chorea  709, e1602 Medication-induced dystonia  712, e1610 Medium-chain acyl CoA dehydrogenase deficiency, and Reye’s syndrome  e2797 Medium-chain triglyceride (MCT) oil  1136 for fatty acid oxidation disorders  e2560–e2561 MEDNIK syndrome  482t–486t Medulla, herniation in  775 Medulloblastoma  960t, 963–968, e2201– e2210, e2202f, e2202t algorithm of  966f biology of  963–964, e2201–e2203 clinical features of  964, e2203 definition of  e2201 etiology of  963, e2201 future therapy for  967, e2207–e2208 imaging features of  e2203–e2204, e2203f–e2204f management and outcome of  964–968, e2204–e2208 staging and stratification  965–966, e2204–e2205, e2205t, e2206f surgery  964–965, e2204 molecular subgrouping of  964t neuroimaging MRIs  965f postsurgical management of  966–967, e2205–e2207, e2206f radiographic features of  964 relapsed  967, e2207 sequelae in survivors  967–968, e2208 secondary tumors  968 Turcot’s syndrome and  963, e2790 WHO classification of  e2202b Medulloepithelioma  969–970, 971f, e2211–e2212, e2213f MEF2C disorder  245, e590 Mefloquin toxicity  1196b Mefloquine, sensorium changes  e2682b MEFV gene, mutations in  e2760 “Mega-cisterna magna”  180–181, e422–e424 Mega cisterna magna, prenatal diagnosis of  253, e607–e608

Index Megalencephalic leukoencephalopathy, with subcortical cysts  752f, 755, e1685f, e1697 Megalencephaly  212–216, e493–e504 anatomic  e495 clinical features of  e500–e501 definition and classification of  212–213, e493–e495, e495b, e496t–e499t etiology of  214–216, 215f, e497t–e499t, e501–e504, e503f metabolic  e495 nonsyndromic  e500–e501 pathology and pathogenesis of  213–214, e500 Megalencephaly capillary malformation syndrome (MCAP)  216, 586t, 587, e501–e502, e1368 etiology of  587 neurologic features  587 Megalencephaly perisylvian polymicrogyriapostaxial polydactyly hydrocephalus syndrome  216, e502 Megalencephaly polymicrogyria-polydactyly hydrocephalus syndrome  587 Melanocortin  1170 Melanocytic hamartoma  362 Melarsoprol, for T. b. rhodesiense disease  e2096–e2097 MELAS  1, 335, 345, 482t–486t headache and  650 Melatonin therapy, for ASD  469 Melnick-Fraser syndrome, with kidney malformation  1224t, e2764t Memory, of neuropsychological measure  68t–69t Menarche  1166 Mendelian disorders, rare, treatment of  e2823–e2824 Ménière’s disease, vertigo and  56, e122 Meningiomas  1008, 1013t, e2269 clinical presentation of  1008–1009, e2269, e2269t epidemiology of  1008, e2269 genetic conditions and  1009, e2269 histopathology of  1009–1010, e2270– e2271, e2270f, e2270t molecular genetics of  1008–1009, e2269 neuroimaging in  1009, e2270, e2270f observation of  1009–1010, e2271 pathologic classification of  1009t radiation in  1010, e2271 surgery for  1010, e2271, e2271f symptoms and signs of  1008t treatment of  1009, e2270 Meningitis aseptic. see Aseptic meningitis bacterial. see Bacterial meningitis cerebellar pressure cone effect in  776 and febrile seizures  520 sinovenous thrombosis and  e1956 tuberculous. see Tuberculous meningitis viral  896 Meningocele  190, e441, e442f Meningococcal conjugate vaccines  922, e2127 Meningoencephalitis  1219–1220 amebic  910 Menkes disease  359, 424, 482t–486t, 1182, e416, e883, e1705, e2655 and infantile onset epilepsies  560t–562t Mental state assessment  782 Mental status  7, 8t, e11 Mephenytoin, in myasthenia gravis  1103b

1363

Mercury  e2688 neuroteratology  1203t poisoning  1197 renal toxicity of  1225t, e2765t toxicity  1200b Merosin  1034, 1121, e2307 deficiency (LAMA 2)  1161 Merosinopathy, serum CK levels found in  1039t MERRF syndrome  e2560 Mescaline  1196b, 1199b–1200b associated with tremor  e2685b in ataxia  e2685b sensorium changes  e2682b Mesial temporal lobe epilepsy with hippocampal sclerosis  579, 580f, 588, e1356–e1357, e1357f–e1358f, e1368–e1369 etiology of  588 neuroimaging of  588 neurologic features of  588 treatment of medical  588 surgical  588 Mesial temporal sclerosis, and febrile seizures  521–522 Metabolic acidosis in drowning  808–809 intellectual disability and  e1012b Metabolic decompensation, with fasting  e2548 Metabolic disorders/diseases  1178, e657–e670 acute fulminant  e405–e413 affecting muscle  1044, e2326 approach to patient with  277–285 classification  e657–e658, e659t–e660t clinical presentation of in childhood and adolescence  e665–e668 in neonate or infant less than 2 years of age  e658–e665 and developmental language disorders  435–436 dystonia associated with  711–712 inheritable  286 inheritance  e657 laboratory evaluation  e657 and Ohtahara syndrome  554 producing renal and neurologic dysfunction  1223, e2761 Metabolic disturbances, seizures and  131 Metabolic encephalopathies, perinatal  171–177, 172b, e401–e421, e402b general approach to  171, 173f, 173t, e401–e402, e402t–e403t, e403f glucose and salt balance, correctable disturbances of  171, e402–e405 inborn errors of metabolism  171–177, 172b Metabolic epileptic encephalopathies  131 as cause of neonatal seizures  e311 Metabolic/genetic cerebellitis  e1587, e1587t Metabolic imaging, in high-grade glioma  e2228, e2229f Metabolic megalencephalies  213, e495 Metabolic myopathies  1131–1140, e2537–e2584 bioenergetic substrates, in exercise, utilization of  e2537–e2538, e2538b fatty acid oxidation disorders in  1133– 1137, e2547–e2559

1364

Index

Metabolic myopathies (Continued) glycogenoses in  1132–1133, 1133t, e2538–e2547, e2539f, e2540t glycolytic/glycogenolytic defects in  1133 pathophysiology of  1133 mitochondrial diseases, therapeutic approaches in  e2567 mitochondrial encephalomyopathies in  1137–1139, e2557 mtDNA disease, management of  e2562–e2565 myoadenylate deaminase deficiency in  e2567 myoglobinuria in  1132, 1132b, e2538 Metabolic neuropathies  1082–1083, e2412–e2417 abetalipoproteinemia  1082–1083, e2414–e2415 acute intermittent porphyria  1082, e2413–e2414 alpha-lipoprotein deficiency  e2415 Chédiak-Higashi syndrome  e2416–e2417 congenital pernicious anemia  1082, e2414 diabetes mellitus  1082, e2412 Krabbe’s disease  1083, e2415–e2416 metachromatic leukodystrophy  1083, e2416 peroxisome biogenesis disorders  1083, e2416 Refsum’s disease  1083, e2416 Tangier disease  1083 uremic neuropathy  1082, e2412–e2413 vitamin deficiency  1082, e2414 Metabolism, inborn errors of  171–177, 172b, 1181–1182, e402t–e403t, e405–e419, e406t–e408t Metabotropic glutamate receptors  508 Metachromatic leukodystrophy  327, 482t–486t, 752f, 753–754, 1083, e795–e797, e795f–e796f, e1692f, e1694–e1695, e2416 variants of  754 Metachromatic leukodystrophy-like variants  e1695 Metaiodobenzylguanidine (MIBG)  85 Metaiodobenzylguanidine (MIBG) scintigraphy, for acute cerebellar ataxia  704, e1589 Metaldehyde associated with tremor  e2685b in ataxia  e2685b sensorium changes  e2682b toxicity  1196b, 1199b–1200b Metals  1195–1198, e2688–e2689 associated with Parkinsonism  e2684b and inborn errors of metabolism  482t–486t Metamorphopsia  901 Metastatic disease, in DIPG  992, e2245 MetCbl defects  e928 Methadone, for pain management  1257t Methanol associated with Parkinsonism  e2684b toxicity  1198b Methaqualone associated with myoclonus  e2685b toxicity  1199b Methcathinone  1196b sensorium changes  e2682b Methionine  292 Methionine synthase deficiency  e686–e687 Methotrexate  e2695 for CIDP  e2436–e2437 in CNS leukemia  1017

Methotrexate (Continued) for dermatomyositis  1144t high dose, for AT/RT  998 for multiple sclerosis  764 neuroteratology  1203t for opsoclonus myoclonus syndrome  942t, 943, e2157 toxicity  1202 Methsuximide  601t–602t 3-Methyglutaconic acidurias  e1382 l-Methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) associated with Parkinsonism  e2684b toxicity  1198b Methylation studies  261, e618t, e619–e620 2-Methylbutyryl-CoA dehydrogenase deficiency  297, e699 3-Methylcrotonyl-CoA carboxylase deficiency  295, e693 3-Methylcrotonyl glycinuria  482t–486t Methyldopa  e2755b Methylene tetrahydrofolate dehydrogenase deficiency  380, e934 Methylenetetrahydrofolate reductase  163 deficiency  380, 596, e687, e933 3-Methylglutaconic aciduria  295, 482t–486t, e695–e696 3-Methylglutaconyl-CoA hydratase deficiency  e695–e696 Methylmalonic acidemia  292–295, 482t–486t, e691–e692, e1380–e1382 clinical manifestations of  292–294 inherited metabolic epilepsies  594–595 laboratory tests of  294–295 pathophysiology of  292 treatment of  295 Methylmalonic aciduria  424 Methylphenidate  476 for ADHD  450, 453, 455t–457t, e1085, e1087t–e1089t for ASD  467t–468t for excessive daytime sleepiness  675 Methylprednisolone for acute demyelination  760–761 in dermatomyositis  1143 for spinal cord injury  826–827, e1884–e1885 Methylxanthines sensorium changes  e2682b toxicity  1196b Metoclopramide for cyclic vomiting syndrome  1229 for gastroesophageal reflux  1161 Metoprolol  e2755b Metronidazole associated with Parkinsonism  e2684b for brain abscess  893–894 causing peripheral neuropathy  e2684b toxicity  1197b–1198b Mevalonate kinase deficiency  297, e700 Mexiletine in ataxia  e2685b for familial pain syndromes  408 for paramyotonia congenita  1154 toxicity  1199b MFN2 gene, mutations in  1077 MFSD8  e951t–e952t, e964–e965 MG. see Myasthenia gravis (MG) MHBD deficiency  482t–486t mHMG-CoA synthase deficiency  482t–486t MIB-1, in atypical teratoid/rhabdoid tumor  e2252

Mice knock-out and knock-in  e289–e292, e291f–e292f transgenic  e287–e289, e288f–e290f Microadenomas, nonsecreting, and hypogonadotropic hypogonadism  e2631 Microarray, chromosomal  261 Microarray analysis  2 Microarray studies, for progressive encephalopathies  428 Microbiome  1232–1233 disease states and influences of  e2788–e2789 Microbiota  1232–1233, e2788 disease states and influences of  e2788–e2789 and nonimmune-mediated CNS disorders  e2788–e2789 Microbiota-gut-brain (MGB) axis  1232 therapeutic implications in  1233 Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1)  210–211 Microcephaly  208–212, e484–e493, e485t abusive head trauma and  795 Amish lethal  374 antenatal diagnosis of  212, e493 audiological abnormalities with  210 clinical features of  209–210, e486–e488, e488t–e491t epilepsy and  209 etiology of  210–212, 211f, e487t, e488– e493, e492f extrinsic causes of  210, e488 familial mild  e491 genetic counseling of  212, e487t, e493 genetics of  212, e487t, e493 IEMs and  279 isolated congenital  e491 isolated congenital (primary)  208, 210 neuroimaging of  208–209, e485–e486, e487t ophthalmologic abnormalities with  209–210 pathology of  208, e484–e485, e485t primary  233, e491 severe with cortical brain malformations  210, e492 with proportionate growth deficiency  210–211, e493 with simplified gyral pattern  208–209, e485 summary of  212, 212f–213f, e493, e494f Microdeletion 2p15p16.1  e652 2q37  e652 3q29  e652 15q13.3  e652 15q24  e652 16p11.2  e652 16p11.2p12.2  e652–e653 16p13.11  e653 17q21.31  e653 22q13  e653 distal 1q21.1  e652 distal 22q11.2  e653 Microdeletion/microduplication syndromes  270, 272, e647t Microduplication 7q11.23  e652 16p11.2  e652 16p13.11  e653 distal 1q21.1  e652 “Microdysgenesis”  e535–e536 Micrognathia  271

Microlissencephaly (MLIS)  212, e493 Micronutrients  385–389, e944–e948 minerals  385–386 vitamins  387–388 Microorganisms, in CSF  76, e156–e157 Microsporidia  e2080t Microsporidial infections, of nervous system  e2085–e2086 Microsporidiosis  e2086 Microstructural connectivity  97, e256–e257, e257f assessment strategies for  97–99, 98t current clinical applications  105, 105f in developing brain  97–106, e256–e276 Microstructural networks, maturation of  101 Micturition, disorders of  1184, e2660, e2675b afferent mechanisms in  1185–1188 anterior cingulate cortex (ACC)  1187 insula  1187 periaqueductal gray (PAG)  1186–1187 pontine micturition center (PMC)  1186–1187 prefrontal cortex (PFC)  1187–1188, 1188f diagnosis of  1188–1189, e2670–e2672 clinical testing in  1189, e2671–e2672 history in  1188–1189, e2670–e2671 physical examination in  1188–1189, e2670–2671 efferent pathways for control of  1186f epidemiology of  1184, e2660–e2661 lower urinary tract (LUT) in, anatomy of  1185, 1185f neuropsychiatric comorbidity in  1184–1185 Mid-hindbrain malformations, classification for  180b Midazolam, for status epilepticus  546–548 Middle cerebral artery  848 Middle cerebral artery pulsatility (MCA PI)  e2716–e2717 Middle ear  e91–e92 malformations, reconstructive surgery for  50 Middle interhemispheric variant  e450 Midline cerebellar disease  689, e1557 Miglustat  326 Migraine  1258, e982–e983 with aura  647, e1490–e1491 chronic  647–648, e1491 exacerbation, emergency room management of  653 management of  649–653 pain management of  e2851 pathophysiology of  648 posttraumatic  791–792 variants  648, e1491 without aura  647, e1490 Migraine/ataxia syndromes episodic ataxia  409 familial hemiplegic migraines  409 spinocerebellar ataxia  409–410 Migraine-related dizziness  56, e122 Migraines, hemiplegic, familial  409 Migrainous infarction  854 arterial ischemic stroke and  e1941 Milestones  1300, e2921, e2921t Miller-Dieker syndrome  275, e516f–e517f, e517, e651 and infantile onset epilepsies  558t–560t prenatal diagnosis of  252, e604, e604f–e605f Miller Fisher syndrome (MFS)  1086, 1087t

Index Mills v Board of Education of the District of Columbia  1283–1284, 1284t, e2894 Miltefosine, for granulomatous amebic encephalitis  911 Mineral metabolism, disorders of  e660t Minerals  385–386 developing brain and  e944–e945 iodine  386 iron  385–386 zinc  386 “Mini-brain” model  e296 Minimal brain damage syndrome  e1076 Minimal brain dysfunction  e1076 Minimal hepatic encephalopathy  1234, e2793 Minimally conscious state  770t, 771, 790, e1737–1740, e1737t, e1739b diagnostic criteria for  771b Minimally conscious states, in traumatic brain injury  e1796 Minimally invasive surgical techniques, in epilepsy surgery  617 Minimum clinically important difference (MCID)  1293 Minimum detectable change (MDC)  1293 Minocycline  480 for spinal cord injury  e1885–e1886 Minoxidil  e2755b associated with myopathies  e2683b toxicity  1197b Mirtazapine  e1171t, e1172–e1173 Mirtazapine, for ADHD  455t–457t Miscellaneous vasculitic disorders  e2182 Mismatch negativity  e1733 disorders of consciousness and  767 Missense mutation  e614t Mitochondria adenine nucleotide translocator  342 genotype  334 and inborn errors of metabolism  482t–486t metabolism  336f Mitochondrial biogenesis, for mitochondrial diseases  1139 Mitochondrial citrate carrier SLC25A1, defects in, myasthenic syndrome associated with  1096, e2448 Mitochondrial deafness  49, e104 Mitochondrial diseases/disorders  279t, 334–346, 1044, e659t, e839–e857, e1383–e1384, e2326 classification of  334–336, e839–e841, e841b and developmental language disorders  435–436 epilepsies and  596 genetic and biochemical classification of  e2563t histopathologic disturbances and  337–345, e841–e843, e843f history of  e839, e840f, e841t and infantile onset epilepsies  560t–562t Krebs cycle, defects of  e843–e851 metabolic disturbances and  336–337, e841, e842f pyruvate metabolism, defects of  e843–e851 respiratory chain  338–340 Mendelian defects of  e845–e851 therapeutic approaches in  e2567 therapy for  345–346, e851–e852 Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)  695, e1569

1365

Mitochondrial DNA (mtDNA)  335f, e841t, e844f depletion of  e2566 maintenance, defects of  342, e848, e849f multiple deletions  343–344 mutation, diseases due to primary  344 translation, defects of  341 Mitochondrial dynamics alteration of  346 defects of  342 Mitochondrial dysfunction  e2777 Mitochondrial encephalomyopathies  1137– 1139, e2557 biochemical classification of  1137–1138, e2558, e2561f–e2562f clinical considerations in  1137, e2558 genetic classification in  e2558 historical considerations in  e2557–e2558 morphologic considerations in  1137, e2558 MRI abnormalities in  338f mtDNA, defects of  e2558 management of  e2562–e2565 mitochondrial protein synthesis, defects in  e2558 point mutations  e2560 protein-coding genes  e2560–e2561 mutations in nDNA, diseases caused by  e2562–e2565 mitochondrial DNA, depletion of  e2566 multiple mitochondrial DNA deletions  e2566–e2567 respiratory chain, defects of  e2564 substrate oxidation, defects of  e2562–e2565 substrate transport, defects of  e2562–e2565 physiologic considerations in  1138, e2558 therapeutic approaches in  1138–1139 Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). see MELAS Mitochondrial fatty acid oxidation defects  e2725 Mitochondrial genetics  e839 Mitochondrial genome, replicative segregation  334 Mitochondrial inheritance  334 Mitochondrial membrane associated disorders  e696 Mitochondrial motility, alterations of  e2566 Mitochondrial neurogastrointestinal encephalomyopathy  343–344, 1230 Mitochondrial neurogastrointestinal encephalopathy  e850, e2782 Mitochondrial nucleotide pool  343f Mitochondrial protein importation, defects of  e2565 Mitochondrial protein synthesis, defects in  e2558 Mitochondrial replacement therapy (MRT)  345 Mitochondrial respiratory chain  335f diseases/disorders  e2351–e2352 genetic classification of  e2563t peripheral hypotonia and  1055t–1056t Mitochondrial transfer  e851–e852 Mitoribosomes, defects of  341 Mitosis  268 Mitotic centromere-associated kinesin  993 Mitotic segregation  334 Mitoxantrone, for multiple sclerosis  764 Mixed cerebral palsy  e1656

1366

Index

Mixed connective tissue disease  851, 947t, 952, e2175 Mixed-density hematoma, abusive head trauma and  e1816f–e1817f, e1817, e1819f Mixed episodes  656 MKRN3 gene  e2628 MLIS Barth-type  e519 MLIS MOPD1-type  e519 MMR vaccine, autistic spectrum disorders and  e1099 Möbius syndrome  e15f, e2382–e2383, e2383f, e2383t Modafinil  675 for ADHD  455t–457t Moderate-level (level B) recommendations, writing  1279t, 1280 Modified Ashworth Scale  472, 473t, e58t, e1128t Modified Atkins diet  625 Modified Checklist for Autism in Toddlers (M-CHAT)  4, 5f, e5, e8f, e1103 Moebius syndrome  207 MOGS-CDG (IIb)  e761 Molar tooth-related syndromes, prenatal diagnosis of  254, e609, e610f “Molar tooth sign”  202 Molecular cytogenetics  e635–e637, e636f Molecular epilepsy genetics  581–582 Molecular studies, in fatty acid oxidation disorders  e2555 Molecularly targeted treatment  e2823–e2824 Mollaret’s meningitis  889, 900 Molybdenum cofactor deficiency  131, 175, 482t–486t, e311, e415–e416, e416f, e1383, e1705–e1706 and infantile onset epilepsies  560t–562t inherited metabolic epilepsies  596 Monoamine oxidase deficiency  356t, 358–359, e876t, e881–e882 monoamine oxidase A  358 monoamine oxidase A and B  359 monoamine oxidase B  359 Monoamine oxidase inhibitors (MAOIs), for ADHD  455t–457t Monoaminergic neurotransmitter deficiency states with hyperphenylalaninemia  355–357, 356t, e875–e878, e876f, e876t–e877t without hyperphenylalaninemia  357–359, e878–e882 Monoclonal antibody therapy for CIDP  e2437 for opsoclonus myoclonus syndrome  942, e2156 Monomelic amyotrophy  1072, e2385 Mononeuropathies  e2723 Monosaccharides, lysosomal storage diseases and  e772t–e773t Monosomy  270 Monroe-Kellie doctrine  813 Mood disorders antiseizure medications  638 and selective serotonin reuptake inhibitors  491–492 Mood disturbances, in systemic juvenile idiopathic arthritis  e2164 Mood instability, and ADHD  451 Mood stabilizers  492–493, e1175–e1181, e1176t carbamazepine  493, e1178–e1179 gabapentin  e1180 lamotrigine  493, e1179–e1180 lithium  492–493, e1175–e1177

Mood stabilizers (Continued) oxcarbazepine  e1180 topiramate  e1180–e1181 valproic acid  493, e1177–e1178 Morality, common  1264 Morbidity and febrile seizures  520 in status epilepticus  548–549 Morning glory  1196b Morning glory, sensorium changes  e2682b Moro reflex  17, e34–e35 Morpheme  433b, e1054b Morphine associated with myoclonus  e2685b for pain management  1257t toxicity  1199b Morquio syndrome  e772t–e773t, e805 Mortality in children with epilepsy  e1482–e1489 epidemiology of  e1482–e1483 five categories of  e1483t prevention of not related to seizure  e1487 related to seizure  e1486–e1487 sudden unexpected death in  e1483, e1483b in comatose patients  779 and febrile seizures  520 in status epilepticus  548–549 in West syndrome  567 Mosaicism  270 Mossy fiber sprouting  508 Motor disabilities, arterial ischemic stroke and  856 Motor dyspraxia, and ASD  465 Motor-evoked potentials (MEPs) impairment of consciousness and  e1752 spinal cord injury and  e1879 Motor function neuropsychological measure  68t–69t term infant  20–21 Motor function scales  1049, e2336 Motor function testing  1048, e2333–e2334 Motor impairment abusive head trauma and  796 posttrauma  791 rehabilitation treatment of  1250–1253, e2833–e2838 intrathecal baclofen therapy for  1252 neuromuscular blockade for  1252 oral medications in  1251–1252, 1251t orthopedic surgery in  1252 overview  1250 rehabilitation therapy  1250–1251, 1251f selective dorsal rhizotomy for  1252 spasticity  1250 Motor neuron diseases  926t, 1045t–1046t, 1065–1072, e2374–e2389 anterior horn cells  1065 with arthrogryposis  1066t–1068t, 1069, e2381 atypical and acquired  1071, e2383–e2385 infections  e2383–e2384 trauma in  e2385 unknown etiologies in  e2385, e2386f vascular etiologies in  e2384–e2385, e2385f with central nervous system manifestations  1065–1068, 1066t– 1068t, e2380 clinical features of  e2374 diagnostic workup in  1065, e2374 with distal weakness  1069, 1070t, e2381

Motor neuron diseases (Continued) hereditary  1065–1071, 1066t–1068t infections in  1071–1072 with predominant bulbar weakness  1068– 1069, e2380–e2381 Brown-Vialetto-Van Laere (BVVL) disease  1066t–1068t, 1068 Fazio-Londe (FL) disease  1066t–1068t, 1068 Kennedy’s disease  1066t–1068t, 1068–1069 SMA-like  1065 spinal motor neurons, hereditary diseases affecting  e2374–e2383, e2375t– e2378t, e2379f SMA-like motor neuron disorders in  e2374–e2381, e2380f spinal muscular atrophy. See Spinal muscular atrophy (SMA) trauma  1072 treatment of  1072, e2385–e2386 unknown etiologies in  1072 vascular etiologies in  1071–1072 α-Motor neurons. see Anterior horn cells Motor regression cognitive and  e1019–e1050 metabolic disorders and  e667 Motor skills, and nonverbal learning disabilities  438 Motor tics  741 Motor unit number estimation  1041, e2319 Motor vehicle accidents  820 Mouse models genetically engineered  115–119, e287–e293 knock-out and knock-in  116–118, 117f–118f transgenic  115–116, 116f Movement disorders  706–716, 932–937, e1593–e1626 antiseizure drug therapy and  609 approach to treatment of  707, e1600 autoimmune encephalitis associated with  934–935 basal ganglia and  e1594–e1596, e1595f–e1597f characteristic features of  706, e1593 classification of  707t, 708, e1594t, e1597–e1600 diagnosis of  706–707, e1593–e1594 drug-induced  728–733, e1641–e1649 acute  e1645 ADHD treatment and  732–733, e1646 anti-infectious medications and  733, e1647 antiseizure medications and  733, e1647 chemotherapeutic medications and  733, e1647 chronic  e1645 classification of  729t, e1642t clinical characteristics of  728, 729t, e1641, e1642t definition of  728, e1641 dopamine receptor blockade  728–732, e1641–e1646 immunomodulatory medications and  733, e1647 serotonin reuptake inhibitors and  733, e1646–e1647 vitamin administration and  e1647 etiologies of  707, e1596–e1597 functional (psychogenic)  e1618–e1619, e1618b

Movement disorders (Continued) of infancy  724–727, 725t, e1636–e1640, e1637t benign idiopathic dystonia of infancy  727 benign myoclonus of early infancy  724–725 benign neonatal sleep myoclonus  724–727 benign paroxysmal torticollis  726–727 head nodding  726 jitteriness  725 paroxysmal tonic upgaze of infancy  725–726 posturing during masturbation  727 shuddering  725 spasmus nutans  726 infection-associated  936t systemic autoimmune disease, associated with  936t tardive  e1645–e1646 Mowat-Wilson syndrome  245, e589f, e591, e2782 Moyamoya arteriopathy  871–873, 872f, 872t, e1986–e1989, e1987t, e1988f Moyamoya disease  851f, 852, e1937–e1939, e1938f Moyamoya syndrome  852, e1937–e1939 MPDU1-CDG (If)  e764 MPI-CDG (Ib)  320, e751–e760 MPZ gene, mutations in  1074 MRC scale  1048 mtDNA. see Mitochondrial DNA (mtDNA) mtDNA depletion syndromes (MDS)  342, e848–e849 coexistence of  343–344 encephalomyopathic  342, e848 hepatocerebral  342, e848–e849 myopathic  342, e848 MTHFD1-encoded enzyme deficiency  380, e934 MTHFR deficiency  482t–486t MTMR2 gene, mutations in  1077 MTMR13 gene, mutations in  1077 mTOR pathway inhibition, in low-grade glioma  990, e2240–e2241 Mu rhythm  87, e220 Mucolipidoses  328–330, e812–e815 type I  e812–e813 type II  330–331, e813–e814, e813f–e814f type III  330–331, e813–e814 type IV  331, e814–e815, e815f, e1707 Mucopolysaccharides, lysosomal storage diseases and  e772t–e773t Mucopolysaccharidoses  327–328, e772t– e773t, e799–e807, e799f–e800f, e1707 type I  e801–e803 type II  e803–e804 type III  e804–e805 type IV  e805–e806 type VI  e806 type VII  e806–e807 type IX  e807 Mulberry molars  890–891 Mulibrey nanism  e870–e871 Mullen Scales of Early Learning  68t–69t, e143t–e146t Multidisciplary needs, for spinal cord injury  829 Multidisciplinary treatment model, for pediatric psychogenic nonepileptic seizures  e1467–e1468 Multifocal seizures  531–537, e1262–e1272 Multimini-core disease (MmD)  1128

Index Multiphasic acute disseminated encephalomyelitis  764 Multiple acyl-CoA dehydrogenase deficiency  e2552 Multiple carboxylase deficiency  378, e694–e695, e930 biotinidase deficiency  e694–e695 holocarboxylase synthetase deficiency  e695 Multiple independent spike foci  95 Multiple mitochondrial DNA deletions  e2566–e2567 Multiple mtDNA deletions, syndromes due to  342–343 Multiple sclerosis (MS)  702, 761–764, 761f, 1232, e1718–e1723, e2788 clinical course of  762–763, e1719 demographics and epidemiology of  e1718 diagnostic criteria for  761–762, 762f, e1718–e1719, e1721f epidemiology of  761 etiology, influenza virus  919 general care issues of  764 genetic and environmental risk factors for  e1720–e1722 immunomodulatory therapy in  763–764, 763t, e1722–e1723, e1723t influenza virus vaccine and  e2124–e2125 magnetic resonance imaging features of  763, e1719–e1720 pathobiological insights into  763, e1720–e1722 Multiple sleep latency test (MSLT)  673, e1530, e1530f Multiple subpial transections  617, e1430 Multiple sulfatase deficiency  754, e797–e798 Multiplex ligation-dependent probe amplification (MLPA), progressive encephalopathies and  428 Multiplex ligation probe amplification  e618t Mumps vaccines  921, e2126 Mumps virus  e2052 MURCS syndrome, with kidney malformation  e2764t Murine models, of SMA  e2365, e2366f Muromonab-CD3 sensorium changes  e2682b toxicity  1196b Muscle  1157 bulk and quality, of neuromuscular disorders  e2332 development, in health and disease  1029– 1037, e2299–e2315 disorders of  1045t–1046t fiber development of  e2300f types of  e2307–e2308 inherited disorders of  e2723 metabolism  e2313 Muscle biopsy for congenital myopathies  1123–1127 in dermatomyositis  1142–1143 of DMD and BMD  e2477 in polymyositis  1144–1145 Muscle contractions, colorectal motility and  1190, e2673–e2674, e2674f Muscle-eye-brain disease  317, 1120, e525, e2506–e2507 serum CK levels found in  1039t Muscle glycogen storage disease  315 Muscle membrane, in DMD  1106 Muscle phosphofructokinase deficiency  314, e739–e740

1367

Muscle relaxants  828 Muscle-specific kinase (MuSK) antibody  e2318 Muscle strength and weakness, assessment of, in neuromuscular disorders  e2332– e2333, e2334f Muscle stretch reflexes  1049, e2338 Muscle twitching/fasciculation, in uremic encephalopathy  e2744 Muscular dystrophies (MDs)  1044, 1045t–1046t, 1112–1122, 1113f, e2483–e2518, e2484f, e2486t–e2487t Becker. see Becker muscular dystrophy (BMD) congenital  1119 α-dystroglycan, abnormalities of  1119–1122 extracellular matrix proteins, abnormalities of  1121 lamin A/C-associated  1121 nesprin-associated  1121 peripheral hypotonia and  1055t–1056t Duchenne. see Duchenne muscular dystrophy (DMD) dystrophinopathies  1112 dystrophinopathy therapeutics for  1110–1111 Emery-Dreifuss muscular dystrophy. see Emery-Dreifuss muscular dystrophy (EDMD) facioscapulohumeral  1117–1118 Fukuyama  1120 limb-girdle muscular dystrophies. see Limb-girdle muscular dystrophies (LGMDs) oculopharyngeal  1119 Muscular dystrophy-dystroglycanopathies  1033– 1034 Muscular tone/muscle tone  27–32, 1051, e54–e67 clinical laboratory studies  28 definition of  27 diagnosis of  28, 29f, e57, e57t–e58t, e58b, e59f evaluation of patient  27–28, e55–e57 examination  27–28, e55–e57, e60f history  27, e55 pathology of  27, 28f, e54–e55, e55f–e56f phasic  27–28 postural  27–28 Musculoskeletal deformities  473–474 Mushrooms sensorium changes  e2682b toxicity  1196b MuSK myasthenia  1095, e2447 Mutant animals, spontaneously occurring  114–115, e286–e287, e287t Mutations  259, e614t, e618 analysis, of DMD  e2475–e2476 detection, general, methods of  260–262 detection of, methods of  e618–e623 Mutism, akinetic  770t, 771 Myasthenia gravis (MG)  926t, 1036–1037 autoimmune  1098 categories of  1098–1099 juvenile  1098 neonatal transient  1098 clinical and laboratory tests for  1099–1105 antibody testing  1100–1105 edrophonium (Tensilon) test  1099 electrophysiologic testing  1099–1100 clinical features of  1098 drugs to avoid in  1103, 1103b

1368

Index

Myasthenia gravis (MG) (Continued) treatment of  1100 acetylcholinesterase inhibitors for  1100 azathioprine for  1102 corticosteroids for  1101–1102 cyclophosphamide for  1102 cyclosporine for  1102 intravenous immunoglobulin for  1103 mycophenolate mofetil for  1102 plasmapheresis for  1103 tacrolimus for  1102 thymectomy for  1100–1101 Myasthenic syndromes  1096 congenital  1092–1097 Mycobacterium leprae  e2024–e2025 Mycophenolate mofetil for juvenile myasthenia gravis  e2463–e2464 for myasthenia gravis  1102 for neuromyelitis optica  765 Mycoplasma pneumoniae  892, e2024 Mycotoxin, renal toxicity of  1225t, e2765t Mydriasis, lightning and  809 Myelin-associated inhibitors, for spinal cord injury  e1887 Myelin basic protein (MBP)  751 Myelinated axon, longitudinal anatomy of  1035, 1036f Myelination, and nutritional status  385–386 Myelitis, transverse  759, 761f, 896 Myelomeningocele (MMC)  186–188, 186f, e432, e433f antenatal diagnosis of  186–187, e432–e433, e433f bladder and bowel dysfunction of  187 central nervous system complications of  187 Chiari II malformation  187–188 clinical features of  187, e434 counseling of  e437 fetal repair of  188, e436–e437, e436f management of  188, e436–e437 in newborn period  188, e437 orthopedic problems of  187 outcome of  188, e437 prevention of  e433–e434 secondary abnormalities of  187–188, e434–e436 bladder and bowel dysfunction  e434 central nervous system complications  e434 Chiari II malformation  e435–e436 orthopedic problems  e434–e435 Myelopathy, in polyarticular juvenile idiopathic arthritis  e2164–e2165 MYH7-related myopathies  e2532 Myoadenylate deaminase deficiency  1139, e2567 biochemistry and molecular genetics in  1139 clinical presentation in  1139 laboratory tests in  1139 pathology of  1139 Myoclonic absences, epilepsy with  570, e1252 Myoclonic-astatic epilepsy of Doose  538, e1274 EEG for  539 etiology of  538 outcome for  539 semiology of  538–539 treatment for  539

Myoclonic encephalopathies in nonprogressive disorders  557–563, e1317–e1325 differential diagnosis of  563, e1324 EEG for  557–563, e1317–e1318, e1324f etiology of  557, e1317, e1319t–e1321t laboratory studies for  563, e1318–e1324, e1319t–e1323t neuroimaging for  563, e1318 neurologic findings in  563, e1318 outcome of  563, e1325 seizures in  557–563, e1317–e1318 treatment of  563, e1324 Myoclonic epilepsy in infancy  e1198t juvenile  408, e1198t Myoclonic epilepsy in infancy  557 differential diagnosis  557 EEG findings in  557 etiology of  557 laboratory studies in  557 outcome for  557 seizures in  557 treatment for  557 Myoclonic epilepsy in infancy, in electroclinical syndrome, infantile onset  e1316–e1317 differential diagnosis of  e1316, e1324f EEG findings of  e1316, e1317f–e1318f etiology of  e1316 laboratory studies for  e1316, e1319t–e1323t neuroimaging of  e1316 neurologic findings in  e1316 outcome of  e1317 seizures in  e1316 treatment of  e1316–e1317 Myoclonic epilepsy with ragged red fibers (MERRF)  335, 345, 579, 596, e1277, e1355, e1384 Myoclonic jerks  528 Myoclonic seizures  528, e1256 clinical features of  528 delayed postanoxic  810 electroencephalographic findings in  528 epilepsy syndromes with  538 epileptic spasms and  538–542, e1273–e1291 and Lennox-Gastaut syndrome  571, e1340 lysosomal storage diseases and  e782 Myoclonus  707, 707t, 715–716, e1599, e1615–e1617 benign, of early infancy  e1636 benign neonatal sleep  e1636–e1639 classification of  715, 715b, e1616, e1616b essential  715 focal  533 physiologic and developmental  715, e1616 symptomatic  715, e1616–e1617 treatment of  716, e1617 Myoclonus-dystonia syndrome  711, e1606–e1607 Myoclonus epilepsy, progressive, infantile  403 Myocyte enhancer factor 2 (MEF2C) gene, mutation in  515 Myoglobinuria  1132, 1132b, e2538 phosphofructokinase deficiency  314 Myokymia  409

Myopathies  e2723 congenital  1123–1130 cardiac management of  1130 centronuclear  1127–1128 classification of, by genes  1123, 1124t–1125t congenital fiber-type disproportion  1129 core  1128–1129 diagnostic testing in  1123–1127 diagnostics in  1123, 1126f gastrointestinal management of  1129–1130 general management of  1129–1130 genetics in  1127 multimini-core disease  1128 muscle biopsy for  1123–1127 muscle imaging in  1127 nemaline  1123–1127 nutrition in  1129–1130 oromotor management of  1129–1130 orthopedic management of  1130 peripheral hypotonia and  1055t–1056t physical therapy/exercise for  1130 prevalence of  1123 respiratory management of  1129 RYR1-related  1128–1129 SEPN1-related  1129 subtypes of  1127–1129 SLE-associated  950 in systemic lupus erythematosus  e2170 uremic  1219 Myophosphorylase deficiency  e728t, e737–e739, e737f Myosin  1031–1032 Myosin ATPase  1131 Myositis eosinophilic  1145 focal nodular  1145 infectious  1044, 1045t–1046t influenza  1145 in systemic juvenile idiopathic arthritis  e2164 Myotilinopathy  1115–1116, e2494 Myotonia congenita  1150–1151, 1151t autosomal-dominant (Thomsen’s disease)  1150–1151, 1151t, e2603– e2605, e2603t autosomal-recessive (Becker’s disease)  1150–1151, 1151t, e2603– e2605, e2603t clinical features of  1150–1151, e2603 clinical laboratory tests for  e2604–e2605, e2604f genetics of  1151, e2603 laboratory tests for  1151 pathophysiology of  1151, e2603–e2604 treatment of  1151, e2605 Myotonia fluctuans  1151–1152, 1152t, e2605–e2606, e2606t Myotonic dystrophies  1148–1149, e2495, e2595–e2599, e2596t, e2726 acetazolamide-responsive sodium channel myotonia. see Acetazolamideresponsive sodium channel myotonia animal models for  e2599 congenital, peripheral hypotonia and  1055t–1056t current human research for  e2599 diagnostic approach for  e2599–e2600, e2599f–e2600f, e2601t disease mechanisms for  e2597–e2599 experimental therapeutics in  e2602–e2603 genotype-phenotype correlations  e2596–e2597

Myotonic dystrophies (Continued) human studies supporting RNA-mediated pathomechanism for  e2598–e2599 laboratory testing for  e2602 management of  e2621 mode of inheritance of  1148, e2595, e2597f myotonia congenita. see Myotonia congenita in peripheral hypotonia  e2348 RNA-mediated diseases  e2597–e2598, e2598f treatment of  e2602–e2603 type 1  1148, 1149t, e2595–e2596, e2726 clinical features of  1148 diagnostic approach in  1149–1150 in disorders of excessive sleepiness  e1535 genotype-phenotype correlations in  1149 laboratory testing for  1150 serum CK levels found in  1039t treatment of  1150 type 2  1148–1149, 1149t, e2596, e2726 clinical features of  1148–1149 diagnostic approach in  1149–1150 genotype-phenotype correlations in  1149 laboratory testing for  1150 treatment of  1150 Myotonic-like disorders, stiff-person syndrome  926t Myotubular myopathy  e2525–e2526, e2527f serum CK levels found in  1039t Myotubularin (MTM1)  1124t–1125t, 1127 Myxopapillary ependymoma  1013t

N

N-Acetylglutamate synthase (NAGS) deficiency  298, 482t–486t N-carbamyl-l-glutamate  303 N-glycosylation, congenital disorders of, in central hypotonia  e2348 N-linked glycan biosynthesis  e749, e750f N-linked glycan oligosaccharide, pathway for catabolism of  329f N-linked glycosylation  317–318, e749 N-methyl-D-aspartate. see NMDA NAA. see N-Acetylaspartate (NAA) Nabilone sensorium changes  e2682b toxicity  1196b Nadolol  e2755b Naegleria fowleri  910, e2079–e2083 Nalidixic acid associated with myopathies  e2683b toxicity  1197b Naloxone in coma  776 for spinal cord injury  826–827, e1884–e1885 Naltrexone, for ASD  466, 467t–468t Naphthalene sensorium changes  e2682b toxicity  1196b Naproxen, for pain management  1257t Naratriptan  650t Narcolepsy etiology, influenza virus  919 influenza virus vaccine and  e2125

Index Narcolepsy (Continued) type 1 (narcolepsy with cataplexy)  674– 675, e1531–e1533, e1531f diagnosis of  674–675, 675f, e1532, e1532f onset of  674, 674f pathophysiology of  674, e1532 treatment of  675, e1532–e1533 type 2  676, e1533–e1534 Narcotics in ataxia  e2685b toxicity  1199b Natalizumab for inflammatory bowel disease  e2785 for multiple sclerosis  764 National Child Abuse and Neglect Data System  794 National Comprehensive Cancer Network Clinical Guideline framework  e2887, e2888t National Infantile Spasms Consortium (NISC)  e1284 National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS)  831 National Institute of Neurologic Disorders and Stroke  e339 on perinatal stroke  147 National Institute on Deafness and Other Communication Disorders (NIDCD)  60, e128 National Institutes of Health (NIH)  59, e128 National Institution for Special Education (NISE)  1287, e2898 National Organ Transplant Act  839, e1916 National Resuscitation Program (NRP)  e302 Natowicz syndrome  e772t–e773t, e807 Natriuresis  1172 Natural law  1264, e2860 Nausea and vomiting, post-head injury  791 Navajo familial neurogenic arthropathy  1181, e2654 N.B. v Warwick School Committee  1284, 1284t, e2894–e2895 nDNA, mutations in, diseases caused by  e2562–e2565 “Near brain death”  e305 “Near card”  7 Near-infrared spectroscopy (NIRS) for coma  777 for impairment of consciousness  e1752 Nebulin  1032, 1124t–1125t, 1128 Nebulin (NEB)-related nemaline myopathy  e2529–e2530, e2529f Necroptosis  e331 Necrosis  804, e1769 cell  805–806 Necrotizing sarcoid granulomatosis  954, e2180–e2181 Necrotizing vasculitis  952–953, e2176–e2178 Cogan syndrome  947t, 953 Kawasaki disease  947t, 953 polyarteritis nodosa  947t, 952–953 Nefazodone, for ADHD  455t–457t Negative allosteric modulator (NAMs)  480 Neiman pick disease type C, in disorders of excessive sleepiness  e1535 Neisseria meningitidis, meningitis  883 Nelson-Denny Reading Test  445 Nemaline myopathy  1128, e2524, e2528–e2530 serum CK levels found in  1039t

1369

Nematode  e2080t Neocerebellum  e1555 Neocortex, in epilepsy  e1210–e1211 Neonatal-onset multisystem inflammatory disease (NOMID)  946–947, e2165 Neonatal Resuscitation Program (NRP)  124 Neonate/neonatal adrenoleukodystrophy  349–350, e863–e866 clinical features of  e864 laboratory of  e864–e865 prenatal diagnosis of  e865 antiseizure drug therapy in  603 cerebral sinovenous thrombosis (CSVT)  152–154 clinical presentation and diagnosis of  152–153, 153f epidemiology of  152 management of  153 outcomes of  154 pathophysiology and risk factors of  152 electroclinical syndrome in  552–556, e1308–e1315, e1309t benign  552–553 benign familial neonatal epilepsy  553–554, e1309–e1310, e1309t, e1310f benign neonatal seizures in  e1308, e1309t early myoclonic encephalopathy  555, e1313–e1314 Ohtahara syndrome  554–555, e1310, e1311t–e1312t encephalopathy  138, e321–e322, e322t management of  138–140, e322–e325 neurointensive care approach to  e301 outcomes of  e325–e327, e326t epilepsy  513–514 benign familial  513, e1198t, e1226 benign familial neonatal-infantile epilepsy  514, e1228 epileptic encephalopathy associated with SCN2A  514, e1228 KCNQ2 encephalopathy in  e1226–e1227 Ohtahara syndrome  513–514, e1198t, e1227–e1228 with hypoxic-ischemic encephalopathy, treatment options for  124–125 inborn errors presenting in  e1029t–e1030t meningitis, clinical presentations of  884, e2010 metabolic disorders in  e658–e665 motor function testing  1048, e2333–e2334 myasthenia gravis  e2460 serum CK levels found in  1039t nervous system trauma  156–160, e359–e371 neurocritical care units  138 neurointensive care  123–128, e299–e307 seizures  129–137, e308–e320 diagnostic considerations for  133–135, 134f status epilepticus  549–550, 550t, e1301–e1302, e1302t transient myasthenia  e2349 Neostigmine associated with paralysis and muscular rigidity  e2684b toxicity  1198b Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)  1172 Nephrolithiasis, lysosomal storage diseases and  e783

1370

Index

Nephropathic cystinosis  1223, e2762–e2763 nonverbal learning disabilities and  440, e1065 NEPSY  e1001t–e1004t NEPSY II  68t–69t, e143t–e146t Nerve agents  e2687–e2688 sensorium changes  e2682b toxicity  1196b Nerve conduction studies  1040–1041, e2318–e2319 Nerve conduction velocity (NCV) testing  1074 in CMT  e2393–e2394 Nerve development, in health and disease  1029–1037, e2299–e2315 Nerve-sheath tumors (NSTs)  1014 Nervous system  e256 bacterial infections of  883–894 fungal, rickettsial, and parasitic diseases of  907–916, e2065–e2121 inherited disorders of  e2723 mechanisms underlying functional recovery in  1248–1249 paraneoplastic syndromes  926t plasticity of  1248–1249 stimulation of, to improve stroke recovery  1254 trauma  156–160, e359–e371 during newborn period  e366–e368 vascular malformations, trauma and  e368f, e369 viral infections of  895–906 Nesprin-associated congenital muscular dystrophy  1121 Nestin  1034 NET1 single-nucleotide polymorphism, and ADHD  450–451 Network connectivity  e258–e259 Network integration  99, e258–e259 Network science, tools of  99, e258–e259, e258t, e259f Network segregation  99, e258–e259 Neural control, of movement  e2309–e2310 Neural correlates of consciousness  767–769, e1732–e1736 approaches to studying  767–768, e1732–e1733 in DOC patients  768–769, e1735–e1736 neuroimaging and  768, 768f neuroimaging of  e1733–1735, e1734f neurophysiology and  768 Neural crest cells  e2642 Neural plate formation  183 Neural stem cells (NSCs)  107, e277, e332–e333 biology of  107–110, e277–e280 definition of  107, e277 in developing CNS, stem cell niche and  107 donor detection of, in host mouse brain  109, e279 engrafted, bystander effects of  110, e280 function of, in developing CNS  e277 future applications of  112–113, e282–e283 generation of, from iPSCs  108–109, 108f homing of  109–110, e279–e280 human and murine, generation of, from embryonic stem cells  108, e278 from iPSCs  e278–e279 therapeutic potential of  110–112, e280–e282 transplantation of  109, 110f, e279, e280f in vitro, isolation and propagation of  107–108, e277–e278

Neural tube anatomy and embryology of  183–185, e427–e430 closure of  186 development, disorders of  183–190, e427–e448 formation of  183, 184f, e427–e429, e428f–e429f, e987f molecular patterning of  183–185, e429–e430 Neural tube defects (NTDs)  183, e427 classification of  186, e432 embryologic  186, e432 nomenclature  186 complex genetic contributions in  185, e430 epidemiology and pathogenesis of  185– 186, e430–e432 gene-diet interactions in  e431 gene-environment interactions influencing  185, 185t, e431 incidence of  185, e430 nomenclature of  e432 teratogens and  185–186, e431–e432 Neurexin  421 Neuro-oncology  957–962, e2192–e2200 Neuroacanthocytosis  e1609, e1609f Neuroanatomical damage, in neurocognitive deficits  1025, e2294 Neuroaxonal dystrophy  e2403 Neuroaxonal leukodystrophy with spheroids  758, e1702f, e1704 Neurobehavioral disorders  e256 Neurobehavioral domains  243f Neuroblastoma  1019, e2284 Neuroblastoma, ataxia and  704 Neurocardiogenic syncope  660, e1512 prognosis of  e1515 treatment of  e1515b Neurocognitive deficit, risk factors for  1024–1025 Neurocognitive development, nonsyndromic craniosynostosis  e573–e574 Neurocognitive sequelae, medulloblastoma  968 Neurocranium  233, e567 Neurocristopathy syndromes  1230, e2781–e2782 Neurocritical care team  e299 Neurocutaneous melanosis  370, e904–e905 Neurocutaneous stigmata  427 Neurocysticercosis  590, 915, e2103 Neurodegenerative disorders  425 dystonia associated with  711 Neurodevelopmental disabilities  413–417, e986–e996 approach to evaluation of child with suspected  415–416 care of the child with  e992 commonalities of  415, e990 determinants of  414, e990 evaluation of a child with suspected  e991–e992 frequently encountered  414b general conceptions and considerations when approaching  413–417 multidisciplinary approach to care of child with  416–417 nature and nurture in  e988–e989 overlap in  415, e990–e991 overview of  414, e989–e990 policy in  e992–e994, e994b risk factors for  414, e990 scope of problem  414, e989–e990

Neurodevelopmental disabilities (Continued) spectrum of  413–414, e989, e989b testing for  416, e992, e993t Neurodevelopmental disorders association of agenesis of corpus callosum with  196 common comorbidities associated with, management of  472–477 behavior  476–477 feeding and gastrointestinal issues  474–475 fragility fractures (osteoporosis) as  476 hypertonia  472–473 musculoskeletal deformities  473–474 seizures  475–476 sleep disorders  476 management of common comorbidities associated with  e1127–e1136, e1134t atlanto-axial instability  e1130 behavior  e1133–e1135 feeding and gastrointestinal issues  e1130–e1131, e1130t fragility fractures  e1133 hips subluxation/dislocation  e1129 hypertonia  e1127–e1129 muscle contractures  e1129 musculoskeletal deformities  e1129 scoliosis  e1129 seizures and special considerations in  e1131–e1132 sleep disorders  e1133 treatment of  478–488, 479t, e1137–e1157, e1138t autism spectrum disorder  e1145 congenital hypothyroidism  e1154–e1155 Down syndrome  479, e1139–e1140 fragile X syndrome  480, e1141–e1145, e1142f general concepts in  e1137–e1138 general concepts surrounding  478 generalization in, from single-gene disorders to ASD  480–481 inborn errors of metabolism  481–487, e1145–e1154, e1146t–e1150t, e1151f, e1152b newborn screening and  e1154 Rett syndrome  478–479, e1138–e1139 single-gene disorders  e1145 tuberous sclerosis  479–480, e1140– e1141, e1141f Neuroethics  1263, e2867–e2868 Neurofibroma  1013t, e2278 cutaneous  362 Neurofibromatoses  362–364, 479t, e887–e894 schwannomatosis  364 type 1 (NF1)  67–71, 216, 275, 362–363, 958t, 1272, e147, e502–e504, e651, e887–e892, e888b clinical characteristics of  362–363, e887–e891, e889f–e891f diagnostic criteria for  363b genetics of  363, e891–e892 management of  363, e892 nonverbal learning disabilities and  440, e1065 pathology of  363, e891 and pediatric low-grade glioma  e2241, e2241f transitional care and  e2874 treatment of  e1138t, e1141f

Neurofibromatoses (Continued) type 2 (NF2)  363–364, 364b, e892–e893, e892f, e893b clinical characteristics and pathology of  363–364, e892 genetics of  364 management of  364 meningiomas and  1008 Neurofunctional domains  243f Neurogenetics  e613–e633, e625b chromosome analysis and  e614–e623 diagnostic technologies, genomic  e618–623 genomic testing, resources for interpreting  e623–e628, e624t human genome and  e613–e614 principles in practice, examples of  e628– e630, e628f, e630f somatic mosaicism  e625–e626 Neuroimaging  78–86, 281–282, e163–e201 angiography  85, e192 for autistic spectrum disorders  e1101 for cerebral palsy  735 computed tomography  78–79, e166– e169, e167f–e173f cranial ultrasound  78, e163–e166, e164f–e165f diffusion tensor imaging  82–83, e184–e188, e187f–e188f diffusion-weighted imaging  82, e183– e184, e185f–e186f for disorders of consciousness  768, 768f functional magnetic resonance imaging  84, e190–e191 for headache  648–649 iron and  680 magnetic resonance imaging  79–80, e169–e176, e173f–e178f magnetic resonance spectroscopy  80–81, e176–e183 magnetic source imaging  84, e191–e192 perfusion magnetic resonance imaging  83, e188–e189, e189f progressive encephalopathies and  428 single-photon emission computed tomography and positron emission tomography  85, e192–e194 spinal imaging  84–85, e192, e192f–e193f susceptibility-weighted imaging  83–84, e189–e190, e190f–e191f Neuroinflammation detection of, in opsoclonus myoclonus syndrome  939, e2149–e2150 hypoxic-ischemic encephalopathy and  807–808 integration of, with clinical assessment  940, 941b Neurointensive care, neonatal  123–128, e299–e307 brain imaging for  127, e305 brain monitoring in  125–127, 126f clinical scenarios demonstrating approach to  e301–e302 continuity of  e306 establishing a multidisciplinary  e299– e301, e300f multidisciplinary, establishing  123–124 palliative care  127 resuscitation and supportive care in  124, e302 seizure management in  125–127, 126f work flow in  e301, e301t Neurokinin B  1165–1166

Index Neuroleptic malignant syndrome  1200, e1646 antipsychotic medications and  e1182t, e1183 drug-induced movement disorders and  732 Neuroleptics  1200 atypical  490t typical  490t Neuroligin  421 Neurologic abnormalities associated with liver transplantation  e2796 hepatic encephalopathy  e2792 in primary biliary cirrhosis  e2796–e2797 Neurologic disorders/diseases cellular and animal models of  114–122, e286–e298 counseling children with, and families  e2813–e2820, e2815b–e2816b challenges  e2817–e2819 clinician-patient relationship  e2813 communication skills  e2813, e2814b conveying empathy  e2814, e2814b nonverbal communication  e2813–e2814 providing information  e2814–e2817, e2815b–e2816b gastrointestinal diseases and  e2775–e2812 measurement of health outcomes in  1289–1294 novel human cell model for  120–121 relationships to  181 special education law and  e2893–e2899 case for  e2893–e2896, e2894t case studies and  e2897 federal legislation and  e2895 history of  e2893 international  e2897–e2898 special education law in  1283–1288 stem cell transplantation for  107–113, e277–e285 transitional care for children with  e2871–e2879 barriers to effective transition  e2871–e2875, e2872b–e2873b models of care for transition  e2876–e2877, e2876b poorly managed  e2875–e2877 vision loss and optic atrophy  40t Neurologic examination after newborn period until 2 years of age  14–19, 15b, e29–e38, e30b approach to evaluation  e29 cranial nerves  14, e31 developmental reflexes  17–18, 18t, e34–e36, e35t, e36f general considerations  e37–e38 head  14, e30–e31 motor evaluation  15–16, e31–e33, e32f motor performance instruments  17, e34, e34b patient evaluation  e29–e37 sensory testing and cutaneous examination  16–17, 16f, e33, e33f stage 1  14–17, e29–e33 stage 2  17–18, e33–e36, e34f stage 3  18, e36–e37 stage 4  18–19, e37, e37b, e37f evaluation of patient  14–19 general considerations  19

1371

Neurologic examination (Continued) of older child  7–13, e11–e28, e12t cerebellar function  13, e27 cranial nerve examination  7–10, e11–e17 deep tendon reflexes  10–12, e19–e23, e25t gait evaluation  13, e27 muscle testing  e17–e19, e17f, e24t–e25t, e25f observation/mental status  7, 8t, e11 other reflexes  12, e23–e25 physical examination  7–13, e11–e27 screening gross motor function  7, e11 sensory system  12–13, e25–e27, e26f–e27f skeletal muscles  10, 11f–12f, 11t–12t, e17–e19, e18f–e23f, e18t–e21t, e23t of term and preterm infant  20–26, e39–e53 Neurologic history age of onset  1 family history  2, e3 focal/generalized  1 general aspects of  1–6, e1–e10 medical history  2, e3 progressive/static  1–2 screening tools for  e9t Neurologic impairment acute onset, causes of  1022b posttreatment encephalopathy with  1022–1024 Neurologic manifestations mucopolysaccharidoses and  327 neuronal ceroid lipofuscinoses and  332 Neurologic sequelae in AT/RT  998–999 of CNS tumors  1021–1027 chronic leukoencephalopathy  1024 cognitive impairment  1024–1025 growth and other sequelae neuroendocrine component  1026 mortality in long-term tumor survivors  1021 neurosensory deficits  1025 peripheral nervous system impairment  1026 posttreatment  1021–1025 Neurologic symptoms, associated  281 Neurologist duties of, ethics and  1268–1269 role of, in PNES  633–634 Neurometabolic disease  798 Neurometabolic retinal dysfunction  39, e79–e80 Neuromodulation in epilepsy  619–623, e1436–e1441 anterior nucleus of the thalamus deep-brain stimulation  620 deep-brain stimulation in  e1437 diagnostic transcranial magnetic stimulation  622, e1438–e1439 repetitive transcranial magnetic stimulation  621, e1438 responsive neurostimulation  620–621, e1437–e1438 transcranial direct current stimulation  622, e1439 trigeminal nerve stimulation  621, e1438 vagus nerve stimulation  619–620, e1436–e1437 for impairment of consciousness  e1751 Neuromotor development, in CHD  e2730 Neuromotor screening instruments  e9t

1372

Index

Neuromuscular blockade intracranial pressure and  789 spasticity  e2836 for traumatic brain injury  e1784–e1785 Neuromuscular disorders  1044–1050 adaptive devices for  1158 assessment of muscle strength and weakness in  1048 bone health and  1162 cardiac involvement in  1161 chronic  e2328t classification of  1044–1046, 1045t–1046t, e2326–e2328, e2327t–e2328t clinical assessment of  e2326–e2340 definition of  1044, e2326–e2328 disability scales in  1050 dysphagia and  1162 epidemiology of  1044, e2326–e2328 evaluation of  1044–1050, 1047f, e2328–e2339, e2329f disability scales in  e2338 examination in  e2332–e2338, e2334f, e2335t, e2337t history  e2330–e2332 localization and classification  e2330, e2330t quality of life in  e2338 examination for  1046–1050, 1048f growth and  1162 history of  1046 individual education plan (IEP) in  1162 inspection in  1046 joint mobility and tone in  1046 laboratory assessment of  1038–1043, e2316–e2325 chemistries and serologies in  e2316– e2318, e2317t electrical impedance myography  1041, e2319 genetic testing  1042, e2320, e2320b imaging studies  1041–1042, e2319–e2320 laboratory chemistries and serologies  1038–1040 motor unit number estimation  1041, e2319 nerve conduction studies and electromyography  1040–1041, e2318–e2319 serum CK levels  1039t in various age groups  e2317t workup  1039t localization of  1044–1046 management of  1157–1163, e2616–e2626, e2617f Andersen-Tawil syndrome  e2622 Becker muscular dystrophy in  e2621 bone health in  e2622–e2623 cardiac management in  e2621–e2622 congenital myopathies  e2622 Duchenne muscular dystrophy in  e2621 Emery-Dreifuss muscular dystrophy in  e2621–e2622 endocrine management in  e2623 gastrointestinal and nutrition management in  e2622 Kearns-Sayre syndrome  e2622 limb-girdle muscular dystrophy in  e2621 myotonic dystrophy in  e2621 orthotics and adaptive devices  e2616– e2617, e2617f psychosocial management in  e2623

Neuromuscular disorders (Continued) respiratory management in  e2619–e2621 scoliosis management in  e2618–e2619, e2619f therapeutic exercise  e2616 transition and aging  e2623–e2624 motor function scales in  1049 motor function testing in  1048 muscle bulk and quality in  1046 muscle stretch reflexes in  1049 Quality of Life (QOL) in  1050 respiratory involvement in  1160 sensory testing for  1049–1050 swallowing and  1162 therapeutic treatment in  1157 in toddlers and children  1160 Neuromuscular function  e2309–e2313 excitation-contraction coupling in  e2311– e2312, e2311f–e2312f gamma efferent system in  e2312–e2313, e2313f neural control of movement  e2309–e2310 neuromuscular transmission in  e2310– e2311, e2310f–e2311f Neuromuscular junction  1035–1036, 1036f, e2452, e2453f acquired diseases of  1098, e2452–e2471 autoimmune myasthenia gravis in  e2452–e2467 botulism in  e2467 foodborne botulism in  e2467 infant botulism in  e2467 Lambert-Eaton myasthenic syndrome (LEMS)  1098, 1103 myasthenia gravis. see Myasthenia gravis (MG) wound botulism in  e2468 disorders of  1045t–1046t, e2349 Lambert-Eaton myasthenic syndrome  927 electrodiagnostic approach  1041 embryology and development of  1030, e2301 Neuromuscular transmission  e2310–e2311, e2310f–e2311f Neuromuscular weakness  282 Neuromyelitis optica  702, 764, 766f, e1586, e1724–e1726 clinical features of  764, e1724 demographics and epidemiology of  e1724 diagnostic criteria for  764–765, e1724 epidemiology of  764–765 laboratory features of  765, e1724–e1725 magnetic resonance imaging in  765, 766f, e1725, e1726f symptomatic brain involvement in  764, e1724 systemic autoimmunity in  765, e1724 treatment of  765, e1725–e1726 Neuromyotonia  926t Neuron-specific enolase  800 Neuronal ceroid lipofuscinosis (NCL)  331– 333, 332t, 390–404, 579, e772t–e773t, e819–e821, e820t, e821f, e950–e976, e1277–e1278, e1355–e1356, e1387, e1685f, e1707 clinical trials in  396, e957 CLN1  e957–e960 CLN2  e960–e961 CLN3  e961–e962 CLN4  e962–e963 CLN5  e963 CLN6  e964 CLN7  e964–e965

Neuronal ceroid lipofuscinosis (NCL) (Continued) CLN8  e965 CLN10  e965–e966 CLN11  e966–e967 CLN12  e967 CLN13  e967–e968 CLN14  e968–e970 diagnosis of  e957, e958f FTLD biology/pathology  e966–e967 historical clinical characterization of  e950–e956 clinical description and characterization  e950–e953, e954t–e955t molecular genetics  e953 nomenclature  e950, e951t–e952t pathobiology  e953–e956, e956f pathology  e953, e955f juvenile form of  398 management and treatment of  403–404, e968–e969 masqueraders  394t–395t models  396, e956–e957 NCL-FTLD overlap  e967 protein localization  396f resources in  e969–e970 Neuronal connections, reorganization of  1249 Neuronal damage acute bacterial meningitis and  886 bacterial meningitis and  e2014 Neuronal firing, abnormal  508–509, 509f and epileptogenicity, glial mechanisms for modulating  508 and physiology of absence epilepsy  508– 509, 510f synchronizing mechanisms in  508 Neuronal heterotopia  221–222, e526–e529, e528f–e529f antenatal diagnosis of  e527–e529 brain imaging of  e526–e527, e526t, e528f–e529f clinical features of  e526t, e527 genetic testing of  e527 pathology of  e526 syndromes, genetics, and molecular basis  e527 types of  e526t, e528f–e529f, e529 Neuronal intranuclear inclusion disease  e1614 Neuronal networks  e208–e209 Neuronopathies riboflavin transporter deficiency  374 subacute sensory  929, e2135 Neuropathic pain  1258, e2850–e2851 Neuropathies acute autonomic and sensory  1179 peripheral, genetic  1073–1080 in systemic juvenile idiopathic arthritis  e2163 Neuropathological studies, chronology of sulcation according to  250t Neuropathology of ASD  462 in autistic spectrum disorders  e1100 mechanism of  301 altered glucose metabolism  301 downregulation of astrocytic glutamate transporters of  301 elevated glutamine levels of  301 oxidative/nitrosative stress of  301 potassium ion flux interference  301 water transport, altered  301

Neuropeptide Y (NPY)  1165 Neuropeptide Y1 receptor (Y1R)  1170 Neurophysiologic evaluation  e202–e255 Neurophysiologic evaluation, pediatric  87– 96, e202–e255 clinical neurophysiology training  e202–e203 electroencephalography abnormal electrical patterns  e209 abnormal patterns of  e226–e237 abnormal suppression or slowing of  e209–e210, e210f–e211f guidelines for interpretation  e210–e211 maturational patterns  e210–e223 neurophysiological basis for  e205–e210, e206f–e208f newborn electroencephalographic patterns  e211–e212, e212f–e215f normal variation in, significance of  e210–e223 ontogeny of  e212–e219 potential fields and neuronal networks  e208–e209 sleep patterns  e223–e226 instrumentation and recording techniques in  e203–e205 artifact recognition  e204, e204f filter settings  e203–e204 instrumental control settings  e203–e204 paper speed  e204 physiologic noncerebral channels  e204 polarity localization  e203 recording setting  e205 sensitivity settings  e203 neurophysiological studies, utility of  e202 Neurophysiological studies drowsy patterns  89–90 electroencephalographic patterns beta activity  88 in infancy through adolescence  87–89 lambda waves  89 newborn  87 theta and delta slowing  88–89, 88f waking patterns  87, 88f guidelines for interpretation  87 sleep activation procedures  90 utility of  87–90 Neuropraxia cervical cord  823 cervical nerve root/brachial plexus  823 Neuroprotection for arterial ischemic stroke  855 of urea cycle disorder  303–304 Neuropsychiatric comorbidity  e2661 Neuropsychiatric disorders, intracranial arachnoid cysts and  232 Neuropsychiatric lupus  950, e1992 in systemic lupus erythematosus  e2169 Neuropsychological assessment  65–72, e140–e149 definition of  65–66, e140–e141 multicultural factors  66, e141 Neuropsychological evaluation, referring for  67, e142 Neuropsychological impairments, arterial ischemic stroke and  856, e1947 Neuropsychological measures, commonly used  68t–69t Neuropsychological report  67–72, 70t, e142–e148, e146t Neuropsychological testing  66–67, 67f, 68t–69t, e141–e142, e142f, e143t–e146t

Index Neuropsychopharmacology  489–495, 490t, e1158–e1196, e1159t for ADHD nonstimulant medications for  489–491 stimulants for  489, 490t alpha2-agonists  e1164–e1165 antidepressants  491–492, e1165–e1173 others  492 selective serotonin reuptake inhibitors  491–492 tricyclic  491 anxiolytics  492, e1173–e1175 atypical antipsychotics  e1184–e1189, e1184t dopamine receptor antagonists  e1181– e1184, e1181t aripiprazole  494–495 atypical antipsychotics  494–495 clozapine  495 olanzapine  494 quetiapine  494 risperidone  494 side effects of  494 typical antipsychotics  493–494 ziprasidone  494 mood stabilizers  492–493, e1175–e1181, e1176t carbamazepine  493 lithium  492–493 others  493 valproic acid  493 nonstimulant medications  e1163–e1164 stimulants  e1158–e1163 Neurorehabilitation  e2829–e2845 principles of  e2831, e2831b Neurorehabilitation, pediatric, medicine  1248–1255 criteria for admission to  1250 principles of  1249 see also Rehabilitation Neuroretinitis, cat scratch disease  892 Neurosensory deficits  e2294–e2295 Neurosensory deficits, CNS tumor posttreatment sequelae  1025 Neuroteratology  1202–1204, 1203t Neurotheology  e2868 Neurotransmission efferent  e2643 and inborn errors of metabolism  482t–486t posttraumatic  781 Neurotransmitter abnormalities, tic disorders and  744 dopamine  744 GABA  744 glutamate  744 serotonin  744 Neurotransmitter receptors changes in, in seizing brain  544–545 in seizing brain  e1297 self-sustaining seizures and  e1292–e1294, e1293f Neurotransmitter-related disorders  355–361, e875–e886, e1385 amino acid neurotransmitter, disorders of  e882–e883 deficiency, amino acid neurotransmitters  359–360 dopamine B-hydroxylase, deficiency  356t, 358 excess neurotransmitter levels, neurologic disorders characterized by  360, e884 glycine encephalopathy  360

1373

Neurotransmitter-related disorders (Continued) inherited metabolic epilepsies and  597 monoaminergic neurotransmitter deficiency  356t, 357–359, e875–e878 secondary  359–360 treatment of  360, e884 undefined neurotransmitter deficiency states  360, e883–e884 Neurotransmitters in ASD  462 autistic spectrum disorders and  e1100–e1101 development of  510–511, e1219–e1220, e1219f metabolism, disorders of  131, e311 Neurotrauma, autoregulation-directed therapy in  815, e1863 Neurotrophic tyrosine kinase-1 receptor (NTRK)  1181 Neurovascular regulation  781 Neurovascular unit, hypoxic-ischemic encephalopathy and  807–808 Neurulation, secondary, disorders of  e443–e444 Nevoid basal cell carcinoma syndrome  e2201 Newborn screening  1245–1246 for spinal muscular atrophy  1061 for XALD  353 Newborns brain death in  836–839, e1914–e1916 ancillary studies  837, e1913t, e1914–e1915 apnea testing of  e1914 clinical examination of  837, e1914 comatose pediatric patient and  e1915– e1916, e1915f discussions with family members and staff in  e1916 duration of observation of  e1914 epidemiology of  837, e1914 organ donation for  e1916 cerebrovascular disorders in  147–155, e339–e358 with encephalopathy, brain imaging of  139–140, 139f epilepsy and seizures in  498–499 health outcome measurement in  1292, e2905 Next-generation sequencing  262, e618t, e622–e623, e622f, e623t NextGxDx gene test shopping service  1297 NF1. see Neurofibromatoses, type 1 (NF1) NF2. see Neurofibromatoses, type 2 (NF2) NGFB gene, mutation in  1181 NGLY1-CDG  320, e762 Niacin  374, e918t–e919t, e922 associated with myopathies  e2683b deficiency  e922 dependency  374, e922 sensorium changes  e2682b toxicity  1196b–1197b “Niches”  107, e277 Niclosamide, for cysticercosis  915, 1146 Nicotine toxicity  1196b, 1200b Nicotinic ACh receptors  405 Niemann-Pick disease  326, e772t–e773t type C  482t–486t types A and B  326, e788–e790, e789f types C and D  326, e790–e791, e791f Nifedipine  e2755b Nifurtimox, for Chagas disease  913, e2094 Night awakenings, triggers for  476

1374

Index

Night terrors  e1737 Nightmares  669, e1525 Nimodipine, for spinal cord injury  e1885 Nipah virus  905, e2057, e2786 Nitric oxide  806–807 synthesis  e1842–e1843, e1843f, e1843t hypoxic-ischemic encephalopathy and  806–807, 807f Nitric oxide supplementation therapy  e719 for urea cycle disorder  304 Nitric oxide synthase, in urea cycle disorders  300 Nitrofurantoin  e2694 causing peripheral neuropathy  e2684b toxicity  1197b, 1201 Nitroprusside associated with myoclonus  e2685b toxicity  1199b Nitrosative stress, and urea cycle disorders  301 Nitrous oxide abuse in  e2690 causing peripheral neuropathy  e2684b sensorium changes  e2682b toxicity  1196b–1197b Nitrous oxide-induced polyneuropathy  1084, e2417–e2418 NKCC1  510 NLGN3 gene mutation  421t NLGN4 gene mutation  421t NMDA  129, 405 NMDA receptors  508, 510, 934t, e2368 No Child Left Behind Act (NCLB)  1286, e2896–e2897 Nocardia spp.  908, e2068–e2069 brain abscess and  908 N. asteroides  908 N. brasiliensis  908 N. farcinica  908 Nociceptors  1256 Nocturnal bladder control  1184 Nocturnal bowel control  1184 Nocturnal enuresis  669, e1525 Nocturnal frontal lobe epilepsy  e1631 Nocturnal groaning  670 Nocturnal panic attacks  670–671, 670t, e1526–e1527, e1526t Nocturnal paroxysmal disorders  667–671, e1523–e1528 nocturnal panic attacks in  e1526–e1527, e1526t parasomnias in  e1523–e1526 Sandifer syndrome  e1527 Nocturnal polysomnography, for excessive sleepiness assessment  673, e1529–e1530 Nocturnal sleep fragmentation narcolepsy in  674 treatment of  676, e1533 Nogo, for spinal cord injury  e1888 Nomograms  1297 Non- (NMDA) receptors  508 Non-5q spinal muscular atrophies  e2362 Non-5q13-associated spinal muscular atrophies  e2358 Non-dopa-responsive disorders, of dopamine synthesis and metabolism  712 Nonaccidental head injury  794 see also Abusive head trauma (AHT) Nonbenzodiazepine antiseizure drugs, for status epilepticus  e1299–e1300 Nonconvulsive status epilepticus  550, e1302–e1303

Nondisjunction  270 mitotic  270 mosaicism  270 Nonepileptic paroxysmal disorders, EEG and  e239–e240 Nonepileptiform patterns, abnormal, in EEG  e237 Nongerminomatous germ cell tumors (NGGCTs)  1000, e2257 Nonhomologous end-joining (NHEJ)  118–119 Nonimmune-mediated CNS disorders, microbiota and  1232–1233, e2788–e2789 Noninvasive prenatal testing (NIPT)  430 Nonketotic hyperglycinemia  131, 482t–486t, e311 and infantile onset epilepsies  560t–562t Nonkinesigenic paroxysmal dyskinesia  720– 721, e1629–e1630 Nonmaleficence, as precepts of natural law  1265 Nonneurologic disorders, vertigo and  e123 Nonneurotologic disorders, vertigo and  57 Nonpolio enteroviruses  899t Nonprogressive cerebellar ataxia (NPCA)  203 Nonsense mutation  e614t Nonsteroidal antiinflammatory drugs (NSAIDs) for pain management  1257 sensorium changes  e2682b toxicity  1196b Nonstimulant medications, for ADHD  454 Nonsyndromic congenital muscular dystrophies, merosin-positive  e2508 Nonsyndromic hearing loss  46–47, e101–e102 genetic diagnostics for  47, 47t Nonthyroidal hypermetabolism  e850 Nontraumatic brain injury, prognosis for  778 Nonverbal communication  e2813–e2814 in counseling children with neurologic disorders  1239–1240 deficits in, and autistic spectrum disorder  459 Nonverbal learning disabilities  437–441, e1060–e1067 coexistent issues in  437–438, e1060–e1061 definition of  e1060 diagnosis of  437, e1060 neuroimaging in  439–440, 439t, e1063–e1064, e1063t neurologic aspects of  440–441, e1064–e1065 neuropsychological findings in  438–439, e1061–e1063 achievement  438 executive functioning and  438–439 language  438 social perception and psychopathology  439 verbal-performance IQ split  438 visual-spatial and motor skills  438 original conceptualization of  437 Nonvertiginous disequilibrium  e122–e123 Noonan syndrome, congenital heart defects and  1206t Noradrenergic potentiation, for ADHD  454–457 Norepinephrine, cerebrovascular system and  846 Norrie disease  358, e1535

North American blastomycosis  e2067 Nortriptyline  491, e2825t for ADHD  455t–457t associated with tremor  e2685b for migraine  652t toxicity  1200b Norwegian nonprogressive infantile cerebellar ataxia  e1568 Nova Scotia cohort  642 Novel human cell model, for neurologic diseases  120–121, e295 Noxious compounds, elimination of  346 Noxious metabolites, removal of, for mitochondrial diseases  1138 NPHS1 gene, mutations in  e2746 NRXN1 disorders  247, e592 Nuchal rigidity  883–884 Nuclear chain fibers  27 Nuclear DNA  e841t Nuclear membrane proteins  1034–1035, e2307 Nucleotide polymorphisms, single  259–262 Nucleotide variants, single  259–262 Nucleus of tractus solitarius (NTS)  e2644 Nucleus pulposus, herniation of  825, e1883 Null point  e82–e83 Nurse-run transition clinic, referral to  1274 Nutmeg  1196b sensorium changes  e2682b Nutrition assessment of, in children with neurodevelopmental disorders  474, 474t developing brain and  383–389, 384b, e942–e949 micronutrients  385–389 protein-calorie malnutrition  383–385 important during late fetal and neonatal brain development  384t neurodevelopmental disorders and  e1130–e1131 in SMA  e2370 spinal muscular atrophy and  1064 white matter injury and  166 Nutritional deficiencies, postural orthostatic tachycardia syndrome and  665 Nutritional folate deficiency  e931–e932 Nutritional management, of congenital myopathies  e2533 Nystagmus  e14, e73 caused by cerebral disease  e82 caused by visual deprivation  e82, e83t congenital motor  e82–e83 in infancy  40, 41t, e81–e83 opticokinetic  9 spontaneous  9 vision loss and  35

O

O-glycan synthesis  e1704 Obesity  1178, e2650 hypothalamic  1170–1171 monogenic  1171 Obidoxime  1195 Objective audiometry  45, 45f, e97 Objective methods, for evaluation of auditory function  45, e97–e99 Obscurin  1032 Observation  7, 8t, e11 Obsessive-compulsive disorder (OCD) tic disorders and  742 Tourette syndrome and  e1666 Obstructive sleep apnea, in neurodevelopmental disorders  476

Obtundation  769–770, e1737 Occipital horn syndrome  482t–486t Occipital horns  241, e583 Occipital sharp transients  91 Occipitofrontal circumference (OFC)  e29, e484 and hemimegalencephaly  584 Occipitotemporal region, in reading  443–444 Ochoa urofacial syndrome  1189 Octamer binding protein 4 (OCT4)  121, e295 Ocular albinism  36, e75 Ocular anomalies, causing vision loss  37–39 Ocular coloboma  36, e74, e74f–e75f Ocular compression, in pallid breathholding spells  657 Ocular dysmetria  689, e1557 Ocular motility, assessment of  34, e69–e70, e71f Ocular motor apraxia, early onset ataxia with  e1567 Oculocephalic maneuver, for neurological examination, of coma  e1746 Oculocerebrorenal syndrome of Lowe (OCRL)  754 Oculocutaneous albinism  36, e75 Oculodentodigital dysplasia  750, e1688 Oculomotor apraxia  692, e1565–e1566 Oculomotor nerve  7–9, 8f, e13–e14, e13f, e13t Oculopharyngeal muscular dystrophy (OPMD)  1119, e2504 Oculovestibular reflex  e116 Oddball paradigm  e1733 disorders of consciousness and  767 Ofatumumab, for neuromyelitis optica  765 Ofloxacin associated with Parkinsonism  e2684b toxicity  1198b Ohtahara syndrome  132, 513–514, 554–555, e312, e1198t, e1227–e1228, e1310–e1313 clinical features of  554, e1310 diagnosis of  554, e1312 differential diagnosis  554–555 differential diagnosis of  e1313 early myoclonic epilepsy versus  e1312t etiology of  554, e1310–e1312, e1311t–e1312t prognosis of  555, e1313 treatment of  555, e1313 OKT3  e2694 for organ transplantation  1201 Olanzapine  494, e1184t, e1186 Olanzapine, for tic disorders  745t Oleander  1196b sensorium changes  e2682b Olesoxime  1063, e2368 Olfaction clinical significance of, in infants and children  61b, 62t, 63–64, e135 disturbances of, conditions associated with  61b, e128b ontogeny of  62t, 63–64, e132–e135 fetus  e132 infants  e133–e134 newborns  e132–e133 young children  e134–e135 Olfactory ensheathing cells (OECs), for spinal cord injury  e1887–e1888 Olfactory nerve  7, e11–e12 Olfactory system  58–59, e124–e125, e126f Olig2, in DIPG  992

Index Oligosaccharides, lysosomal storage diseases and  e772t–e773t Oligosaccharidoses  328–330 Olivopontocerebellar atrophies (OPCAs)  695, e1570 Olivopontocerebellar atrophy 1  e1570–e1571 Omeprazole for gastroesophageal reflux  1161 sensorium changes  e2682b toxicity  1196b OnabotulinumtoxinA, for migraine  653 Oncogenes, in ependymomas  e2219t Onconeural antibodies, in paraneoplastic cerebellar degeneration  e2136 Ondansetron  652 for cyclic vomiting syndrome  1229 Onion skin facial anesthesia  823–824 Ontogeny, of focal seizures  535 OPA1, mutations in  343, e849–e850 Opacity, corneal  e73–e74, e74f OPHN gene mutation  421t Ophthalmologic manifestations mucopolysaccharidoses and  327 neuronal ceroid lipofuscinoses and  331–332 Ophthalmoplegia internal  9 intranuclear  759 lysosomal storage diseases and  e782 Opiate antagonists, autistic spectrum disorder and  e1109t–e1110t, e1111 Opiates abuse in  1198, e2689 associated with Parkinsonism  e2684b sensorium changes  e2682b toxicity  1196b, 1198b Opioid-induced toxidrome  1194 Opioids associated with Parkinsonism  e2684b for pain management  1257–1258, 1257t, e2849 sensorium changes  e2682b Opitz-Kaveggia syndrome  e504 OPMD. see Oculopharyngeal muscular dystrophy (OPMD) Oppenheim’s dystonia  e1605 see also Dystonia musculorum deformans Opsoclonus-myoclonus ataxia-like syndrome  403 Opsoclonus-myoclonus-ataxia syndrome  702, 704, 926t, 927–929, 928f, e1586–e1587, e2134–e2135, e2134f Opsoclonus myoclonus syndrome (OMS)  938–944, e2148–e2161 clinical aspects of  e2148–e2151 CNS inflammatory mediators  940, e2153 diagnostic testing of  939, e2149–e2150, e2150f differential diagnosis of  938, e2148 epidemiology of  939, e2149 etiology of  938–939, e2149 factoring clinical and neuroinflammatory severity in patient assessments  941b future directions  944 genetics of  938, e2148–e2149 immunization issues in  943–944, e2158–e2159 immunopathogenesis of  939–940, e2151–e2153, e2152f inadequate response  943 management of relapse and progression of  e2157–e2159, e2159b

1375

Opsoclonus myoclonus syndrome (OMS) (Continued) presentation and course of  938, e2148, e2149f progression, management of  943 relapse, management of  943, 943b standard of care for  939 and quality of life  e2150–e2151 supportive therapy  943 treatment of  940–943, e2153–e2157 antitumor therapy  940–941, e2154 front-loaded approach for  e2153, e2154t immunotherapy  941–943, 942t, e2154–e2157, e2156t inadequate response of  e2157 neuroinflammation and  e2154, e2155b safety monitoring and measures in  e2157 side effects/adverse events of  e2157 staggered approach for  e2153–e2154, e2154t strategies  940 supportive therapy in  e2157 tumor immunology  939–940, e2153 Optic ataxia  703, e1588 Optic atrophy  e81, e82t in children  39–40, 40t infantile Refsum disease  350 lysosomal storage diseases and  e782 neonatal adrenoleukodystrophy  350 neurologic disease associated with  40t Optic chiasm  1165 Optic disc, edema  759 Optic nerve  7, e12–e13, e13f disorders of  39–40, e80–e81 fiber layer integrity of, assessment of  34, e70, e72f Optic nerve hypoplasia  36, e75, e75f Optic nerve sheath hemorrhage  797 abusive head trauma and  e1823, e1825 differential diagnosis of  798–799 intracranial pressure and  814 Optic neuritis  39, 759–761, 761f, e80–e81, e81f, e1715, e1716f Optical coherence tomography (OCT)  759 Opticokinetic nystagmus  9, e14 Optimal drug concentration  607, e1408 “Optimal therapeutic ranges,” in antiseizure drug therapy  607 Orexin, on narcolepsy  674 Organ donation  839 Organ Procurement Organization (OPO)  e1916 Organ transplantation, drugs used in  e2694 Organic acid disorders, inherited metabolic epilepsies  594–596 Organic acidemias  279t, 292–297, e409, e409f, e410t, e659t, e671–709, e1609 beta-ketothiolase deficiency  e696 Canavan’s disease  e696–e697 diagnosis of  e671–e672 differential diagnosis of  301 dystonia associated with  711–712 glutaric aciduria type 1  e698–e699 3-hydroxyisobutyric aciduria  e699 inheritance and genetic counseling in  e672–e673 isobutyryl-CoA dehydrogenase deficiency  e699 isovaleric acidemia  e692–e693 2-methylbutyryl-CoA dehydrogenase deficiency  e699 3-methylcrotonyl-CoA carboxylase deficiency  e693

1376

Index

Organic acidemias (Continued) 3-methylglutaconic aciduria  e695–e696 methylmalonic acidemias  e691–e692 mevalonate kinase deficiency  e700 multiple carboxylase deficiency  e694–e695 5-oxoprolinuria  e699 physical findings of  e671 propionic acidemia  e688–e691 signs and symptoms of  e671 treatment of  e672 Organic acidopathies  e409–e410 Organic acids , and inborn errors of metabolism  482t–486t Organic mercury, associated with tremor  e2685b Organophosphate associated with paralysis and muscular rigidity  e2684b insecticides  1195, 1196b pesticides, causing peripheral neuropathy  1197b, e2684b sensorium changes  e2682b Orientia tsutsugamushi  e2073t–e2074t Ornithine transcarbamylase deficiency  299, 424, 482t–486t, e711–e712 Orofacial dystonia  357f Orofaciodigital I syndrome, with kidney malformation  1224t, e2764t Oromotor management, for congenital myopathies  e2533 Orphenadrine, spinal cord injury and  828 Orthography  443 Orthomyxoviruses  896b, e2054–e2055 Orthopedic follow-up, in SMA  e2370 Orthopedic management for congenital myopathies  e2533 for spinal muscular atrophy  1064 Orthopedic manifestations, mucopolysaccharidoses and  328 Orthoses, for spinal cord injury  828–829 Orthostatic intolerance  e2642 and disorders of autonomic nervous system  e2645–e2646, e2645f abnormal gastrointestinal motility and  e2646 ocular symptoms of  e2646 respiratory symptoms of  e2646 syncope and  e2645–e2646 thermoregulatory abnormalities and  e2646 urinary symptoms of  e2646 without tachycardia  e2650 Orthostatic stress-active standing and passive upright tilt  e2646 Oscillating field stimulation (OFS), for spinal cord injury  e1886 Osler, William  e1650 Osmotic demyelination  1218, e2747 Osteogenesis imperfecta  240 Osteomalacia, antiseizure drug therapy and  609 Osteomyelitis  825 Osteopenia lysosomal storage diseases and  e783 neurodevelopmental disorders and  e1133 Osteoporosis  476 neurodevelopmental disorders and  e1133 Osteosarcoma  1019, 1020f, e2284–e2285, e2284f Otitis media, and developmental language disorders  432 Otoacoustic emissions (OAEs)  45, e97 Otolaryngologic manifestations, mucopolysaccharidoses and  327

Otorrhea  787 Ototoxicity  46, 1202, e100 Outcome measures in adolescence  1292 child’s age and stage as determinant of  1292–1293 in infancy  1292 International Classification of Functioning, Disability and Health (ICF) as framework for  1290–1292, 1291f, 1291t new directions in  1293 in newborns  1292 in preschool age  1292 prioritizing  1289–1290 properties of  1289–1290 purpose of  1289–1290 in school age  1292 Outliers, in spinal muscular atrophy  1059 Outpatient abortive therapy, for migraine  e1495 Overactivity, in childhood epilepsy  636 Overgrowth syndromes  214 of megalencephaly  e501 Overheating, in sudden infant death syndrome  687, e1550 Oxaliplatin toxicity  1202 Oxcarbazepine  511, 601t–602t, e1176t, e1180, e1475 for antiseizure drug therapy in children  e1399 behavioral and cognitive effects of  639 pharmacokinetics of  604t–605t for renal disease  e2763–e2764, e2767 in renal failure  1226 β-Oxidation  1131 Oxidation-phosphorylation coupling defects  344, e850, e2565 Oxidative phosphorylation  1131 defects/disorders in  e2725 primary lactic acidosis resulting from  e410–e412, e411f–e412f Oxidative stress  e330–e331 Oxidative stress, and urea cycle disorders  301 Oximes  1195 5-Oxoprolinuria  296, e699 Oxycephaly  e568 Oxycodone, for pain management  1257t Oxygen radicals, hypoxic-ischemic encephalopathy and  807 Oxygenation, in coma  776 Oxytocin  1165

P

P-450 isoenzyme, drug interactions and  603 P protein  290–291 p-values  1279–1280 1p36 Deletion syndrome  273 “Pachygyria”  e422–e424 “Pachymeningitis”  327 Paclitaxel associated with myopathies  e2683b causing peripheral neuropathy  e2684b toxicity  1197b Paeonia spp., sensorium changes  e2682b PAG. see Periaqueductal gray (PAG) Paget’s disease  238–240 Pain  1163, 1256 cerebral palsy and  739 congenital indifference  408 headache  1258, e2851

Pain (Continued) management of  1256–1259, e2846–e2851 acetaminophen in  e2848–e2849 analgesia in  e2849–2850 aspirin in  e2848–e2849 clinical assessment of  1256, 1257b, e2847, e2847b, e2848t developmental differences in  1256, e2846–e2847 historical background of  1256, e2846 medications for  1257–1258 NSAIDs in  e2848–e2849 opioids in  e2849 physiology of  1256, e2846 procedural sedation in  e2849–e2850 sedation in  e2850 types of pain medication in  e2848– e2850, e2849t migraine  1258, e2851 neurological impairment and  1258 neuropathic  1258, e2850–e2851 significant neurologic impairment and  e2851 types of  1258, e2850–e2851 “Pain matrix”  1256 Pain syndromes, channelopathies and  e978t, e981–e982 Painful gait  32, e65 PAK3 gene mutation  421t Paleocerebellum  e1555 Palilalia  434 tics and  741 Palliative care  1259–1262, e2851–e2857, e2852b barriers to  1262, e2857 components of  1259–1262, e2852–e2857 assessment and treatment of symptoms in  e2855 bereavement  1262, e2855–e2857 communication  1260, 1260b, e2854, e2854b developmental, emotional, and spiritual concerns  1262, e2855 environment for death and dying  1260, e2855 follow-up conference  1262, e2857 healthcare decision making  1260, e2854–e2855 identifying the need  1259, e2852– e2853, e2853f levels of care  1260, e2853–e2854 persistent vegetative state  1260, e2855 support during dying  1260 symptoms, assessment and treatment of  1260–1262 transition in goals of care  1259, e2853, e2853f definitions of  1259, e2852, e2852b elements in approach to  1261f essential elements of  e2856f historical background of  1259, e2851–e2852 interdisciplinary team for  1259b for neurologic conditions  e305–e306 Palliative therapy, for mitochondrial diseases  1138 Pallid breath-holding spells  656–658 Pallid spells  e1507–e1508 Pallido-pyramidal syndrome  e1614 Pallister-Hall syndrome, with kidney malformation  1224t, e2764t Palmar grasp reflex  17, e36 Palmitoyl protein thioesterase 1 (PPT1) gene  397 Pan-encephalitis  933, e2141

Panayiotopoulos syndrome  573, 1183, e1343, e2656–e2657 PANDAS  935–936, 949, e2145, e2167 Tourette syndrome and  743 Panencephalitis, subacute sclerosing  902–903 Panhypopituitarism  1169 Panic attacks, nocturnal  670–671, 670t Pantothenate kinase-2 (PANK-2)  e1607 Pantothenate kinase-associated neurodegeneration (PKAN)  711, e1607–e1608, e1608f Papilledema  39, 228, e80, e80f, e555–e556 in brain abscess  893 intracranial pressure and  816t Paracoccidioides brasiliensis  908, e2066t Paracondylar process  e583 Paradichlorobenzene in ataxia  e2685b toxicity  1199b Paragangliomas  1178, e2651 Paragonimiasis  916, e2106–e2107 Paraldehyde  601t–602t rectal administration of  606t Paramyotonia congenita  1153t, 1154–1155, e2607t, e2608–e2610 clinical features of  1154 genetics  1154 with hyperkalemic periodic paralysis  1153t laboratory tests for  1154 pathophysiology of  1154 treatment for  1154 Paramyxoviruses  896b, 902–903, e2050–e2052 Paraneoplastic cerebellar degeneration  e2135–e2136 Paraneoplastic cerebellitis  e1586–e1587 Paraneoplastic neurologic syndromes  925– 931, 926t, e2132–e2139, e2138t associated tumors/antibodies  926t autoimmune encephalitides  931, e2137 anti-N-methyl-d-aspartate receptor encephalitis  931 limbic encephalitis  930 cancer-associated retinopathy  930, e2137 cerebellar degeneration  926t, 929–930 classical  e2133–e2135 definition of  925, e2132, e2133t diagnosis of  925–927, e2132–e2133, e2133t diagnostic criteria for  926t encephalitis in anti-N-methyl-D-aspartate receptor  e2137 limbic  e2136–e2137 history of  925, e2132 Lambert-Eaton myasthenic syndrome  926t, 927 nonclassical  e2135–e2136 opsoclonus myoclonus ataxia syndrome  926t, 927–929, 928f stiff-person syndrome  926t, 930, e2136 subacute sensory neuronopathy  929, e2135 treatment of  927, e2133 Paraparesis  1087t progressive encephalopathy and  e1037t Parasitic diseases  907–916, e2078–e2079, e2080t Parasomnias  667–670, 668f, e1523–e1526, e1524f associated with REM sleep  669, e1525 classification of  668t, e1524t

Index Parasomnias (Continued) diagnosis of  669 differential diagnosis of  668t, e1524t disorders of arousal from NREM sleep  667–669, e1523–e1525, e1524f normal variants of  670, e1525–e1526 other  669 Parasympathetic afferents  1173, e2644 Parasympathetic efferent pathways  1173, e2643 Parasympathetic function, cardiac, measurements of  e2647–e2648 Parasympathetic neurons  1173, e2643 Parechoviruses  905, e2057 Parent-completed screening instruments  e9t Parents’ evaluation of developmental status  4, e5 Parietal foramina  237, 237f, e576–e577, e576f Parinaud’s syndrome  e556 PARK2  e1614 PARK6  e1614 PARK19  e1614 Parkinsonism  707t, 713–714, e1599, e1613–e1615 antipsychotic medications and  e1182t causes of  714b, e1613b, e1615 genetic disorders causing  e1614–e1615 juvenile Parkinson disease and  714 secondary  714 tics and  741 treatment of  714, e1615 Parkinson’s disease  402, e1613–e1614 Paromomycin, for cysticercosis  1146 Parosmia  63 Paroxetine  e1168t, e1169 for ADHD  455t–457t Paroxysmal depolarization shift  e1214– e1215, e1216f Paroxysmal dyskinesias  718–723, e1606, e1627–e1635 classic phenotypes of  718–721, e1628– e1631, e1628t clinical features of  719t exertion-induced  721, e1630–e1631 generalized epilepsy and  720 genetic causes of  722f genotype-phenotype association in  721– 722, e1631–e1632, e1632f historical context of  718, e1627–e1628 hypnogenic  721, e1631 kinesigenic  719–720, e1628–e1629 nonkinesigenic  720–721, e1629–e1630 terminology in  718, e1627–e1628 treatment of  722t strategies for  e1632t Paroxysmal extreme pain disorder  e981 Paroxysmal fast activity  571–572 Paroxysmal hemicrania  e1491 Paroxysmal kinesigenic dyskinesia (PKD)  514 Paroxysmal sympathetic hyperactivity  785, 810, e1772–e1773 hypoxic-ischemic encephalopathy and  e1848 Paroxysmal tonic upgaze of infancy  725–726, e1637–e1638 Parry-Romberg syndrome  370, e904, e904f Partial laminin α2 deficiency  e2493 Partial trisomy 10S syndrome, with kidney malformation  1224t, e2764t Participation and Environment Measure for Children and Youth (PEM-CY)  1290–1291

1377

Pase v Hanson  1283, 1284t, e2893 Passive stimulation paradigms  e1732 disorders of consciousness and  767 Patau syndrome. see Trisomy 13 Patent foramen ovale (PFO)  852 Patient engagement, genomics application to personalized medicine  1246–1247 Patient intervention comparison outcome (PICO) format  1290 Patient-reported outcomes (PROs)  1293, e2906 PatientsLikeMe  1295, e2908 Pauciarticular juvenile idiopathic arthritis  e2165 PC1 gene, mutation in  1167 PCBD deficiency  482t–486t PCDH19, gene mutations in, and infantile onset epilepsies  558t–560t PDGFRA, expression in DIPG  993 Peak torque strength  1048 Pearson syndrome  344, e851 Pediatric acute onset neuropsychiatric syndrome (PANS)  935–936, e1668, e2145 Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. see PANDAS Pediatric Cerebral Performance Category Scale  777, e1753 Pediatric Coma Scale  772, 772t, e1741, e1741t Pediatric Evaluation of Disabilities Inventory  778, e1753–e1754 Pediatric Evaluation of Disability Inventorycomputer adaptive tests (PEDI-CAT)  1292 Mobility Domain  1290–1291 Pediatric Imaging, Neurocognition and Genetics (PING)  e270 Pediatric population epilepsy surgery in  e1417–e1435 goals of  e1431 historical background of  e1418 indications for  e1418–e1420 invasive intracranial electroencephalography monitoring in  e1429 preoperative evaluation in  e1420–e1429 types of  e1429–e1431 hearing problems in  e99–e100 Pediatric Status Epilepticus Research Group (pSERG)  e1300 Pediatrician, duties of, ethics and  1268 Peer relationships, in childhood epilepsy  640 Pelizaeus-Merzbacher disease  749f, 750 in central hypotonia  e2347 peripheral hypotonia and  1055t–1056t Pelizaeus-Merzbacher-like disease  749f, 750, e1685f, e1686 Pellagra  e922 Pelvic girdle myopathy  e2751 Pendred syndrome  48, e103 Penetrating trauma  e359–e360 D-Penicillamine associated with myopathies  e2683b associated with paralysis and muscular rigidity  e2684b in myasthenia gravis  1103b toxicity  1197b–1198b Penicillamine, Wilson’s disease  e2799 Penicillin for actinomycosis  908 associated with myopathies  e2683b in myasthenia gravis  1103b

1378

Index

Penicillin (Continued) for syphilis  e2022 toxicity  1197b for Whipple’s disease  e2790 Penicillin G, for syphilis  891 Penning’s pincer mechanism  823 Pennsylvania Association for Retarded Children v Pennsylvania  1284, 1284t, e2894 Pentamidine, for T. b. rhodesiense disease  e2096 Pentazocine, renal toxicity of  1225t, e2765t Pentobarbital infusion, for refractory status epilepticus  548 Pentose phosphate pathway, disorders of  e660t PEO1, mutations in  e849 Peony  1196b sensorium changes  e2682b Peptides, lysosomal storage diseases and  e772t–e773t Perampanel  511, 601t–602t, e1477 for antiseizure drug therapy in children  e1402 behavioral and cognitive effects of  640 pharmacokinetics of  604t–605t Perceiving development  413 Perforating arteries  848 Perfusion magnetic resonance imaging  83, e188–e189, e189f in high-grade glioma  982, e2228–e2229 Perfusion-weighted imaging (PWI)  83, e188 Pergolide, for tic disorders  745t Periaqueductal gray (PAG)  1186–1187, e2664–e2665, e2665f Perinatal arterial ischemic stroke (PAIS) acute symptomatic  147–151, e339–e345 clinical presentation of  e341–e342 diagnosis of, neuroimaging  e340f, e342 epidemiology of  e339, e340f investigations and treatment  e342–e345 cerebral palsy  e343–e344 cognition  e344 epilepsy  e345 executive function and attention  e344 language  e344–e345 outcome prediction  e345 psychology and mental health  e345 recurrence  e345 somatosensory  e344 visuospatial  e344 outcomes and rehabilitation of  e343 pathophysiology and potential risk factors of  e339–e341 cardiac  e341 genetics  e341 infection  e341 intrapartum  e340–e341 maternal and antepartum  e340 placental disease  e339–e340 prothrombotic  e341 in preterm infant  e341 Perinatal counseling, for avoidance of birth-associated trauma  160, e366 Perinatal intracerebral hemorrhage  154–155, e350–e352 clinical presentation and diagnosis of  154, 154f definitions and epidemiology of  154 management of  155 outcomes of  155 pathophysiology and risk factors of  154 Perinatal metabolic encephalopathies  171–177, 172b, e401–e421

Perinatal stroke  104, e269 definition of  147, e339 evaluation of  e353t levels of evidence-based knowledge in  e352t–e353t terminology of  e339 Perinatal trauma extracranial injury  156–157 intracranial hemorrhage  157, 158f by location  156–159 peripheral nerve injuries  157–159, 159t Perineurium  e2409 Periodic discharges, in EEG  e236, e236f Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA)  947, e2166 Periodic fever syndromes  946–948, e2165–e2166 chronic infantile neurologic cutaneous and articular syndrome (CINCA)  946–947 CINCA in  e2165 familial Mediterranean fever  947, e2166 hyper-IgG syndrome  948, e2166 neonatal-onset multisystem inflammatory disease (NOMID)  946–947, e2165 periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)  947, e2166 Periodic leg movements of sleep  716, e1617 Periodic limb movement disorder (PLMD), diagnostic criteria for  681b Periodic limb movements of sleep  667 Periodic paralyses  1152–1156, 1153t, e2606–e2613, e2607t Andersen-Tawil syndrome  1155–1156 calcium channel  1153t with cardiac arrhythmia  e2610–e2612, e2611f hyperkalemic  1153–1154, e2607t, e2608 hypokalemic  1153t, 1154, e2607t, e2609 paramyotonia congenita  1154–1155, e2607t, e2608–e2610 potassium channel  1153t sodium channel  1153t with thyroid disease  1153t thyrotoxic  1156, e2612–e2613 Periorbital ecchymosis  782, 799 Peripheral electrical stimulation, for arterial ischemic stroke  e1946 Peripheral hypotonia  1054–1056, 1055t– 1056t, e2344–e2345 central and  e2342t common causes of, distinguishing features of  e2346t specific causes of  e2348–e2351 anterior horn cell disease as  e2348 myotonic dystrophy as  e2348 Peripheral nerve disorders of  1045t–1046t embryology and development of  1030, e2300–e2301, e2300f general anatomy and structure of  1035, e2308–e2309, e2308f–e2309f neural control of movement  1035–1037 Peripheral nerve injuries  157–159, 159t Peripheral nerve tumors  1014, e2278 Peripheral nervous system anatomy of  e2409, e2410f involvement, in SLE  950 systemic lupus erythematosus in  e2170 Peripheral nervous system impairment  e2295 in neurologic sequelae  1026 Peripheral neuromuscular injury  e2722

Peripheral neuropathies  926t, e2348–e2349 Charcot-Marie-Tooth (CMT) disease  1073 distal hereditary motor neuropathies (dHMNs)  1077, 1078t genetic  1073–1080 hereditary sensory neuropathies (HSNs)  1077 inflammatory bowel disease  e2785 with inherited metabolic disease  1077– 1078, 1079t lysosomal storage diseases and  e782 Peripheral polyneuropathy, uremic  1219 Perisylvian polymicrogyria  223, e530f–e531f, e532–e533 and developmental language disorders  432 Periventricular leukomalacia (PVL)  165 Periventricular nodular heterotopia (PNH)  221, e526, e528f–e529f FLNA-associated  e527 prenatal diagnosis of  252, e604–e606, e605f unilateral  e527 Periventricular venous infarction (PVI)  151– 152, 152f, e347–e348, e347f–e348f Peroxisomal α-methylacyl-CoA racemase defect  e870 Peroxisomal biogenesis disorders  131, e311 Peroxisomal diseases  e1387 inherited metabolic epilepsies and  598 Peroxisomal disorders  177, 279t, 347–354, 348b, e419, e659t, e858–e874, e859b central hypotonia and  1055t, e2347 classification of  347, e861 clinical and pathologic features of  e863–e866 defective peroxisome biogenesis  347–348 infantile Refsum disease  349–350 neonatal adrenoleukodystrophy  349–350 rhizomelic chondrodysplasia punctata  347, 348f defects of single peroxisomal enzymes  e866–e871 diagnostic biochemical plasma profile of  e865t diagnostic evaluation of  348f, e861f historical overview of  e858–e861, e859f and infantile onset epilepsies  560t–562t molecular etiology of  348–349, e862 peroxisome biogenesis, conditions resulting from  e862, e862t secondary leukoencephalopathies to inborn errors of metabolism excluding classical lysosomal and  758 Zellweger spectrum disorders  349–350, e862–e863 Peroxisomal enzyme 3-ketoacyl-coenzyme A (CoA) thiolase  347 single, defects of  350–354 Peroxisomal fatty-acid β-oxidation, single enzyme deficiencies of  e1694 Peroxisomal fatty acid oxidation  e859f, e860 Peroxisome biogenesis disorders  753, 1083, e1692f, e1693–e1694, e2416 Peroxisome proliferators activated receptor (PPAR) agonists, for fatty acid oxidation disorders  e2563 Peroxisomes and inborn errors of metabolism  482t–486t metabolic function of  347, e859–e860 plasmalogen synthesis  350 structure and function of  347, e858–e859

Perrault syndrome  341, e847 Persistent posttraumatic headache  655 Person-centered medicine and outcome research (PCOR)  1293 Personality change, intracranial pressure and  816t Personhood, in ethical problems  e2865–e2866 Persons with Disabilities Act  1287 Pertussis vaccines acellular  921, e2127 whole-cell  e2125 Pesticides  1198b associated with paralysis and muscular rigidity  e2684b Peters plus syndrome  e752t–e760t Petit mal seizures  525–526 Peyote  1196b, 1199b–1200b associated with tremor  e2685b in ataxia  e2685b sensorium changes  e2682b Pfeiffer syndrome  235 PGE2, cerebrovascular system and  845 Phakomatoses  362–372, 427, e887–e916, e888b clinical features of  e888t epidermal nevus syndrome  370, e903–e904 hypomelanosis  371 incontinentia pigmenti  371, e905–e906 incontinentia pigmenti achromians  371 Klippel-Trénaunay-Weber syndrome  370– 371, e905 Maffucci syndrome  370, e902–e903 neurocutaneous melanosis  370, e904–e905 neurofibromatoses  e887–e894 Parry-Romberg syndrome  370, e904 Sturge-Weber syndrome  e900–e902 tuberous sclerosis complex  364–368, e894–e898 diagnostic criteria for  365b von Hippel-Lindau disease  e898–e900 Wyburn-Mason syndrome  371, e906 Phantosmia  63 Pharmacogenetics  e2824–e2825 for epilepsy treatment  581–582 in pediatric neurology  1245, 1246t polymorphisms important in pediatric neurology  e2825t in treatment of epilepsy  e1360–e1361 Pharmacologic approaches, for mitochondrial diseases  1139 Pharyngeal-cervical-branchial variant (PCB)  1087t Phase I reactions, pharmacogenetics  1245 Phase II reactions, pharmacogenetics  1245 Phase III reactions, pharmacogenetics  1245 Phasic tone  27–28, e54 Phelan-McDermid syndrome  479t, e653 treatment of  e1138t Phencyclidine palmitate (PCP) associated with myopathies  e2683b in ataxia  e2685b toxicity  1197b, 1199, 1199b Phenelzine, for ADHD  455t–457t Phenobarbital  511, 601t–602t, e1475 adverse effects of  608 behavioral and cognitive effects of  639 for benign neonatal seizures  553 pharmacokinetics of  604t–605t rectal administration of  606t for status epilepticus  545 for tonic-clonic seizures  525

Index Phenol, for spasticity  1252 Phenothiazines, for cyclic vomiting syndrome  1229 Phenotypic pleiotropy  722 Phenoxybenzamine  e2755b Phenylalanine  286 loading test  356–357 Phenylalanine hydroxylase activity regulation of  287f, e673f Phenylbutyrate  e2367 Phenylketonuria  286–287, 355, 424, 482t–486t, e673–e677, e673f additional and novel therapies in  e677 classification of  e674 clinical manifestations of  e674 diagnosis of  e674–e675 genetic counseling for  e676 genetics of  e675 genotype-phenotype correlations of  e675–e676 maternal, neuroteratology  1203t maternal phenylketonuria syndrome  e674 pathogenesis of  e675 treatment of  e676–e677 untreated, and infantile onset epilepsies  560t–562t Phenyllactic acid  286 Phenylpyruvic acid  286 Phenytoin  511, e1475, e2825t adverse effects of  609 for antiseizure drug therapy in children  e1400–e1401, e1401f behavioral and cognitive effects of  639 causing peripheral neuropathy  e2684b in myasthenia gravis  1103b pharmacogenetics  1246t pharmacokinetics of  604t–605t protein binding  603 for renal disease  e2764–e2767 in renal failure  1225 for status epilepticus  547 toxicity  1197b Phenytoin acid, suspension  601t–602t Phenytoin syndrome  1203 Pheochromocytomas  368, 1178, e2651 PHGDH deficiency  482t–486t Phonemes  433b, 443, e1054b Phonic (vocal) tics  741 Phonologic deficit, in adolescence and adult life  445 Phonological processing, dyslexia and  442, 445, e1072 Phonological programming disorder  434, e1055 Phonological syntactic syndrome  434–435, e1055 Phonology  433b, 444, e1054b Phorias  8 Phosphatase and tensin homolog on chromosome ten (Pten)  e500 related disorders of  e502 Phosphate, inorganic (Pi)  1131 Phosphofructokinase  301 deficiency  e2545 genes encoding  1132–1133 Phosphoglucomutase  305 deficiency  314–315, e728t, e741 Phosphoglycerate kinase deficiency  1132b genes encoding  1132–1133 Phosphoglycerate kinase deficiency  315, e2545–e2546 Phosphoglycerate mutase deficiency  315, 1132b, e2546 genes encoding  1132–1133

1379

Phosphohexose isomerase deficiency  314, e728t, e740–e741 Phospholipase in brain injury  806 release of free fatty acids  806 Phosphorylase activation sequence of  313f deficiency  e2543–e2544 genes encoding  1132–1133 Phosphorylase b kinase deficiency  1132b, e2542–e2543 Photic stimulation  89, 90f, e221, e222f, e225f Photoparoxysmal response, in generalized tonic-clonic seizures  524, 527f Photophobia, in pediatric autonomic disorders  1175 Photosensitive epilepsy, and generalized tonic-clonic seizures  524 PHOX2B gene, mutation in  1182 Phrenic nerve injury  159, e365 Physical disabilities, health outcome measures for  e2903t Physical examination  7–13 cranial nerve examination  7–10 deep tendon reflexes  10–12 in epilepsy surgery  614 other reflexes  12 sensory system  12–13 skeletal muscles  10, 11f–12f, 11t–12t Physical therapy, for congenital myopathies  e2533 Physical therapy, for spinal cord injury  828 Physician, duties of, and ethics  1267–1268 Physiologic tremor  e1612 Physostigmine, in coma  776 Phytanic acid, age-related increase  350 Phytanoyl-CoA hydroxylase  347 Phytohemagglutinin-stimulated peripheral blood  268 Picornaviruses  896b, e2043–e2045 clinical features of  e2032f, e2036f, e2043–e2044 diagnosis of  e2044, e2044f treatment and outcome of  e2044–e2045 PIK3CA, gene mutation in, and megalencephaly capillary malformation syndrome  587 Pilocytic astrocytoma  985–986, e2236 Pilomyxoid astrocytoma  986, e2236 Pimozide  e1181t, e1183–e1184 tic disorders and  745t Pineal germinoma, symptoms of  1001 Pineal tumors  971–972, e2211–e2214 outcomes  972 pineoblastoma  971–972, 972f pineocytomas  971–972, 971f treatment and outcomes in  e2214 treatment of  972 types of  e2213–e2214 pineoblastomas  e2213–e2214, e2214f pineocytomas  e2213, e2213f Pineoblastomas  971–972, 972f, e2213– e2214, e2214f Pineocytomas  971–972, 971f, e2213, e2213f “Ping-pong” fractures  157 “Pink disease”  1197 Pipecolic acid oxidase  e861 Piperazine associated with myoclonus  e2685b associated with tremor  e2685b toxicity  1199b–1200b Piracetam, for breath-holding spells  658–659, e1508–e1509

1380

Index

PIT-1 gene, mutation in  1170 Pitt-Hopkins syndrome  245, 1182, e590 Pituitary adenoma and hypogonadotropic hypogonadism  e2631 transsphenoidal resection of  e2632 Pituitary gland  e2627 adenohypophysis in  1165 anatomic and physiologic aspects of  1165, e2627–e2628, e2628f development of  1165 disorders of. see Hypothalamic/pituitary disorders neurohypophysis in  1165 organogenesis of  e2627 Pivotal Response Treatment (PRT)  469, e1114 PLA2G6-associated neurodegeneration (PLAN)  e1608 Placental disease, perinatal arterial ischemic stroke and  e339–e340 Placing reflex  17, e36 Plagiocephaly  e568 deformational  233–236, 234f, e567–e574 Plasma catecholamines  e2647 Plasma concentrations, of carnitine  e2549 Plasma exchange for CIDP  1090, e2436 for GBS  1178 Plasmalogen synthesis  e861 single-enzyme defects of  e870 Plasmapheresis for juvenile myasthenia gravis  e2464 for myasthenia gravis  1103 for opsoclonus myoclonus syndrome  943, e2157 Plasmodium spp. P. falciparum  912 P. knowlesi  912 P. malariae  912 P. vivax  912 Plasticity  511, e2830 brain  e988 of nervous system  1248–1249 Platinum agents  e2695 Platinum agents, toxicity  1202 Play audiometry  e95–e96 Plectin  1034 deficiency, congenital myasthenic syndrome and  1095, e2446 Pleiotropy, and developmental language disorders  432 Pleocytosis, in neuromyelitis optica  765 Pleomorphic xanthoastrocytoma  986, e2236–e2237 Plexiform neuroma  363 Plexopathies  e2722–e2723 PMC. see Pontine micturition center (PMC) PMM2-CDG (Ia)  319–320, e751, e752t–e760t PMP22 gene, mutations in  1074–1075 PNES. see Psychogenic nonepileptic seizure (PNES) Pneumococcal conjugated vaccines  922, e2127–e2128 PNKD mutation  e1630 Podophyllum  1197b, 1199b in ataxia  e2685b causing peripheral neuropathy  e2684b Point mutations mtDNA  e2560 in protein coding genes  e851

Poison hemlock associated with paralysis and muscular rigidity  e2684b in ataxia  e2685b sensorium changes  e2682b Poisoning  1193–1204, e2679–e2712 adverse drug reactions in  e2696–e2699 drug administration, technique of  e2696–e2697 drug interactions  e2697 method of preparation  e2696 neuroteratology  e2697–e2699, e2698t pharmacogenetic susceptibility  e2697 ancillary testing  1193 drugs of abuse in  1198–1204, e2689–e2696 amphetamines  e2690 antibiotics  1201–1202, e2694 antineoplastic drugs  1202, e2695–e2696 antiviral agents  e2694–e2695 baclofen  e2691 barbiturates  e2691 benzodiazepines  e2691 cannabis  e2689–e2690 cocaine  e2689 ecstasy  e2691 emerging  1200, e2690 ethanol  e2691 gamma-hydroxybutyrate  e2690 hallucinogens  e2690 hydrocarbons  e2690 nitrous oxide  e2690 opiates  e2689 organ transplantation  e2694 other sedatives  e2691 steroids  e2696 drugs used in organ transplantation  1201 emergency evaluation in  1193, e2679–e2680 common toxidromes in  e2683–e2686 management of  e2680, e2680b neurologic examination in  e2681– e2683, e2682b–e2685b, e2683t testing in  e2680–e2681 environmental toxins  1194–1198 biologic toxins  1194–1195, 1195t insecticides  1195 management of  1193, 1194b neurologic examination in  1193 neuroteratology and  1202–1204, 1203t specific agents for  e2686–e2689 biologic toxins  e2686–e2687 insecticides  e2687 metals  e2688–e2689 nerve agents  e2687–e2688 poisons and environmental toxins  e2686–e2689 testing of  1193 toxidromes  1193–1194 Poisons  e2686–e2689 POLG, mutations in  e849 POLG1, gene mutations in, and infantile onset epilepsies  558t–560t POLG1 deficiency  749f POLG1 disease  596, e1383–e1384, e1384f Polio vaccines  918 inactivated  e2123 oral  921, e2126 Poliodystrophies  425 Poliovirus  1071, e2383–e2384 Polyarteritis nodosa  851, 947t, 952–953, e2176–e2178, e2177f Polyarticular juvenile idiopathic arthritis  e2164–e2165

Polydactyly, trisomy 13 and  271 Polyethylene glycol, for constipation  475 Polyfocal demyelination  759, 760f, e1715–e1716, e1718f Polyglucosan body disease  757, e1702f, e1703 Polyhydramnios  271 Polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome  587–588 Polymerase γ (POLG), mutations in  343 Polymicrogyria  222–223, 587, e529–e534 bandlike intracranial calcification with simplified gyration and  756 brain imaging of  e530f–e531f, e532, e533t clinical features of  e532–e533 epilepsy and  e533 etiology, genetics, and molecular basis  e533–e534, e535t pathology of  e529–e530, e530f patterns of  e533 prenatal diagnosis of  252–253, e606, e606f Polymyoclonus, progressive encephalopathy and  e1042t–e1043t Polymyositis  1144–1145, e2589–e2590 clinical features of  1144, e2589 overlap syndromes  1144, e2589, e2589f laboratory features of  1144–1145, e2589–e2590 muscle biopsy in  1144–1145, e2589– e2590, e2590f pathogenesis of  1145, e2590 treatment of  1145, e2590 Polymyxin B causing peripheral neuropathy  e2684b toxicity  1197b Polyneuritis cranialis (PC)  1087t Polyneuropathies, peripheral hypotonia and  1055t–1056t Polyneuropathy  e2723 progressive encephalopathy and  e1044t–e1045t Polyostotic fibrous dysplasia  e581f Polypharmacy neurodevelopmental disorders and  e1131–e1132 and seizures  475 Polyploidy  270–271, e640–e641 Polysomnography, for breath-holding spells  657 Polyuria  1171 POMC gene, mutation in  1171 Pompe disease  309–310, e730f, e732–e733, e772t–e773t, e815–e817 biochemistry of  309–310 clinical characteristics of  310 clinical laboratory tests of  310 genetics of  310 management of  310 pathology of  309 peripheral hypotonia and  1055t–1056t serum CK levels found in  1039t Pontine micturition center (PMC)  1186– 1187, e2664–e2665, e2665f Pontine tegmental cap dysplasia (PTCD)  206, e480 Pontocerebellar hypoplasia  200t–202t, 204–206, 205f, 1065–1068, 1066t– 1068t, e478, e479f utero diagnosis of  253 Poor vision, diagnostic evaluation of infants with  e76f, e77 Popliteal angle, in hypotonia  1052–1054, e2342

Porencephaly, neuroimaging of  e379, e380f Porphyria variegata  1182 Porphyrias  1182, 1233, e2656, e2790–e2791 Posaconazole for aspergillosis  909 for zygomycosis  909 Positron emission tomography (PET)  85, e192–e194 for ADHD  450, 454 for brain death determination  836 for disorders of consciousness  768, 768f in epilepsy surgery  615, e1424–e1425, e1425f for measurements of cerebral perfusion  e1912–e1913 for neural correlates of consciousness  e1733–e1734 Postanoxic myoclonus  e1617 Postcardiac-arrest brain injury  812 Postcardiac-arrest syndrome  804, e1839–e1840 Postconcussive syndromes  792, e1777, e1799–e1800 Posterior cerebral artery  848 Posterior fossa anomalies  253–254 prenatal diagnosis of  e607–e610 arachnoid cyst  253 hemorrhage  e362, e363f mutism syndrome  965 normal development of, prenatal assessment of  249–250 Posterior fossa syndrome. see Postoperative cerebellar mutism syndrome Posterior reversible encephalopathy syndrome  1022, 1023f, 1221 in central nervous system posttreatment sequelae  e2289–e2290, e2289f Posterior reversible leukoencephalopathy syndrome (PRES)  e2754–e2756 brain imaging in  e2755 clinical features of  e2754–e2755 diagnostic considerations in  e2755 management of  e2755–e2756, e2755b seizures in  e2756 Posterior spinal fusion  1159, 1159f Postexercise exhaustion  1101f Posthemorrhagic hydrocephalus (PHH)  227, e381–e382, e381f, e555 Posthemorrhagic ventricular dilation (PHVD)  161 Postictal generalized EEG suppression (PGES), in proposed mechanisms for sudden unexpected death in epilepsy  e1485 Postictal state, in generalized tonic-clonic seizures  524 Postinfectious Tourette syndrome  e2167 Postinjury seizures, in acquired brain injury  1253 Postischemic seizures  809–810 Postmenstrual age (PMA)  97 Postnatal circulation  1207–1211 in CHD  e2718–e2722 Postnatal onset microcephaly  e484 Postnatal period  e2787 brain development in  e987–e988, e988f Postneonatal epilepsy  137, e317–e318 Postoperative cerebellar mutism syndrome  1024, e2290 Poststroke epilepsy  592, e1375–e1376 early versus late  592 epidemiology of  592 natural history and treatment of  592 risk factors for  592

Index Postsynaptic congenital myasthenic syndromes  1094–1095, e2445–e2446 Posttransplant lymphoproliferative disorders (PTLDs)  1220, e2752 Posttraumatic epilepsy  590–592, 791, 796, 1253, e1373–e1375, e1374t early  591 versus late  591 epidemiology of  591 late, versus early  591 natural history and treatment of  592 occurrence of  591t risk factors for  591–592 age as  591 severity as  591 Posttraumatic neurometabolic cascade  781, 783f, e1767–e1769, e1768f Posttraumatic seizures  789–790, 795 Posttreatment encephalopathy, in central nervous system posttreatment sequelae  e2289–e2290 Posttreatment neuroendocrine effects  1026 Posttreatment neurologic sequelae, of central nervous system tumors  1021–1027, e2287–e2298, e2288f chronic leukoencephalopathy in  e2290, e2291b, e2291t, e2292f–e2293f cognitive impairment in  e2291–e2294 growth and, with neuroendocrine component  e2295 long-term survivors, mortality in  e2287 neurosensory deficits in  e2294–e2295 peripheral nervous system impairment in  e2295 posttreatment encephalopathy in  e2289–e2290 seizures in  e2288–e2289 tools in  e2287 weakness in  e2288 Posttreatment sequelae  1021 Postural orthostatic tachycardia syndrome  663–665, e1516–e1520, e1517b clinical and laboratory evaluation of  664, e1518, e1518b clinical features of  663, e1517 coexistent conditions associated with  e1518 comorbidities in  664 diagnostic evaluation of  e1519b hypovolemic and deconditioned  665 pathophysiology of  663–664, e1517–e1518 treatment of  664, 665b, e1518, e1519b Postural tachycardia syndrome (PoTS)  1174, 1177–1178, 1177f, e2646, e2650 Postural tone  27–28, e54 Posturing  775 during masturbation  e1639 Posturography, and vestibular disorders  e121 Postvaricella angiopathy  e1934–e1935, e1935f Potassium abnormalities  e2740, e2741t AKI and  1215, 1216t Potassium ATPases  1131 Potassium channel  506–507 development of  510 mutation in, and benign familial neonatal epilepsy  553 Potassium channel periodic paralysis  1153t Potassium chloride, in hypokalemic periodic paralysis  1155 Potato sensorium changes  e2682b toxicity  1196b

1381

Potential fields  e208–e209 Potocki-Lupski syndrome  275, e651 Potocki-Shaffer syndrome  e651 POU5F1  121, e295 PPAR agonists, for fatty acid oxidation (FAO) disorders  1136 PPT1  e951t–e952t, e957–e960 PQBP1 gene mutation  421t Practice guidelines, in pediatric neurology  1276–1282, 1277t, e2880–e2892 American Academy of Neurology (AAN) process in  1278–1281, 1279t, e2884–e2887 collecting and grading evidence  1279, e2884–e2886 drawing conclusions  1279–1280, e2886 panelists in  1278–1279, e2884 topics selection in  1278–1279, e2884 writing recommendations  1280–1281, e2886–e2887 development process of  1276–1278, e2881–e2883, e2883b ethics in  1281, e2889 history of  1276, e2880–e2881, e2881b, e2882t law in  1281, e2889 processes used by other groups  e2887, e2888t utilization in  1281, e2889 Practice Parameter, in neuroimaging  648–649 Prader-Willi syndrome (PWS)  246–247, 273, 274t, 479t, e592, e646–e648, e648f, e650t central hypotonia and  1055t, e2345 in disorders of excessive sleepiness  e1535 treatment of  e1138t Pragmatic language  438 Pragmatics  433b, e1054b Pralidoxime  1195 Pramipexole for restless legs syndrome  e1543 for tic disorders  745t Praxis, motor disturbances in, and ASD  465 Praziquantel for cysticercosis  915, 1146, e2104 for paragonimiasis  916 for schistosomiasis  916 for sparganosis  914 Prazosin  e2755b “Pre-Wallerian degeneration”  e342 Precocious puberty  1166 management of  1166 “Precursor”  107 Prednisolone, for infantile spasms  541t, 542 Prednisone associated with myopathies  e2683b in dermatomyositis  1143 for DMD  1109–1110 for myasthenia gravis  1101 for neuromyelitis optica  765 toxicity  1197b Predominant bulbar weakness, motor neuron diseases with  e2380–e2381 Preemie Hypothermia for Neonatal Encephalopathy study  e333 Preferential looking test (PLT)  33, e69 Prefrontal cortex (PFC)  1187–1188, 1188f, e2666, e2668f Pregabalin  511, 601t–602t, e1400 pharmacokinetics of  604t–605t Pregnancy, folate and  e932 Premature Infant Procedural Pain (PIPP) scores  e330–e331

1382

Index

Premature newborn, white matter injury of  165–170 Prematurity and ASD  461 cerebral palsy and  735, e1653 retinopathy of  35, e73 sudden infant death syndrome and  687, e1550 Prenatal assessment of brain, normal development of  e597, e599f of cortex, normal development of  e597– e600, e599t, e600f–e601f of posterior fossa, normal development of  e600–e602 Prenatal congenital myasthenic syndrome, acetylcholine receptor subunits in, mutations in  e2446 Prenatal diagnosis  249–254, e597–e612, e598f, e640, e640b abnormalities of corpus callosum  252, e603, e603f agenesis of corpus callosum  254 Arnold-Chiari  253 Blake’s pouch cyst  253, e607–e608 brainstem anomalies  254, e610 cerebellar hypoplasia  254, e609 Chiari type II  253, e607 cobblestone complex  252, e604, e605f complex cortical malformations  252, e606, e606f cortical development, malformations of  252–253, e603–e607, e604f Dandy-Walker malformation  253, e607, e608f lissencephaly type 1  252, e604, e604f–e605f mega cisterna magna  253, e607–e608 molar tooth-related syndromes  254, e609, e610f periventricular nodular heterotopia  252, e604–e606, e605f polymicrogyria  252–253, e606, e606f posterior fossa anomalies  253–254, e607–e610 rhombencephalosynapsis  e609, e610f schizencephaly  e606–e607, e607f ventriculomegaly  250, e602–e603, e602f vermis hypoplasia/agenesis  253–254, e609 Zellweger spectrum disorders  350 Prenatal period  e2787 PREPL deletion syndrome  1096, e2448 Preschool age, outcome measurement in  1292, e2905 Preschool Language Scale-4  432 Pressure palsies, hereditary neuropathy with liability to  275 Pressure reactivity index (PRx)  815 Presumed perinatal ischemic stroke (PPS)  151 Presumed perinatal stroke (PPS)  e345–e346 Presynaptic congenital myasthenic syndromes  1092–1093, e2443–e2444 Preterm infant erebral palsy and  736 general examination  22, 22t, e43, e44t head growth pattern assessment  25f, 26, e51, e52f hydrocephalus in, management of  e560 hypoxic-ischemic brain injury in  145–146 neurologic examination of  20–26, e39–53 body attitude  22, e44 cranial nerves  23–24, e46–e50

Preterm infant (Continued) deep tendon reflex assessment  22, e44, e48f, e48t developmental reflexes  24–25, 25t, e50–e51, e51f, e51t environmental interaction  22, e44 formal scale of gestational assessment  22, 23f–24f, e44, e45f–46f, e47t muscle tone  22–23, e44–e46, e49f–e51f, e49t perinatal arterial ischemic stroke (PAIS) and  e341 Pretreatment immune health, for opsoclonus myoclonus syndrome  939, e2150 Primapterinuria  356t, 357, e876t, e878 Primary acetylcholine receptor deficiency  1094, e2445 Primary angiitis of central nervous system  851–852, 874, 947t, 954, e2179–e2180, e2180f Primary biliary cirrhosis (PBC), neurologic abnormalities with  1235, e2796–e2797 Primary central nervous system tumors. see Tumors Primary central nervous systems vasculitis  e1991 Primary cilium  203 Primary erythermalgia  e981 Primary fissure  250 Primary lactic acidosis, resulting from oxidative phosphorylation defects  174, e410–e412, e411f–e412f Primary measles encephalitis  e2050 Primary microcephaly  e484 Primary monoaminergic neurotransmitter deficiency disorder  356t Primary tremor disorders  713 Primary vasculitic diseases  952–955, e2164t, e2176–e2184 antiphospholipid antibody syndrome  955, e2183–e2184 Behçet’s disease in  e2182 Churg-Strauss syndrome in  e2179 Cogan syndrome in  e2178 erythermalgia  955, e2184 erythromelalgia  955, e2184 giant cell arteritis  954–955, e2181–e2182 granulomatosis with polyangiitis in  e2179 granulomatous angiitis  953–954, e2179–e2181 Henoch-Schönlein purpura  e2178–e2179 hypersensitivity angiitis  e2179 Kawasaki disease in  e2178 leukocytoclastic vasculitis  953, e2178–e2179 miscellaneous disorders  955, e2182–2184 necrotizing sarcoid granulomatosis in  e2180–e2181 necrotizing vasculitis  952–953, e2176–e2178 polyarteritis nodosa in  e2176–e2178, e2177f primary angiitis, of central nervous system  e2179–e2180, e2180f sarcoidosis in  e2181 Takayasu’s arteritis in  e2181–e2182 temporal arteritis in  e2181 thrombotic thrombocytopenic purpura  955, e2182–e2183 Primidone  601t–602t pharmacokinetics of  604t–605t Principlism  1264–1265, e2860–e2861 PRKRA gene  e1607

Probenecid, in dermatomyositis  1143 Procainamide associated with myopathies  e2683b in myasthenia gravis  1103b toxicity  1197b Procaine, in myasthenia gravis  1103b Procarbazine causing peripheral neuropathy  e2684b toxicity  1197b Prochlorperazine  650–651 Professors of Child Neurology  1298, e2920–e2921 “Progenitor”  107 Program for the Education and Enrichment of Relational Skills (PEERS)  469, e1114–e1115 Progranulin  401, e966 Progression, CNS, OMS and  943 Progressive encephalopathies  424, e1019 in adulthood  e1046t–e1048t brain biopsy for  428 definition of  424 diagnosis of  425, 425t–426t, e1020t–e1022t diagnostic approach to  428–429 diagnostic evaluation of  426 in early childhood  e1036t–e1037t epidemiology of  424 etiology of  424–426 examination in  427 future directions for  430 history of  426–427 developmental  426–427 environmental  427 family  427 general medical  427 maternal  427 neonatal  427 in infancy  e1030t–e1035t laboratory testing for  427–428 management of  429 in middle to late childhood  e1037t–e1046t pathophysiology  424 screening diagnostic tests for  e1027t Progressive external ophthalmoplegia (adPEO), autosomal dominant  695 Progressive hepatocerebral disease  1236, e2800 Progressive myoclonus epilepsy (PME)  578, 695, e1276–e1277, e1277t, e1354, e1355f infantile  403 Progressive scoliosis  206–207, e480 Progressive/static condition  e3 Prohormone convertase  1167 Projection tracts  e260 PROK2 gene, mutations in  1166–1167 Prokineticin-2 (PROK2)  1166–1167 Prokineticin receptor-2 (PROKR2)  1166–1167 PROKR2 gene, mutations in  1166–1167 Prolactin  1165, e2368 biochemistry and physiology of  1168 normal biochemistry and physiology of  e2631–e2632 secretion disorders of  1168, e2631–e2632 clinical features and management of  1168 hyperprolactinemia, clinical features and management of  e2632 Prolactinoma  1168 and hypogonadotropic hypogonadism  e2631

Proline-rich transmembrane protein 2 gene (PRRT2)  e1629 Prominent brain malformations, relationship to disorders with  242 PROMIS  1293 Promyelocytic leukemia, acute  1018 Prone position, in manual muscle testing  1048 Prone sleep position, sudden infant death syndrome and  687 Proopiomelanocortin (POMC)  1165, 1170f PROP-1 gene mutation  1170, e2630, e2632–e2633 Propionic acidemia  292, 424, 482t–486t, e688–e691, e689f–e690f, e1382 clinical manifestations of  e688–e690 diagnosis of  e690–e691 inherited metabolic epilepsies  595 treatment of  e691 Propofol, for refractory status epilepticus  548 Propofol infusion syndrome  548 Propranolol  e2755b for migraine  652t for thyrotoxic periodic paralysis  1156 Propylthiouracil associated with myopathies  e2683b neuroteratology  1203t toxicity  1197b Prosencephalic cleavage  192, e449, e450t Prosencephalon patterning  192, 193f, e449, e450f Prosody  433b, e1054b Prostacyclin, in cerebrovascular system  845, e1924 Prostaglandin in cerebrovascular system  844, e1924 degradation  e861 Proteases, in brain injury  806 Protein C deficiency arterial ischemic stroke and  853 in genetic thrombophilia  879 Protein-calorie malnutrition  383–385, e942–e944, e943b, e943t Protein-coding genes, defects of  e2560–e2561 Protein-energy  384t Protein importation, defects of  334 Protein kinases, in brain injury  806 Protein N-glycosylation, defects of  e751–e762 Protein O-glycosylation, defects of  e762 Protein restriction, urea cycle disorders and  303, e718 Protein S deficiency, in genetic thrombophilia  879 Proteins brain-related, in OMS  940 in CSF  76–77, 77t, e157–e159, e158f, e158t inflammatory, in OMS  940 Proteinuria, lysosomal storage diseases and  e783 Proteolipid 1 (PLP1) gene  e1683 Proteus syndrome  370, e903t Prothrombin G20210A  853 Prothrombotic disorders arterial ischemic stroke and  853, e1940–e1941 sinovenous thrombosis and  860 Protocadherin 19 (PCDH19), epilepsy associated with  516

Index Proton magnetic resonance spectroscopy diseases studied with  81, e179–e183, e180f–e182f in high-grade glioma  e2228, e2229f spectral metabolites using  80–81, e178–e179, e179f Proton-pump inhibitors, for gastroesophageal reflux  474–475, 1161 Protoporphyrinogen oxidase (PPOX)  1182 Protozoal infections  910–913, e2079–e2097 amebic infections  910–912 granulomatous amebic encephalitis  910–911 malaria  912 primary amebic meningoencephalitis  910 toxoplasmosis  911 trypanosomal infections  912–913 African sleeping sickness  913 Chagas disease  912–913 Provisional tic disorder  741, e1664 Proximal myotonic myopathy. see Myotonic dystrophies Proximal renal tubular acidosis (proximal RTA)  1223, e2761–e2762, e2763b PRRT2 gene mutations  514 infantile onset epilepsies  558t–560t PSAT deficiency  482t–486t Pseudallescheria boydii  909 Pseudo-ADHD  449 Pseudo-Hurler polydystrophy  e813–e814 Pseudoataxia  705 Pseudoobstruction syndromes  1230, e2782 Pseudopapilledema  39, e80, e80f Pseudoprogression cause of encephalopathy  1023, 1023f in central nervous system posttreatment sequelae  e2289f, e2290 “PseudoTORCH” syndrome  e532 Pseudotumor cerebri. see Idiopathic intracranial hypertension Psoriatic arthritis  e2165 PSPH deficiency  482t–486t Psychiatric comorbidities, in cerebral palsy  740 Psychiatric disorders in childhood epilepsy  636–637 inborn errors of metabolism presenting with  487 PNES and  631–635 Wilson’s disease  e2799 Psychiatric symptoms, of IEMs  284 Psychogenic ataxia  e1588 Psychogenic nonepileptic seizure (PNES)  631–635, e1465–e1470 developmental  631 differential diagnosis  e1466 epilepsy and, differential diagnosis between  632 evaluation of the patient in  e1465–e1466 history of  632, e1466 multidisciplinary assessment of  632 multidisciplinary treatment model for  633–634, e1467–e1468 outcome of  e1468 outcomes of  634 patient evaluation in  631–632 psychiatric treatment for  634, e1468 psychopathology in children with  632–633, e1466–e1467 risk factors for  631–632, e1465 role of neurologist  633–634 Psychogenic syncope  663, e1516 Psychological therapy, for spinal cord injury  829

1383

Psychopathology, nonverbal learning disabilities and  e1062–e1063 Psychopharmacology, for behavior  476–477 Psychosis in antiseizure medications  638 lysosomal storage diseases and  e782 Wilson’s disease  e2798 Psychosocial stressors  416 Psychostimulant drug-induced movement disorders and  732, e1646 response to, and ADHD  449 Psychotherapy, for ADHD  452 Pten-hamartoma tumor syndrome (PHTS)  216, e502 Pten-related disorders  216 Pterin-4a-carbinolamine dehydratase deficiency  e878 Ptosis  9, 38, e14, e78 myasthenia gravis and  1098–1099, 1099f tyrosine hydroxylase deficiency and  358 PTPS deficiency  482t–486t Pubertal development disorders  1165–1168, e2628–e2631 age of onset  1166 delayed/arrested puberty  1166–1168 delayed or arrested puberty  e2630–e2631 normal physiology  1165–1166, e2628–e2631 sexual precocity  1166, e2629–e2630, e2629f Puberty  e2628 delayed or arrested  e2630–e2631 evaluation of  e2631 isolated congenital hypogonadotropic hypogonadism and  e2630 management of  e2631 Pull-to-sit test, for hypotonia  1052, e2342 Pulmonary causes, of spinal muscular atrophy  1063 Pulmonary insufficiency, in DMD and BMD  e2478 Punctate epiphyseal calcifications, lysosomal storage diseases and  e783 Punctate microhemorrhages  1210, e2720, e2720f PURA disorder  247, e592 Purdue Pegboard  68t–69t, e143t–e146t Pure articulation disorders  e1054 Purine biosynthesis defects  176, e417, e417f Purine metabolic disorders/defects  e660t epilepsies and  597–598 Pyknodysostosis  e772t–e773t Pyomyositis  1146 Pyrantel, for trichinellosis  e2099–e2100 Pyrazinamide, for tuberculous meningitis  890 Pyrethrins associated with tremor  e2685b toxicity  1200b Pyridostigmine associated with paralysis and muscular rigidity  e2684b for Lambert-Eaton myasthenic syndrome  1104 for myasthenia gravis  1100 toxicity  1198b Pyridoxal-5-phosphate, dependency disorders, epilepsies  597 Pyridoxal phosphate-dependent epileptic encephalopathies  175, e414–e415, e414f–e415f Pyridox(am)ine 5’-phosphate oxidase deficiency  375–376, e924–e937

1384

Index

Pyridoxamine phosphate oxidase, dependency disorders, epilepsies  597 Pyridoxical phosphate dependency, and infantile onset epilepsies  560t–562t Pyridoxine  388 causing peripheral neuropathy  e2684b deficiency  1218, e923 dependency, and infantile onset epilepsies  560t–562t dependency disorders, epilepsies  597 developing brain and  e947 toxicity  1197b for tuberculous meningitis  890 Pyridoxine-deficiency seizures  e2748 Pyridoxine-dependent epilepsy (PDE)  131, 375, 482t–486t, e311, e923–e924, e924t, e925f Pyridoxine-dependent epileptic encephalopathies  175, e414–e415, e414f–e415f Pyridoxine-induced polyneuropathy  1084, e2417 Pyrimethamine, for toxoplasmosis  911, 1146 Pyrimidine 5-nucleotidase superactivity  482t–486t Pyrimidine metabolic disorders/ defects  e660t epilepsies and  597–598 Pyrithioxine associated with myopathies  e2683b associated with paralysis and muscular rigidity  e2684b toxicity  1197b–1198b Pyruvate  336–337 Pyruvate dehydrogenase  288–290 deficiency  280–281, 482t–486t Pyruvate metabolism  277–278 defects of  e843–e851, e844f Pyruvate oxidation disorders  e410 6-Pyruvoyltetrahydropterin synthase deficiency  355–356, 356t, e876t, e877

Q

Q fever  909, e2076–e2077 18q minus syndrome, hypomyelinating white matter and  751 22q11 deletion, and nonverbal learning disabilities  440 22q11.2 Deletion Syndrome  273 “Quad cough”  1160 Quadriplegia, spastic  e1655 Quality of life (QOL)  1291, e1659–e1660 health outcome measures for  e2904t in pediatric neuromuscular disorders  1050 in scoliosis  1160 Quetiapine  494, e1184t, e1186–e1187 for tic disorders  745t Quinapril  e2755b Quinazoline  e2368 Quinidine  515 in myasthenia gravis  1103b Quinine, neuroteratology  1203t Quinolones associated with myopathies  e2683b causing peripheral neuropathy  e2684b toxicity  1197b

R

Rabies vaccines  919 Rabies virus  899t, 903–904, e2052–e2053 clinical features of  903 diagnosis of  903 treatment and outcome of  903–904

“Raccoon eyes”  782, 787, 799 Radial nerve injury  e365 Radiation-induced meningiomas  1009, e2269–e2270 Radiation therapy for atypical teratoid/rhabdoid tumor  e2255 for CNS tumors  960–961 for ependymomas  e2221–e2222 for germinoma  e2259 for meningiomas  e2271 for pediatric low-grade glioma  e2240 for tumors  e2196–e2197, e2197t Radical surgical resection, for craniopharyngioma  1006–1007, e2266–e2267, e2266f Radiography, for hydrocephalus  e558 Radiology, in germinoma  e2258 Radionuclide imaging in brain death determination  835 for measurements of cerebral perfusion  e1910–e1911, e1911f, e1912t Radiosurgery, stereotactic  617 Radiotherapy in neurocognitive deficits  e2293 as risk factor for neurocognitive deficit  1024 Ragged-red fibers (RRF)  337, 344 Rain Man  e459–e460 Ramipril  e2755b Ramsay Hunt syndrome  695, e1569–e1570, e1617 Ranitidine, for gastroesophageal reflux  1161 Rapamycin  479–480 Rapid Evaluation of Adult Literacy in Medicine-Revised (REALM-R)  1242 Rapid-onset dystonia parkinsonism  e1607, e1631 Rapid onset obesity with hypothalamic dysfunction and autonomic dysregulation (ROHHAD), in disorders of excessive sleepiness  e1535 Rapid Pediatric Trauma Examination  784b RAPSN, mutations in  1095 Rapsyn myasthenia  1095–1096, e2447 RAS/MAP-kinase pathway, in low-grade glioma  989–990, e2240 Rash, in dermatomyositis  1141 Rasmussen encephalitis  566, 589, e1369–e1370 clinical management of  589 etiology of  589 neuroimaging of  589 neurologic features of  589 Rasmussen syndrome epilepsy surgery for  613 surgical indications for  e1419 RASopathies  216, e502 Rathke’s pouch  1165 cyst  1167 Rattlesnake venom, sensorium changes  e2682b RB pathway, in high grade glioma  980 Reactive arthritis  949, e2168 Reading, dyslexia and  e1071, e1073 Reading ability, and IQ  442 Reading disability, and ADHD  451 “Reading frame rule”  1106–1107, e2472– e2473, e2473f–e2474f Receptor, acetylcholine  405 Receptor tyrosine kinases (RTKs)  980, e2227 Receptors, development of  e1219–e1220, e1219f Reconstructive surgery, for external and middle ears malformation  e109

Rectal administration, of antiseizure drug  e1406, e1407t Rectoanal inhibitory reflex (RAIR)  1190 Rectum anatomy of  1189–1190 functional anatomy of  e2672, e2673f Recurrent abdominal pain  1229 episodic gastrointestinal disease and  e2777 neurologic mechanisms of  e2776 Recurrent excitatory circuits  508 Recurrent facial paralysis  e2412 Recurrent isolated sleep paralysis  669, e1525 Recurrent myoglobinuria  e2551 Recurrent rhabdomyolysis, metabolic disorders and  e666 Recurrent vertigo  e122 Recurvatum gait  30–31, e62 “Red flags,” for social communication development  e1103, e1103b, e1104f Red reflex, loss of  809 Reflex anoxic seizures  659, e1509 clinical features of  e1509 clinical laboratory tests in  e1509 pathophysiology of  e1509 treatment of  e1509 Reflex syncope  662, 1176–1177, 1177f, e1516, e2646, e2648–e2650, e2650f Refractory status epilepticus  e1300 Refsum disease  48, 1083, e103, e2416, e2725–e2726 adult  e865t, e870 infantile  e863–e866 Region of interest (ROI)  97–98 Reglan. see Metoclopramide Regression, in ASD  459–460 Rehabilitation  1248 in acquired brain injury  1253 acute pediatric, management  1249–1250 brain injury  e2838–e2839 behavioral disturbances  e2838 communication and cognitive deficits  e2838–e2839 postinjury seizures  e2839 comprehensive, programs  1250 criteria for admission  e2832b dependency  e2829 functional recovery  e2829–e2831 plasticity. see Plasticity reorganization of neuronal connections  e2830 resolution of temporary dysfunction  e2830 through adaptation  e2830–e2831 future directions  e2843 motor impairment  e2833–e2838 principles of  e2831, e2831b spasticity  e2833 ankle-foot orthotics  e2834, e2834f assistive equipment  e2834, e2834f baclofen, intrathecal  e2836–e2837, e2836b–e2837b neuromuscular blockade  e2836 oral medications  e2834–e2836, e2835t orthopedic surgery  e2837 selective dorsal rhizotomy  e2837, e2837b treatment of  e2833, e2833f spinal cord injury  e2841–e2843 American Spinal Injury Association Classification of Spinal Cord Injury  e2841b autonomic dysreflexia  e2842 heterotopic ossification  e2842 medical issues  e2841–e2842

Rehabilitation (Continued) neurologic examination to determine level of  e2841t pulmonary complications  e2841 rehabilitation strategies  e2842–e2843, e2842f in spinal cord injury  1254–1255, 1254t strategies, in stroke  1253–1254 treatment of motor impairment  1250–1253 Reiter syndrome  e2168 see also Reactive arthritis Relapse, CNS, OMS and  943 Relapsed medulloblastoma  e2207 Relapsing CNS inflammatory diseases  1301t Relaxation, for pediatric migraine  649 REM sleep behavior disorder  669, e1525 Remethylation defects  e928 Remote seizures  592 Renal diseases affecting kidney, and nervous system  e2756–e2763 amyloidosis  e2759–e2761, e2759b, e2760t hepatorenal syndrome  e2758–e2759 metabolic diseases, producing renal and neurologic dysfunction  e2761 nephropathic cystinosis  e2762–e2763 proximal renal tubular acidosis  e2761– e2762, e2763b selective tubular dysfunction  e2761, e2762b thrombotic thrombocytopenic purpura  e2756–e2757 vasculitic diseases, with neurologic-renal presentations  e2758 affecting nervous system  e2738–e2756 acute kidney injury  e2738–e2742 chronic kidney disease  e2742–e2746, e2742t dialysis-associated complications  e2746–e2751 hypertension  e2753–e2756 renal transplantation, complications associated with  e2751–e2752 drug-induced encephalopathy in  e2766, e2766b drug therapy for  1224–1226, e2765–e2768 kidney stones in  e2768 nervous system, affecting  1215–1221 acute kidney injury  1215–1216 amyloidosis  1222 chronic kidney disease  1216–1218 dialysis-associated complications in  1218–1219 hemolytic-uremic syndrome (HUS)  1222 hepatorenal syndrome (HRS)  1222 hypertension and  1220 kidney and  1221–1223 metabolic diseases and  1223 nephropathic cystinosis  1223 proximal renal tubular acidosis  1223 renal transplantation, complications associated with  1219–1220 selective tubular dysfunction  1223 thrombotic thrombocytopenic purpura (TTP)  1221–1222 neurologic disorders with  1215–1227, e2738–e2774 neurologic drugs  e2763–e2765, e2763b, e2765t, e2768

Index Renal diseases (Continued) neurologic drugs for, affecting nervous system and kidney  1223–1224, 1226 seizures with, treatment of  1225–1226, e2766–e2768 vasculitic diseases and  1222 Renal stones, ketogenic diets and  628 Renal transplantation, complications associated with  1219–1220, e2751–e2752 Renal tubular acidosis  e2550 Reoviruses  896b, e2049–e2050 Repetitive nerve stimulation (RNS) in autoimmune myasthenia gravis  e2457, e2457f–e2458f for myasthenia gravis  1099, 1100f–1101f Repetitive speech, in ASD  459 Repetitive transcranial magnetic stimulation  e1438 for seizure suppression  621 Replicative segregation  335 Resective surgery, for refractory status epilepticus  549t Reserpine, associated with Parkinsonism  e2684b Reserpine toxicity  1198b Residual language function  e1733 disorders of consciousness and  768 Respiratory acidosis, in drowning  808–809 Respiratory chain defects of  1132b, e2564 coenzyme Q deficiency  1132b complex I deficiency  1132b complex II deficiency  1132b complex III deficiency  1132b complex IV deficiency  1132b “direct hits”  338–340 function, enhancement of  345–346 “indirect hits”  340 Mendelian defects of  337–345 Respiratory chain, Mendelian defects of  e845–e851 “direct hits”  e845–e846 complex I  e846 complex II  e846 complex III  e846 complex IV  e846 complex V  e846 “indirect hits”  e846–e847 coenzyme Q10 defects  e846 complex I  e846 complex III  e846 complex IV  e846–e847 complex V  e847 Respiratory distress, neonatal  1160 Respiratory dysfunction, management of, in congenital myopathies  e2532 Respiratory failure, spinal muscular atrophy and  1063, e2369–e2370 Respiratory mechanism, in proposed mechanisms for sudden unexpected death in epilepsy  e1484–e1486 Respiratory sinus arrhythmia (RSA)  e2647–e2648 Responsive neurostimulation  620–621, e1437–e1438 Resting ankle foot orthoses (AFOs)  1157 Resting state and connectivity studies, disorders of consciousness and  767 Resting state functional MRI (rs-fMRI)  97–98

1385

Restless legs syndrome (RLS)  678–682, 716, e1539–e1544, e1617 coexistent conditions in  680–681, e1541–e1542, e1542b diagnosis of  678–681, 679b, e1539–e1543, e1540b differential diagnosis of  680b, e1541b exacerbating factors of  681b family history in  680, e1541 genetics of  680, e1541 iron and neuroimaging  680 iron deficiency in  680, e1541 presentation of  678, e1539 prevalence of  678, e1539 symptoms of  678, e1539 treatment of  681–682, e1542–e1543, e1542b Resuscitation hypoxic-ischemic encephalopathy and  811–812 metabolism after  808 neonatal, to prevent brain injury  124 and supportive care to prevent brain injury  e302 Resveratrol, for fatty acid oxidation disorders  e2563 RET gene, mutations in  1182 Retigabine  511, e1477 Retina, anomalies of  38, 38t, e78–e79, e79f, e79t Retinal dysplasia  36, e74–e75 Retinal hemorrhages abusive head trauma and  e1822–e1823, e1822f–e1823f, e1822t, e1825 posttraumatic  797 differential diagnosis of  798–799 terminology for  797t Retinal nerve, fiber layer integrity of, assessment of  34, e70, e72f Retinitis pigmentosa  38, e79 lysosomal storage diseases and  e782 Retinocephalic angiomatosis  371, e906 Retinoic acid  388, e431 Retinoids, neuroteratology  1203t Retinol  e917–e921 Retinopathies  926t cancer-associated  930, e2137 of prematurity  35, e73 Retinoschisis  797 Retroauricular ecchymosis  782, 787 Retroviruses  896b, 904–905, e2055–e2057 Rett, Andreas  244 Rett syndrome (RTT)  121, 242–244, 478–479, 479t, 1182, e589, e2656 history of  244 and infantile onset epilepsies  558t–560t treatment of  e1138–e1139, e1138t, e1141f variant  e1228–e1229 Revascularization, for moyamoya arteriopathy  873, e1989 Reversible posterior leukoencephalopathy syndrome (RPLS). see Posterior reversible leukoencephalopathy syndrome (PRES) Revised Conners parent rating scale  4, e5 Rey-Osterreith Complex Figure  68t–69t, e143t–e146t Reye-like syndrome  278, 950 in systemic lupus erythematosus  e2170 Reye syndrome  856, 904, 1235, e2797 EEG and  e239 RFT1-CDG (In)  e761 Rhabdoid cells  996, 996f, 999

1386

Index

Rhabdomyolysis, recurrent  283 metabolic disorders and  e666 Rhabdomyosarcoma  1020, e2285 Rhabdoviruses  896b, 903–904, e2052–e2053 RHADS (repetitive high amplitude delta waves with spikes or polyspikes)  595f Rhagades  890–891 Rheumatic disorders autoantibodies  946t classification of  946b laboratory findings in  947t neurologic manifestations of  945–956, e2162–e2191 arthritis associated with infectious agents  e2166–e2168 autoantibodies in  e2163t classification of  e2163b connective tissue disorders and  e2168–e2176 juvenile idiopathic arthritis in  e2162– e2165, e2164t periodic fever syndromes in  e2165–e2166 primary vasculitic diseases and  e2176–e2184 Rheumatic fever  e2166–e2167, e2166b acute  947t, 948–949 Jones criteria for diagnosis of  948b neurologic manifestations of  948 neuropathology of  948 other central nervous system manifestations  949 postinfectious Tourette syndrome and PANDAS  949 treatment of  948–949 neurologic manifestations of  e2166–e2167 neuropathology of  e2167 other central nervous system manifestations in  e2167 postinfectious Tourette syndrome and PANDAS in  e2167 treatment of  e2167 Rheumatologic drugs, in myasthenia gravis  1103b Rhinorrhea  787 Rhizomelic chondrodysplasia punctata  347, e865–e866, e865t, e866f Rho pathway antagonists, for spinal cord injury  e1888–e1889 Rhombencephalosynapsis (RES)  204, e477–e478, e477f prenatal diagnosis of  254, e609 Riboflavin  374, e918t–e919t, e921 deficiency  374, e921 for fatty acid oxidation disorders  1136, e2561 for headache prevention  e1501 transport, disorders of  374, e921–e924 Riboflavin-dependent enzymatic reactions  374, e921, e921t Riboflavin transporter deficiency neuronopathy  374, e922 Rich club (RC) organization  99, e259 Rickettsia spp. R. felis  e2076 R. prowazekii  e2073t–e2074t R. rickettsii  909, e2072, e2073t–e2074t R. typhi  e2073t–e2074t, e2076 Rickettsial diseases  907–916, e2072–e2078, e2073t–e2074t ehrlichiosis  e2077–e2078 Rocky Mountain spotted fever  909–910, e2072–e2076, e2075f typhus fever group  e2076–e2077

“Rieger’s syndrome”  e73–e74 Rifampicin, for tuberculous meningitis  890 “Right to left shunts”  1205 Rigid spine syndrome (RSS)  1121 congenital muscular dystrophy with  e2508 Rigidity  27, 713–714, e54, e1599 Riley Ray syndrome  e2349 Riluzole  1063, e2368 for spinal cord injury  e1886 Ring chromosomes  270–271, e630f, e638 Risk assessment  1246 Risperidone  494, e1184t, e1185–e1186 for ASD  466, 467t–468t for tic disorders  745t Rituximab for dermatomyositis  1143–1144, 1144t for multiple sclerosis  764 for neuromyelitis optica  765 in OMS  942, 942t Rizatriptan  650, 650t Rnase T2-deficient leukoencephalopathy  e1701 Robertsonian translocations  270 Robot-assisted rehabilitation, for arterial ischemic stroke  e1946 Robot-assisted therapy, for stroke  1254, e2839–e2840 Rocker-bottom foot  271 Rocky Mountain spotted fever  909–910, e2072–e2076, e2075f clinical characteristics of  e2075–e2076, e2075f management of  e2076 Rodenticides  1196b, 1199b–1200b associated with tremor  e2685b in ataxia  e2685b sensorium changes  e2682b Rogers syndrome  373, e920 Rolandic epilepsy  104, e268 and developmental language disorders  432 Romaña sign  912 Romberg maneuver  e37 Rooting reflexes  e50 in preterm infants  24 Ropinirole, for restless legs syndrome  e1543 Rostral vermal lesions  689 Rotational testing  e119–e120 Rotavirus  e2050, e2787 Rotavirus vaccines  921, e2127 Roth spots.  852 RPS6KA3 gene mutation  421t Rpx/Hesx1 gene mutations  1169, e2632–e2633 RSS. see Rigid spine syndrome (RSS) RTK1 protein family, in ependymomas  e2220 Rubella vaccines  921, e2126 Rubella virus  897, e2046–e2047, e2046f Rubeola vaccines  920–921 Rubinstein-Taybi syndrome, with kidney malformation  1224t, e2764t Rufinamide  511, 601t–602t for antiseizure drug therapy in children  e1402 for Lennox-Gastaut syndrome  572 pharmacokinetics of  604t–605t Ryanodine receptor (RYR1)  1128 Ryanodine receptor (RYR1)-related myopathies  e2530–e2532, e2531f RYR1-related myopathies  1128–1129

S

S-100B  800 S-kit, in germinoma  1001 Saber shins  890–891 Sacral agenesis  190, e443–e444, e444f Saddle nose  890–891 Saethre-Chotzen syndrome  235 Salicylates abuse in  e2692–e2693 associated with myopathies  e2683b and Reye’s syndrome  e2799 sensorium changes  e2682b toxicity  1196b–1197b, 1201 Salience Network  769, e1736 Salla disease  749f, 750 Salt and pepper syndrome  e752t–e760t Salt/sodium balance, correctable disturbances of  171, e402–405 Salty taste  e131 Salvia  1200 Sandhoff disease  107, e277, e772t–e773t, e777f, e780 Sandifer syndrome  671, 1229, e1527 Sanfilippo syndrome  482t–486t, e772t– e773t, e804–e805, e804f Sanger sequencing  260, e618–e619, e618t, e621–e622 Saposin A deficiency  754, e1695 Saposins, lysosomal storage of  393 Sappinia pedata  e2085 α-sarcoglycan mutation  1113 β-sarcoglycan mutation  1113 δ-sarcoglycan mutation  1113 γ-sarcoglycan mutation  1113 Sarcoglycanopathies  1113–1114, e2485–e2490 clinical features of  e2486f, e2488–e2489 diagnosis of  e2486f–e2487f, e2489 genetics and mutations of  e2486–e2488 pathophysiology of  e2485–e2486 treatment of  e2489–e2490 Sarcoglycans  1034, e2306 Sarcoidosis  889, 947t, 954, e2181 Sarcolemma  1032 Sarcoma  1019, e2284 Ewing’s  1019–1020 Sarcomere  1031, e2301, e2302f Sarcomeric proteins  1031–1032 Sarcotubular system  1032, e2303–e2304, e2304f Satoyoshi disease  e740–e741 SC4MOL deficiency  482t–486t SCAD deficiency  e2551–e2552 Scala media (SM)  e92 Scala tympani (ST)  e92 Scala vestibuli (SV)  e92 Scaled scores  66, e141 Scalp injuries abusive head trauma and  796 extracranial  e1815, e1816f lacerations and hematomas  787 Scalp lacerations  e1779–e1780 Scalp vertex aplasia  238, e577–e578, e578f Scaphocephaly  233, e568 Scarf sign  27, e45f–e46f in hypotonia  1052, e2342 Scedosporium spp.  909, e2066t, e2071 SCHAD deficiency  e2552 Schaffer collaterals  e1210–e1211 Schindler-Kanzaki disease  330, e812 Schinzel-Giedion syndrome, with kidney malformation  1224t, e2764t

Schistosoma spp. S. haematobium  916, e2105 S. japonicum  915, e2105 S. mansoni  916 Schistosomiasis  915–916, e2104–e2106 clinical characteristics, clinical laboratory tests and diagnosis of  e2105–e2106 epidemiology, microbiology and pathology of  e2104–e2105 management of  e2106 Schizencephaly  222–223, e529–534 brain imaging of  e532, e533t clinical features of  223, e532–e533 pathology of  e529–e530, e530f prenatal diagnosis of  253, e606–e607, e607f Schizophrenia  1233, e2789 inborn errors of metabolism presenting with  487 Wilson’s disease  e2798 School age, outcome measurement in  1292, e2905 School Education Law of 1947  1287, e2898 School Functional Assessment  778, e1754 School inclusion, in childhood epilepsy  640 Schwann cells, for spinal cord injury  e1887 Schwannomas  1010, 1013t, e2271–e2272, e2272f, e2278 clinical presentation of  1010 genetic conditions and  1010 histopathology of  1011 intracranial  1010 neuroimaging  1010–1011 treatment of  1011 Schwannomatosis  364, 1010, e893–e894, e894b diagnostic criteria for  365b SCI. see Spinal cord injury (SCI) SCIWORA (spinal cord injury without radiographic abnormality)  820, 822 Scleroderma  947t, 951, e2174–e2175 laboratory findings in  951 neurologic manifestations of  951 treatment of  951 Sclerosing panencephalitis, subacute  902– 903, e2051 Sclerosis of skull  238–240, e579–e581 SCN1A Dravet syndrome and  516 gene mutations  516, 1183, e979f and infantile onset epilepsies  558t–560t SCN2A epileptic encephalopathy associated with  514 gene mutations in, and Ohtahara syndrome  554 SCN8A, epileptic encephalopathy associated with  516 SCN11A gene, mutation in  1181 Scoliosis  1159, 1159f in BMD  e2478 in congenital myopathies  e2533 in DMD  1110, e2478 management  e2618–e2619, e2619f MRI for patient with  1013b neurodevelopmental disorders and  e1129 progressive, in children with neurologic disorders  474 of spine, evaluation of  e61 Scorpion envenomation  e2686 Scorpion fish associated with paralysis and muscular rigidity  e2684b venom  1198b

Index SCOT deficiency  482t–486t Screening for ASD  462–464 instruments for  463 gross motor function  7 Screening Tool for Autism in Two-Year-Olds (STAT)  e1103–e1104 Scrub typhus  e2076, e2077f Scurvy  e928 SDF-1α  109–110 Seckel syndrome  211, e493 Secobarbital, rectal administration of  606t Second impact syndrome  786 in traumatic brain injury  e1778, e1779f Second-line immunosuppressants, for CIDP  e2436–e2437 Second-look surgery, in germinoma  e2260–e2261 Second-wind phenomenon  1133 Secondary central nervous system vasculitis in  e1991–e1992 Secondary neurulation, disorders of  190, e443–e444 Secondary tremor disorders  713 Sedation intracranial pressure and  789 for pain management  1258, e2850 Sedative-barbiturate toxidromes  1194 Sedatives abuse in  e2691 in ataxia  e2685b toxicity  1199b SEEK questionnaire  3f, e4f Segawa disease  357, 487, e878–e879 Seizure semiology, in epilepsy surgery  613– 614, e1420–e1428 electroencephalography in  e1421 functional mapping in  e1426–e1428 magnetic resonance imaging in  e1421, e1422f–e1423f magnetic resonance spectroscopy in  e1425 magnetoencephalography in  e1425– e1426, e1426f–e1427f physical examination in  e1421 positron emission tomography in  e1424–e1425 single-photon emission computed tomography in  e1421–e1424, e1424f Seizures  1210–1211, e1197–e1201, e2721 absence  525–528, e1251–e1256 atypical  526 behavioral changes with  526 childhood absence epilepsy  408, 517, e1252 classification of  e1252t clinical features of  e1251–e1252, e1251t differential diagnosis of  526t, e1252– e1253, e1254t electroencephalographic findings of  527, 527f–528f, e1253–e1254, e1253f–e1254f etiology of  e1253 eyelid myoclonia in  e1252 initial evaluation of  527, e1253 juvenile  528 juvenile absence epilepsy  517, e1252 juvenile myoclonic epilepsy  408, e1252 myoclonic absence in  e1252 pathophysiology of  e1254–e1255, e1255f prognosis of  528, e1256 treatment of  527–528, e1256 typical  526

1387

Seizures (Continued) acute bacterial meningitis and  886 ancient disease in modern times  497 antiepileptic drugs for adverse effects of  475 withdrawal of  475 antiseizure drug mechanisms in  511 associated with brain tumors  e1376–e1377 atonic  529, e1257–e1258 electroencephalographic findings in  529 attention deficit hyperactivity disorder and  e1132 with autism  466 bacterial meningitis and  e2014 bilateral occipital calcifications with  757 categorization of  533t cellular electrophysiology of  506–509, e1210–e1218 development of ionic channels and  e1218–e1219 and epileptogenesis in developing brain  511 excitation-inhibition balance  506, e1210 glial mechanisms in  e1216–e1217 ion channels  506, 507f, e1211 membrane properties, development of  e1218–e1219 neurotransmitters, receptors, and transporters in  e1219–e1220, e1220f and regulation of ionic environment  511 structural correlates in  e1210–e1211 structural maturation of brain and seizure susceptibility  509f, 511 synaptic physiology  507–508, e1212–e1214 synchronizing mechanisms in  e1215–e1216 voltage-dependent membrane conductance in  506–507, e1211–e1212 in central nervous system posttreatment sequelae  e2288–e2289 cerebral palsy and  e1132 classification of  498t, 506, e1210, e1212f ILAE  e1198t CNS posttreatment sequelae  1021–1022 coma and  776 defined  506 delayed postanoxic myoclonic  810 diagnosis of  475, 499–500 dialysis-associated  1218 drug-resistant  475 early posttraumatic, abusive head trauma and  e1813 epidemiology of  498–499 febrile  498–499, e1240–e1246 counseling and education in  e1244–e1245 definitions of  e1240 epidemiology of  e1240 genetics in  e1243 guidelines for therapy in  e1244 initial evaluation of  e1240–e1241 pathophysiology of  e1241 preventing  e1244 recurrent  e1242 related morbidity and mortality in  e1241–e1242 and subsequent epilepsy  e1242–e1243, e1242t terminating of  e1244 treatment of  e1243–e1244

1388

Index

Seizures (Continued) focal. see Focal seizures gelastic, with hypothalamic hamartoma  535, 588–589, e1369 clinical management of  588–589 etiology of  588 neuroimaging of  588 neurologic features of  588 nonneurologic features of  588 generalized  497, 524–529 comorbidities associated with  525 medical treatment of  525 tonic-clonic  524–525 hypermotor  535 impairment of consciousness and  e1750 inborn errors of metabolism presenting with  486 increased, as adverse drug reactions  609 influenza virus vaccine and  e2124 injuries resulting from  502 intellectual disability and  e1011b intracranial hemorrhage and  865–866, e1969–e1970 juvenile-onset cerebellar ataxia with  399 in Lennox-Gastaut syndrome  e1258– e1259, e1258f, e1259b in low-grade glioma  989, e2240 management of  125–127, 126f myoclonic  528, e1256 clinical features of  528 electroencephalographic findings in  528 epilepsy syndromes with  538 and epileptic spasms  538–542 in NCL  403 neonatal  129–137, e308–e320, e318b acute symptomatic  130–131, e310–e311 acute treatment of  135, e315 benign familial  407–408 with burst suppression background  e304f caused by metabolic disturbances  e310–e311 cerebral palsy after  137, e317 cognitive outcomes after  137, e317 developmental brain abnormalities  e311 diagnosis of  132–135, e312–e315, e313f diagnostic considerations for  133–135, 134f, e314–e315, e314f–e315f effect of, on early brain development  129, e308 epidemiology of  129–130, e308–e309 epilepsy syndromes  e311–e312 etiology of  130–132, 130t, e309–e312, e310t incidence of  129–130, e308–e309, e309t mortality after  137, e317 outcomes after  136–137, e317–e318 pathophysiology of  129, e308 risk factors for  130, 130t, e309, e310t treatment of  135–136, e315–e317 in neurodevelopmental disorders  475– 476, e1131–e1132 neurophysiology of  506–512 new conceptual and practical definitions  497–498 outcome in, predication of  502–504 overview of  497–500 polypharmacy  475 postischemic  809–810 hypoxic-ischemic encephalopathy and  e1847, e1853b poststroke  e1375–e1376 posttraumatic  789–790, 795, e1373– e1375, e1374t

Seizures (Continued) prediction, outcome of  e1204–e1206, e1204t premature neonate with, neurointensive care approach to  e301–e302 progressive encephalopathy and  e1040t prophylaxis  789–790 psychogenic nonepileptic  e1465–e1470 differential diagnosis  e1466 evaluation of the patient in  e1465–e1466 history of  e1466 multidisciplinary treatment model in  e1467–e1468 outcome of  e1468 psychiatric treatment in  e1468 psychopathology in children with  e1466–e1467 risk factors of  e1465 reflex anoxic  e1509 clinical features of  e1509 clinical laboratory tests in  e1509 pathophysiology of  e1509 treatment of  e1509 semiologic classification schemes for  531–533 sinovenous thrombosis and  863, e1964 in SLE  950, e2169 suppression, repetitive transcranial magnetic stimulation for  621, e1438 susceptibility developing brain and  509–511, e1218–e1221, e1218t, e1219f in structural maturation of the brain  e1220 tonic  529, e1256, e1257f electroencephalographic findings in  529 tonic-clonic  e1247–e1251 clinical features of  e1247 comorbidities associated with  e1249 differential diagnosis of  e1247, e1248t electroencephalographic findings of  e1248–e1249, e1248f etiology of  e1249 initial evaluation of  e1249 medical treatment of  e1249–e1251 treatment of  475 associated with renal disease  1225– 1226, e2766–e2768 in attention deficit hyperactivity disorder  476 in children with cerebral palsy  476 versive  535 vertigo and  56, e122 Wilson’s disease  e2798 Selective dorsal rhizotomy  473 in spasticity  1252, e2837 patient criteria selection  e2837b Selective serotonin reuptake inhibitors (SSRIs)  491–492, e1159t, e1167–1171, e1168t for ADHD  455t–457t adverse effects of  e1169–e1171 for cataplexy  675–676 clinical applications of  e1167 drug interactions of  e1171 pharmacology of  e1167–e1169 Selective tubular dysfunction  1223, e2761, e2762b Selegiline for ADHD  455t–457t indications for  358 Selenoprotein N (SelN1)  1124t–1125t, 1129

Self-injurious behavior (SBI) autistic spectrum disorder and  465, e1107 Tourette syndrome and  e1666 Self-limited focal epilepsies of childhood  637 Sella turcica  1165 anomalies of  240, e581 Semantic pragmatic syndrome  435, e1055 Semantics  433b, e1054b Semiology, seizure, in epilepsy surgery  613–614 Senataxin (SETX)  e1602 Sengers syndrome  341, e848 Sensorimotor examination  783 Sensorineural hearing loss  e99–e100 Sensory ataxia  31, 703, e1588 clinical presentation of  e63 Sensory-evoked potentials  777 impairment of consciousness and  e1752 Sensory neuropathy, acute  e2652 Sensory system  12–13, e25–e27, e26f–e27f Sensory testing in infants  16–17, 16f in neuromuscular disorders  1049–1050, e2338 Sensory window  60 Separation anxiety, and selective serotonin reuptake inhibitors  491–492 Sepiapterin reductase deficiency  356t, 358, 482t–486t, e876t, e880 SEPN1 gene, mutations in  1121 SEPN1-related myopathies  1129, e2532 Septic shock  886, e2786 bacterial meningitis and  e2015 Septooptic dysplasia (SOD)  197, 197f, 1167, e461, e461f clinical manifestations of  197, e461 definition and subtypes of  197, e461 epidemiology of  e461 etiology of  197, e461 management of  197, e461 Septum pellucidum, absence of  e462 Serine biosynthesis defects  175–176, e414f, e417 Serine deficiency disorders, and infantile onset epilepsies  560t–562t Serine synthesis defects  750–751, e1382 in hypomyelinating white matter disorders  e1689–e1690 inherited metabolic epilepsies  596 Serotonin deficiency  355 metabolism, metabolite patterns in  e877t tic disorders and  744 Serotonin-dopamine antagonists  494, e1184–e1185, e1184t Serotonin-norepinephrine reuptake inhibitors  490t, 492, e1159t, e1171– e1172, e1171t Serotonin reuptake inhibitors (SRIs)  490t for autistic spectrum disorder  466–468, e1109t–e1110t, e1111 drug-induced movement disorders and  733, e1646–e1647 Serotonin syndrome  1194 neuroleptic malignant syndrome vs.  732 Sertraline  e1168t, e1169 for ADHD  455t–457t Serum antibodies, multiple sclerosis and  e1722 Serum ferritin  680 Serum sickness, neuropathy of  1083, e2417 Setting sun sign  964 Severe childhood autosomal-recessive muscular dystrophy (SCARMD)  1113

Severe myoclonic epilepsy in infancy (SMEI)  521, e1232 Sex chromosome aneuploidies  272 Sexual precocity  e2629–e2630, e2629f management of  e2629–e2630 SFB2 gene, mutations in  1077 SH3TC2 gene, mutations in  1077 Sharp transients, occipital  91, e225, e225f Sharp-wave complex  94–95 Shellfish associated with myoclonus  e2685b poisoning  1199b sensorium changes  e2682b toxicity  1196b SHH-associated medulloblastoma  e2201 Shifting heteroplasmy  345 mitochondrial diseases and  e852 Shigella toxin  1196b sensorium changes  e2682b Shigellosis  e2786–e2787 Shiverer (shi) mouse model  112, e287 Shock electrical  809 septic  886 spinal  823 Short bowel syndrome  1231, e2784 Short-chain L-3-hydroxyacyl CoA dehydrogenase, deficiency  1132b Short-rib polydactyly II syndrome, with kidney malformation  1224t, e2764t Short tandem repeats  259, e614t, e617–e618 Short tau inversion recovery (STIR)  79, e170 Shoulder suspension test, for hypotonia  1054, e2342 Shprintzen syndrome, nonverbal learning disabilities and  440, e1065 Shuddering attacks  528, 725, 725t, e1637 Shunt infection  884 Shunts, for hydrocephalus  e559–e560 Sialic acid storage disorders  750, e772t– e773t, e817–e818, e1685f, e1689 infantile  750 Sialidosis  e777f, e810–e811 mucolipidosis I  330 type II  e812–e813 Sickle cell disease arterial ischemic stroke and  853–854, 880, e1941 arteriopathy of  873 coagulation disorders and  e2001–e2002 Side-lying position, in manual muscle testing  1048 Side sleep position, sudden infant death syndrome and  687 Simpson-Golabi-Behmel syndrome (SGBS)  214–216, e501 type 2  e501 SimulConsult  429 Single enzyme defects  347 β-oxidation enzymes  350 Single-fiber electromyography  1041 in autoimmune myasthenia gravis  e2458, e2459f Single-gene disorders, treatment of  e1141f, e1145 Single-gene-mutation analysis  1245t, e2822t Single-guide RNA (sgRNA)  118–119 Single nucleotide polymorphism (SNP)  259–262, e614t, e618 progressive encephalopathies  428, 430 Single nucleotide variants  259–262, e614t, e618 and ASD  462

Index Single-photon emission computed tomography (SPECT)  85, e192–e194, e2794 for ADHD  450 for epilepsy surgery  e1421–e1424, e1424f for specific language impairment  431 vagus nerve stimulation and  619 Sinopulmonary infections, in ataxia-telangiectasia  694 Sinovenous circulation  858, 859f Sinovenous thrombosis  858–864, e1953–e1967 anticoagulation for  e1963–e1964 cerebral  e1953 acquired thrombophilia in  880–881 genetic thrombophilia in  881 clinical features of  860, e1955 endovascular treatment and thrombolysis for  e1964 epidemiology of  858, e1953 infection and  e1964 neuroimaging for  861–862, e1957f, e1960–e1962 catheter angiography (CA)  862 computed tomography  861, e1958f, e1961 magnetic resonance imaging (MRI)  861–862, e1960f, e1961– e1962, e1962f nonantithrombotic therapies for  e1964–e1965 outcome of  863, e1965 pathogenesis of  858–860, e1953–e1955 brain injury, mechanisms of  859–860, e1955, e1956f–e1957f intracranial venous physiology  858, e1953–e1954 sinovenous circulation  858, 859f, e1953, e1954f thrombosis, mechanisms of  858–859, e1954–e1955 risk factors for  860, e1955–e1959 acute systemic conditions in  e1957– e1959, e1958f–e1960f anemia as  e1956, e1956f chronic systemic conditions in  e1959, e1961f infection as  e1956, e1958f management of  863 prothrombotic disorders in  e1957 treatment of  862, e1963 anticoagulation therapy (ACT)  862 antithrombotic therapy  862–863 endovascular treatment and thrombolysis  862–863 nonantithrombotic  863 Sirolimus  479–480 Sitting position, in manual muscle testing  1048 Situational syncope  662, e1516 6-minute walk test distance (6MWT)  1049 Sjögren-Larsson syndrome  754, e1695–e1696 Sjögren’s syndrome  851, 947t, 952, e2175 Skeletal dysplasias  e504 Skeletal muscles  10, 11f–12f, 11t–12t, e17–e19, e18f–e23f, e18t–e21t, e23t contractile  1031–1032 contraction  1035 cross-sectional anatomy of  1031f cytoskeletal proteins  1032–1035 caveolin  1034 dysferlin  1034 dystrophin  1032–1033

1389

Skeletal muscles (Continued) dystrophin-glycoprotein complex  1033–1034 intermediate filaments  1034 merosin  1034 nuclear membrane proteins  1034–1035 sarcoglycans  1034 utrophin  1034 embryology and development of  1029– 1030, e2299–e2300, e2300f general anatomy and structure of  e2301–e2308 contractile and sarcomeric proteins in  e2301–e2303, e2302f cytoskeletal proteins  e2304–e2307, e2304f, e2305t morphology  e2301–e2308, e2302f muscle fiber types in  e2307–e2308 sarcomere  e2301, e2302f sarcotubular system in  e2303–e2304, e2304f morphology  1030–1031 muscle fiber, types of  1035 muscle proteins and human genetic disease  1033t muscle testing  10 sarcomere  1031 sarcomeric proteins  1031–1032 sarcomeric structure  1031f sarcotubular system  1032 Skeletal myopathy  282 Skin abnormalities, intellectual disability and  e1011b Skull, congenital anomalies  233–241, e567–e586 basal foramina  240, e582 basilar impression  240–241, e582–e583 cranial dermal sinus  237, e575–e576 craniosynostosis  e567–e574 craniosynostosis of  233–236 craniotabes  238, e579 deformational plagiocephaly  233–236, e567–e574 fontanels  236–237, e574–e575 foramen magnum  240, e582 parietal foramina  237, 237f, e576–e577, e576f scalp vertex aplasia  238, e577–e578, e578f sclerosis and hyperostosis  e579–e581 sclerosis/hyperostosis  238–240 sella turcica  240, e581 temporal bone  240, e581–e582 thick cranial bones  238, e579 thin cranial bones  238, e578–e579 undermineralization  e579 undermineralization of  238 wide cranial sutures  e574 Wormian bones  237–238, e577, e577f Skull fractures  157, 786, e361–e362 abusive head trauma and  796, e1815 late complications of  792 in traumatic brain injury  e1779, e1779f, e1800 Skull x-rays, for traumatic brain injury  787 SLACK channel  515 SLC2A1 gene  e1630–e1631 SLC6A3 gene, and ADHD  450 SLC6A8 gene mutation  421t SLC25A19 mutations, bilateral striatal necrosis resulting from  374, e920–e921 SLC25A22 gene mutations  514 and infantile onset epilepsies  558t–560t and Ohtahara syndrome  554 SLC26A4-related deafness  48, e103

1390

Index

SLC35A1-CDG (IIf)  e752t–e760t, e764 SLC35A2, gene mutations in, and infantile onset epilepsies  558t–560t SLC35A2-CDG  e752t–e760t, e764–e765 SLC35C1-CDG (IIc)  321, e752t–e760t, e765 SLE. see Systemic lupus erythematosus (SLE) Sleep  769–770 ADHD  452, e1083 electrical status epilepticus and  637 Sleep disorders and ADHD  451 in cerebral palsy  740 neurodevelopmental disorders and  476, e1133 posttrauma  791 Tourette syndrome and  e1667 in traumatic brain injury  e1797 Sleep disturbances and ASD  465 pediatric migraine and  649–650 Sleep-onset REM periods (SOREMPs)  673 Sleep patterns  90–92 arousal  91 electroencephalographic neonatal sleep  90–91 frequency distribution  91 infant and childhood  91 occipital sharp transients  91 of uncertain significance  91–92 vertex waves and sleep spindles  91 Sleep patterns, EEG  e223–e226 Sleep-related eating disorder  669, e1525 Sleep-related hallucinations  669, e1525 Sleep-related rhythmic movement disorder  681 Sleep spindles  91, e224, e224f Sleep starts  670 Sleep studies, for ADHD  452 Sleep talking  670 Sleep terrors  669, e1524–e1525 Sleeping sickness, African  913 Sleepwalking  667–668, e1523–e1524 Slit ventricle syndrome  230f, e561, e561f Slow-channel myasthenia  1094, e2445–e2446 Slow-wave complex  94–95 Sly syndrome  e772t–e773t, e806 SMA. see Spinal muscular atrophy (SMA) SMA-like motor neuron disorders  e2374– e2381, e2380f Small molecule disorders  e657 of inborn error of metabolism  277 inherited metabolic epilepsies and  594–598 Small pox vaccines  921 Small-world network  99, e258–e259 Smallpox, vaccines for  e2127 SMARCA4, in atypical teratoid/rhabdoid tumor  e2254 SMARCB1 gene, in atypical teratoid/ rhabdoid tumor  996–997, 997f, e2253 Smell  58–64, e124–139 clinical disorders of  59–60, e125–e128, e127b–e128b dysfunction, drugs associated with  62t Smile, examination of  1189 Smith-Lemli-Opitz syndrome  177, 280, 482t–486t, e419 in central hypotonia  1055t, e2347 Smith-Magenis syndrome  275, e651 SMN gene  1058f, 1059–1060, e2355, e2358–e2359, e2358t, e2359f molecular function of  1061, e2361–e2362 neuroprotective, stabilization agents  1063 small molecules and  1063

“SMN gene dosage analysis”  1060–1061 SMN1 gene  1057, 1058f SMN2 gene  1057, 1058f expression, agents upregulating  1062–1063 genetics of  1060, 1060f small molecules and  1062–1063 Smoking, maternal, sudden infant death syndrome and  687, e1550 Smooth muscle differentiation, in cerebrovascular system  841–842, 842f, e1921–e1922, e1922f Snake venom  1194–1195, 1198b, e2686 associated with paralysis and muscular rigidity  e2684b SNAP25B myasthenia  1093, e2444 SNARE (soluble NSF attachment protein receptor) regulators  514 Snellen acuity, for intracranial hypertension  819 Snellen chart  7 Social communication deficits in, autistic spectrum disorder and  e1094–e1096 development, red flags for  e1103, e1103b, e1104f Social Communication Questionnaire (SCQ)  e1103 Social interaction, deficits in  459 Social isolation, in childhood epilepsy  640 Social perception, nonverbal learning disabilities and  439, e1062–e1063 Social phobia, and developmental language disorders  435 Social skills training (SST), for ASD  469 Sodium ATPase  1131 Sodium benzoate, glycine encephalopathy  292 Sodium channel mutations, and febrile seizures  522 Sodium-channel myasthenia  1095, e2446 Sodium channel myotonia  e2604–e2605, e2605f acetazolamide-responsive  e2605–e2606, e2606t with periodic paralysis  e2607t Sodium channel periodic paralysis  1153t Sodium disorders  e2738–e2740 AKI and  1215 Sodium monofluoroacetate, in ataxia  e2685b Sodium oxybate for daytime sleepiness  e1533 for nocturnal sleep fragmentation  676 Sodium valproate for migraine headache  651 Soft bedding, sudden infant death syndrome and  687 Solanum spp.  1196b sensorium changes  e2682b Soluble-kit (s-kit), in germinoma  e2259 Soluble lysosomal enzyme  397 Solvents in ataxia  e2685b causing peripheral neuropathy  e2684b neuroteratology  1203t sensorium changes  e2682b toxicity  1196b–1197b, 1199b Somatic mosaicism  e614t, e625–e626 Somatosensory-evoked potentials (SSEPs)  141–142, 810, e246–e247, e246f coma and  777 hypoxic-ischemic encephalopathy and  e1849, e1850f

Somatosensory-evoked potentials (SSEPs) (Continued) spinal cord injury and  e1879 for traumatic brain injury  e1796 Somatostatin (SST)  1165 Sonic hedgehog (SHH)  193 Sonographic studies, chronology of sulcation according to  250t Sotos syndrome  214, e501 Sour taste  e130 South American blastomycosis  e2067–e2068 Southern blot  261–262, e618t, e622 SOX10-associated disorders  751, e1690–e1691 Sparganosis  914, e2101 Spasms  539–540, e1278 epileptic, with asymmetric features  535 late-onset epileptic  e1287 Spasmus nutans  725t, 726, e1638 Spastic ataxia 1, autosomal dominant  e1578–e1579 Spastic ataxia 2, autosomal recessive  e1579 Spastic ataxia 3, autosomal recessive  e1579 Spastic ataxia 4, autosomal recessive  e1579 Spastic ataxia 5, autosomal recessive  e1579 Spastic ataxia 7, autosomal dominant  e1579 Spastic ataxia Charlevoix-Saguenay type  e1579 Spastic diplegia  e1655 mimicking cerebral palsy  281 Spastic diplegic gait  30–31, e62–e63 Spastic hemiplegia  e1654–e1655 Spastic hemiplegic gait  30, e62 Spastic paraplegia  e1579 Spastic quadriplegia  e1655 Spasticity  27, 281, 472, e54 ankle-foot orthotics  e2834, e2834f assistive equipment  e2834, e2834f interventions for  472–473 botulinum toxin injections as  473 neurosurgical procedures as  473 nonpharmacologic rehabilitation strategies in  472 oral medications in  472–473 intrathecal baclofen therapy  e2836–e2837 complications  e2837b patient selection  e2836b neuromuscular blockade  e2836 oral medications  e2834–e2836, e2835t orthopedic surgery  e2837 posttraumatic  791 selective dorsal rhizotomy  e2837 patient criteria selection  e2837b treatment of  1250, e2833, e2833f Speaking, dyslexia and  e1071 Special education law, neurologic disorders and  e2893–e2899 case for  1283–1286, 1284t, e2893–e2896, e2894t case studies and  e2897 federal legislation and  e2895 history of  e2893 international  e2897–e2898 Special Education Law (SEL) of 1988  1287, e2898 Specific language impairment (SLI)  431 adolescents with  435 and anxiety disorders  435 heritability rates for  432 neuroanatomy of  431–432 neuroimaging of  431 Specific reading disability  e1068 Specific secondary headache syndrome  e1495–e1496

Spectral domain ocular coherence tomography (sd-OCT)  34 Spectral metabolites, using proton magnetic resonance spectroscopy  80–81, e178–e179, e179f Speech articulation disorders  433 Speech reception threshold (SRT)  e96–e97 Sphenoid bones  e567 Sphingolipidoses  323–327, e772t–e773t, e775–e797, e778f, e1387 Sphingolipids, lysosomal storage diseases and  e772t–e773t Sphingomyelinase deficiency  326 Spike-and-wave patterns  94 Spike discharges, associated with specific neurologic conditions  e236–e237 SPIKES method  1241, 1241b six steps of  e2815–e2816, e2815b Spina bifida  e427 risk factors for  185t, e431t Spina bifida occulta  190, e441, e442f Spinal accessory nerve  10, e16 Spinal and bulbar muscular atrophy (SBMA)  1068–1069, e2381 Spinal cord anatomy of  820, 821f, e1873–e1874, e1873f anterior horn cells in  1057 leukoencephalopathies with  757–758 Spinal cord dysfunction, in SLE  950, e2170 Spinal cord injury (SCI)  157, 820–830, 1178, 1254–1255, 1254t, e363, e1872–e1899 anatomy of  e1873–e1874 catastrophic  825–826, e1883 cervical spine and  820 clinical assessment of  820–823, e1875–e1880 electrophysiologic evaluation  822, e1879–e1880 general physical examination  820–821, e1875 history  820, e1875 laboratory studies in  e1877–e1880 lumbar puncture  823, e1880 neurologic examination  821, 821b, 822f, e1875–e1877, e1876b, e1876f radiographic evaluation  822, e1877– e1879, e1878f–e1879f clinical syndromes of  e1880–e1883 complete  e1880 epidemiology of  820, e1872–e1873 gene therapy for  e1889 incomplete  e1880 intraspinal extramedullary injuries  824– 826, e1881 cauda equina injuries  825 herniation of nucleus pulposus  825 spinal arachnoid cysts  825 spinal epidermoid tumor  825 spinal epidural abscess  825 spinal epidural hematoma  824 spinal subarachnoid hemorrhage  825 spinal subdural hematoma  824–825 intraspinal intramedullary injuries  823–824, e1880–e1883 anterior spinal cord syndrome  824 Brown-Séquard syndrome  824 central spinal cord syndrome  824 cervical cord neuropraxia  823 cervical nerve root/brachial plexus neuropraxia  823

Index Spinal cord injury (SCI) (Continued) cervicomedullary syndrome  823–824 complete spinal cord injuries  823 conus medullaris syndrome  824 incomplete spinal cord injuries  823 posterior spinal cord syndrome  824 management of  826–827, e1883–e1889 adaptive technology  828–829, e1891–e1892 completed randomized controlled clinical trials  826–827, e1884–e1885 functional electrical stimulation (FES)  828 future and concerns in  e1889 gait training  828 long-term  827–829, e1889–e1893 molecular mechanisms and therapeutic approaches for  e1886–e1888 multidisciplary needs  829 nonpharmacologic clinical trials in  e1886 pharmacologic clinical trials in  e1885–e1886 physical therapy  828, e1890–e1891 psychological therapy  829, e1892 short-term  826, e1883–e1884 spine immobilization  826–827 supportive care  826–828 surgical  829, e1892–e1893, e1893f therapeutic approaches currently undergoing human investigation in  e1888–e1889 medical issues in  1254–1255 multidisciplinary needs of child with  e1892 pathogenesis of  820, e1874–e1875, e1874f axial compression  820 forward flexion  820 prevention of  830, e1894 prognosis of  829–830, e1893–e1894 rehabilitation strategies in  1255 spine immobilization and supportive care for  e1883–e1884 supportive medical care for  e1889–e1890 supraspinal changes in  826, e1883 Spinal cord injury without radiographic abnormality (SCIWORA)  e1874, e1878 Spinal cord lipoma  189, e440, e441f Spinal cord syndrome anterior  824, e1881 posterior  824, e1881 Spinal cord tumors, intradural  1012–1016 diagnosis of  1012–1013 ependymomas of the conus-cauda region  1014 epidemiology  1012 extramedullary  1013 intramedullary  1014–1016, 1015f presentation of  1012 subtypes peripheral nerve tumors  1014 spinal meningiomas  1013–1014 tumor subtypes  1013–1014 Spinal dysraphism, occult forms of  189–190, e439–e443 dermal sinus tract  e440, e441f meningocele  e441, e442f spina bifida occulta  e441, e442f spinal cord lipoma  e440, e441f split cord malformations  e441–e443, e443f

1391

Spinal ependymoma  e2215, e2216b, e2218t genetic heterogeneity between intracranial and  974t genetics of  e2219 symptoms and signs of  974b Spinal epidural abscess  e2027 Spinal fluid examination  73–77, e150–e162 Spinal gliomas, malignant  1016 Spinal imaging  84–85, e192, e192f–e193f Spinal meningiomas  1013–1014, e2277–e2278 Spinal motor neurons, hereditary diseases affecting  e2374–e2383, e2375t–e2378t, e2379f Spinal muscular atrophy (SMA)  1057–1064, e2355–e2373, e2356f animal models in  e2365 murine  e2365, e2366f worm, fly, and fish  e2365 approaches for  1063 care of patient with  1063–1064, e2369–e2370 fatigue  e2370 gastrointestinal  e2370 nutrition  e2370 orthopedic  e2370 pulmonary  e2369–e2370 case example in  e2370–e2371 clinical characteristics of  1057–1059, 1058t, e2355–e2358, e2356t clinical trials in  1062, 1062t diagnostic tests for  1061 differential diagnosis of  1061, e2362– e2364, e2363b congenital neuropathies in  e2362 hexosaminidase A deficiency in  e2362–e2363 juvenile muscular atrophy of distal upper extremity in  e2363 non-5q spinal muscular atrophies  e2362 distal forms of  1070t epidemiology of  1057, e2355 fatigue and  1064 gastrointestinal causes of  1064 genetic diagnosis for  1060–1061 genetics of  1059–1061, e2358–e2360 genetic diagnosis  e2359–e2360, e2360f–e2361f newborn screening  e2360 SMN gene  e2358–e2359, e2358t, e2359f newborn screening for  1061 nutrition and  1064 orthopedic and  1064 other  1059 other diagnostic tests in  e2360–e2361 outliers in  1059, e2357–e2358 pathology of  1061, e2364–e2365, e2364f peripheral hypotonia and  1055t–1056t, e2348 pulmonary causes of  1063 5q, differential diagnosis of  1062b with respiratory distress (SMARD)  1065 serum CK levels found in  1039t SMN gene in  1058f, 1059–1060 SMN in, molecular function of  e2361– e2362, e2362f treatment of  1062–1063, e2365–e2369 approaches in  e2368–e2369 outcome measures in  e2366–e2367, e2366t SMN protein stabilization agents, neuroprotective  e2368

1392

Index

Spinal muscular atrophy (SMA) (Continued) therapeutics in  e2367, e2367t upregulate SMN2 gene expression and promote exon 7 inclusion, agents in  e2367–e2368 type I  1057–1059, 1058t, e2355–e2357 type II  1058t, 1059, e2357 type III  1058t, 1059, e2357 type IV  1058t X-linked  e2381 with arthrogryposis  1066t–1068t, 1069 Spinal shock  28, 823, e56 Spinal trauma  797 Spine cervical spine and  820 immobilization  826 for spinal cord injury  e1883–e1884 scoliosis of, evaluation of  e61 Spinocerebellar ataxia  409–410, 695–698, e983 autosomal recessive 1  e1567 autosomal recessive 2  e1567–e1568 autosomal recessive 3  e1568 autosomal recessive 4  e1568 autosomal recessive 5  e1568 autosomal recessive 6  e1568 autosomal recessive 7  e1568 autosomal recessive 8  e1568 autosomal recessive 9  e1568 autosomal recessive 10  e1568 autosomal recessive 11  e1568–e1569 autosomal recessive 12  e1569 autosomal recessive 13  e1569 autosomal recessive 14  e1569 autosomal recessive 15  e1569 autosomal recessive 16  e1569 autosomal recessive 17  e1569 infantile onset  344, 695, e850, e1569 type 1  e1570–e1571 type 2  e1571 type 3  e1571–e1572, e1608–e1609 type 4  e1572 type 5  e1572 type 6  e1572 type 7  e1572–e1573 type 8  e1573 type 10  e1573–e1574 type 11  e1574 type 12  e1574 type 13  e1574 type 14  e1574 type 15  e1574 type 16  e1574 type 17  e1574–e1575 type 18  e1575 type 19  e1575 type 20  e1575 type 21  e1575 type 23  e1575 type 24  e1575 type 25  e1575–e1576 type 26  e1576 type 27  e1576 type 28  e1576 type 29  e1576 type 30  e1576 type 31  e1576 type 32  e1576 type 34  e1576–e1577 type 35  e1577 type 36  e1577 type 37  e1577 type 38  e1577 type 40  e1577 X-linked  699, e1579–e1580

Spinocerebellum  e1555 Spirituality  1242, 1266–1267, e2817–e2818 in theoretical approaches to ethics  e2862–e2863 three ways of looking in  1266 Spirometra sparganum  914, e2101 Spironolactone  e2755b Split cord malformations  190, e441–e443, e443f clinical characteristics of  190, e442–e443 embryology of  190, e441–e442, e443f Spondyloenchondrodysplasia  756, e1699 Spondylolisthesis, spinal cord injury and  822 Spontaneous intracranial hypotension  818, 818t, e1866t, e1867–e1868 Spontaneous nystagmus  e14 Sporadic PEO, with RRF  e2559–e2571 Sports concussion  786, e1777–e1778 epidemiology of  786, e1777 pathophysiology of  e1777, e1778f return to play following  790, 790t, e1793, e1793t sequelae of  786, e1778 symptomatology of  786, e1778 Sports-related concussion  103–104, e267–e268 SPRED1 gene mutation  362 SPTAN1 gene mutations  515 and infantile onset epilepsies  558t–560t Squamous papillary tumors  1006, e2266 SRD5A3-CDG (Iq)  320, e752t–e760t, e761–e762 SREAT. See Steroid-responsive encephalopathy, associated with thyroid autoantibodies (SREAT) St. Louis encephalitis virus  e2047 Staggered approach, for OMS treatment  940 Standard mortality ratio (SMR)  642 Standard scores  66, e141 Standing, motor function testing  1049, e2334 Stanford-Binet Intelligence Scale  e143t– e146t, e1001t–e1004t Stanford-Binet Intelligence Scale 5  68t–69t Staphylococcus spp. coagulase-negative, in shunt infection  884 S. aureus in epidural abscess  894 in pyomyositis  1146 in shunt infection  884 Star fruit  1196b sensorium changes  e2682b Star of Bethlehem  1196b, 1198b, 1200b associated with paralysis and muscular rigidity  e2684b associated with tremor  e2685b sensorium changes  e2682b Static nuclear bag fibers  27 Statural growth disorders  1169, e2633–e2634 growth hormone deficiency  1169, e2634 growth hormone excess  1169, e2634 Status epilepticus  543–551, e304f, e1292–e1307 age dependent effects of, on brain  e1294 age-specific distribution of  e1293f autoimmune  548, e1301 benzodiazepines for  e1297–e1300 clinical presentation of  544, e1295–e1296 definitions of  543, e1294–e1295 economic burden of  e1292 EEG for  776 EEG monitoring for  e1296

Status epilepticus (Continued) epidemiology of  543, e1292 epilepsy and  642 etiology of  544, 544t, e1295, e1295t febrile  590 5-minute cut-off for  543 immune therapies for  e1301 incidence of  543 initial management of  544, e1295–e1296 laboratory testing for  e1296 in Lennox-Gastaut syndrome  571, e1340 lorazepam for  e1298–e1299 morbidity and mortality in  548–549 neonatal  549–550, 550t, e1301–e1302, e1302t nonconvulsive  550, e1302–e1303 outcome in  548–549, e1301 pathologic changes secondary to  e1294 pathophysiology of  e1292–e1294 physiologic changes with  e1294 postischemic  810 refractory  548, 549t, e1300 super-refractory  548, e1300–e1301, e1301t 30-minute cut-off for  543 treatment for  e1297–e1301, e1298f, e1298t algorithm for  546f benzodiazepines as  545–546 changes in neurotransmitter receptors and  544–545 guidelines in  545 immune therapies for  548 intravenous administration of, alternatives to  546–547 lorazepam as  546 nonbenzodiazepine AEDs as  547–548 options for  545–548 rapid, rationale for  544 recommended initial doses in  545t time elapsed from seizure onset to treatment administration in  545 time to  544, e1296–e1297 Status migrainosus  650, e1495 Stem cell niche  e277 Stem cell therapy, for spinal cord injury  e1888 Stem cell transplantation for childhood neurologic disorders  e277–e285 for neurologic disorders  107–113 Stem cells in hypoxic-ischemic brain injury  145 for mitochondrial diseases  1139 for spinal muscular atrophy  1063, e2369 Steppage gait  31–32, e63–e64 Stepping response  e51 in preterm infants  24–25 Stereotactic lesionectomy  617, e1430 Stereotactic radiofrequency thermocoagulation  617 Stereotactic radiosurgery  617 Stereotypical movements  459 Stereotypies  707t, 716, e1599, e1617 motor disturbances in, and ASD  465 Steroid-responsive encephalopathy, associated with thyroid autoantibodies (SREAT)  e2145–e2146 Steroid sparers, for opsoclonus myoclonus syndrome  942–943, e2157 Steroid-sparing immunosuppressive therapy, for inflammatory myopathies  e2588t Steroid sulphatase enzyme deficiency, X-linked ichthyosis resulting from  275

Steroids  e2696 sensorium changes  e2682b for sinovenous thrombosis  863, e1964 toxicity  1196b Stiff baby syndrome  359, e1617–e1618 Stiff knee gait  30–31, e62 Stiff-person syndrome  926t, 930, e2136 Still, George  447 Stillbirth, unexplained  271 Stimulants  e1158–e1163, e1159t abuse in  e2693 for ADHD  452–453, 455t–457t, 489, 490t, e1084–e1085, e1087t–e1089t side effects of  489 adverse effects of  e1162–e1163 autistic spectrum disorder and  e1109t– e1110t, e1111–e1112 clinical applications of  e1158–e1161 clinical management of  e1161–e1162 drug-induced movement disorders and  732 drug interactions of  e1163 for excessive daytime sleepiness  675 Parkinsonism and  e2684b pharmacology of  e1161 sensorium changes  e2682b toxicity  1196b, 1198b, 1200b, 1201 tremor and  e2685b Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE)  620 Stinger injury  823 Stonefish, causing peripheral neuropathy  e2684b Stonefish toxicity  1197b Storage disorders  424–425 of heart and nervous system  e2725–e2726 sialic acid  750 Strabismus  e71–e73 vision loss and  35 STRADA (LYK5)-related megalencephaly  587–588, e1368 Strangulation injury  809 brain swelling  e1819–e1820, e1820f cardiac arrest and  e1846 Strangulation syncope  e1516 Strategy for patient-oriented research (SPOR)  1293 Stratification, disease  e2824 Streptococcus spp. S. agalactiae, meningitis  883 S. pneumoniae, meningitis  883 Streptokinase causing peripheral neuropathy  e2684b toxicity  1197b Streptomycin, indications, Whipple’s disease  e2790 Stress  1233, e2789 management, for pediatric migraine  649 Stretching  1157 Striated muscle antibodies, in autoimmune myasthenia gravis  e2460 Striatum, tic disorders and  743–744 Stroke  112, 592, 1253–1254, e339, e2746 acquired epilepsies from  590–593 AKI and  1217–1218 arterial ischemic  848–857 burden of  848 clinical features and diagnostic delays  854 epidemiology of  848 mortality of  848 neuroimaging for  854

Index Stroke (Continued) outcomes and chronic management  856–857 pathophysiology of  848–849 risk factors for  849–854, 850t treatment for  854–856 cortical involvement in  e1376 hemorrhagic, coagulation disorders in  881–882 hypoxic ischemic brain injury and  e282 nervous system stimulation in  1254 perinatal, cerebral palsy and  735 poststroke epilepsy  e1375–e1376 recurrence  857 rehabilitation for  1253–1254, e2839–e2841 constraint induced movement therapy  1254, e2839–e2840, e2840f medications to improve stroke recovery  1254, e2840–e2841 novel rehabilitation strategies  e2839 practice-based therapies to improve nonmotor function  e2840 robot-assisted therapy  1254, e2839–e2840 stimulation of the nervous system to improves stroke recovery  e2840 sequelae  856 malignant cerebral edema  856 vascular, metabolic disorders and  e666–e667 Stroke-like lesions  278 Stroke-like migraine after radiation therapy (SMART) syndrome  1023–1024, 1023f Stroller falls, abusive head trauma and  e1824 Structural brain anomalies  37, e77 Structural disorders of cerebellum and brainstem (SDCB)  199, e466 clinical features of  199, e466, e469t genetic testing approach to  199, e466–e470 neuroimaging approach to  199, 202t, e466, e469t Strychnine  1196b, 1198b associated with paralysis and muscular rigidity  e2684b sensorium changes  e2682b Stupor  769–770, e302 Sturge-Weber syndrome (SWS)  368–370, 427, 586t, 587, e900–e902, e1366–e1368 clinical characteristics of  369, e900–e902, e901f clinical management of  587 epilepsy surgery for  613 etiology of  587 management of  369–370, e902 neuroimaging of  587 neurologic features of  587 pathology of  369, e902, e902f surgical indications for  e1419 Stuttering  434, e1054–e1055 Stuve-Wiedemann syndrome  1181, e2655 STXBP1 gene mutations and infantile onset epilepsies  558t–560t and Ohtahara syndrome  554 Subacute epileptic encephalopathies  175– 176, e413–e418 asparagine synthetase deficiency  e418 glucose transporter defects  e416–e417 glycine cleavage defects  e413–e414, e414f L-amino acid decarboxylase deficiency  e417–e418, e417f

1393

Subacute epileptic encephalopathies (Continued) Menkes’ disease  e416 purine biosynthesis defects  e417, e417f pyridoxine-dependent and pyridoxal phosphate dependent  e414–e415, e414f–e415f serine biosynthesis defects  e414f, e417 sulfite oxidase and molybdenum cofactor deficiency  e415–e416, e416f Subacute necrotizing encephalomyelopathy  596 Subacute sclerosing panencephalitis  427, 902–903 clinical features of  902 diagnosis of  902, 903f treatment and outcome of  902–903 Subacute sensory neuronopathy  929, e2135 Subaponeurotic hemorrhage  157 Subarachnoid hemorrhage  157, 785, 797 abusive head trauma and  e1817–e1818, e1825–e1826 extensive, differential diagnosis of  799 spinal  825, e1882, e1882f in traumatic brain injury  e1774, e1774f Subcortical band heterotopia (SBH)  218– 219, e512–519 brain imaging for  e514–e515, e514t, e516f–e517f clinical features of  e515 epilepsy and  e515–e517 genetic counseling of  e514t, e518t, e519 neuropathology of  e512–e514 survival of  e517 syndromes, genetics, and molecular basis  e517–e519 Subcortical cysts, megalencephalic leukoencephalopathy with  752f, 755 Subcortical infarcts, and leukoencephalopathy, cerebral autosomal dominant arteriopathy with  756 Subcortical nodular heterotopia  e526t, e529 Subcutaneous immunoglobulin (SCIg), for opsoclonus myoclonus syndrome  e2154–e2155 Subdural effusions, chronic  797 Subdural hematoma  785 abusive head trauma and  796, e1815– e1817, e1817f chronic  797 intracranial arachnoid cysts and  232 mixed-density or “hyperacute”  796–797 spinal  824–825, e1882 subacute and chronic  791 in traumatic brain injury  e1774–e1775, e1775f Subdural hemorrhage  157, 1210, e362, e2720 Subdural hygromas  797 Subgaleal hematoma  20, e39, e361, e361f abusive head trauma and  796 Subgaleal hemorrhage  157 Submersion injury. see Drowning Subpial transection, multiple  617 Substance abuse in ADHD  453 and benzodiazepines  492 Substance-induced tic disorder  742, e1665 Substrate oxidation, defects of  e2562–e2565 Substrate transport, defects of  e2562–e2565 Subtotal resection with irradiation, for craniopharyngioma  1007, e2267 Succinate dehydrogenase  337

1394

Index

Succinic semialdehyde dehydrogenase (SSADH) deficiency  176, 482t–486t, e415f, e418, e883, e1385, e1386f and infantile onset epilepsies  560t–562t Sucking reflexes  e50 in preterm infants  24 Sucralfate for gastroesophageal reflux  1161 sensorium changes  e2682b toxicity  1196b Sudden cardiac arrest  e1847 Sudden infant death syndrome (SIDS)  685– 686, 808, e1547–e1548 in apparent life-threatening event  685 bed-sharing and  687 cardiac arrest and  e1845–e1846 definition of  685, e1547–e1548 disease mechanisms contributing to  e1548–e1549 epidemiology of  686–688, e1549–e1550 genetics of  687–688 5-hydroxytryptamine system in  686 infection and  687 maternal smoking and  687 overheating and  687 pathogenesis of  686, 686f, e1548 prematurity and  687 prevention of  688, e1550–e1551, e1551b prone and side sleep position in  687 risk factors for  687, e1550 risk of  e1547 risk of death in  e1547 soft bedding and bedding accessories in  687 triple-risk model of  e1548, e1548f Sudden unexpected death in epilepsy (SUDEP)  501, 642–643, 643b and adolescent epilepsy  576 body position in  e1484 clinical risk factors for  644 definition of  e1483, e1483b discussions about, with families and patients  644, e1486 and Dravet syndrome  516 and epileptic encephalopathy associated with SCN8A  516 generalized tonic clonic seizures and  644 mechanism for  e1484–e1486 risk factors for  e1483 sleep/awake state in  e1484 Sudden unexpected infant death (SUID)  e1547–e1548 Sudomotor sympathetic function, measurements of  e2648 Suffocation syncope  e1516 Suicidal behavior, antidepressants and  e1170–e1171 Suicide, children with epilepsy and  642, 645 Sulfadiazine, for toxoplasmosis  911, 1146 Sulfasalazine myopathies and  e2683b Parkinsonism and  e2684b sensorium changes  e2682b toxicity  1196b–1198b Sulfatide lipidosis  e795–e797 Sulfide oxidase deficiency  e1383 inherited metabolic epilepsies  596 Sulfite oxidase  175 deficiency  e415–e416, e416f, e687, e1705–e1706 and infantile onset epilepsies  560t–562t Sulfonamides, in myasthenia gravis  1103b Sulfur amino acid metabolism  292, e685–e687, e685f

Sulpiride, for tic disorders  745t Sumatriptan  650t sensorium changes  e2682b toxicity  1196b Super-refractory status epilepticus  e1300–e1301 Superficial pain perception  1181 Superior longitudinal fasciculus (SLF), with specific language impairment  431 Superior olivary complex (SOC)  e93 Supernumerary marker chromosomes (SMCs)  270 Supine position, in manual muscle testing  1048 Supine-to-stand test, motor function testing  1049, e2335–e2336 Supine-to-stand time, in motor function scales  e2337 Supportive care neonatal, to prevent brain injury  124 for spinal cord injury  826–828 Suppression, nonsense  1110 Supra-threshold testing  e96–e97 Supratentorial tumors  e2195t differential diagnosis  959t Suramin, for T. b. rhodesiense disease  e2096 Surgery for germinoma  e2260–e2261 for intradural spinal cord tumors  e2279–e2281, e2280b–e2281b for medulloblastoma  964–965 for tic disorders  745 for tumors  960, e2195–e2196 Surgical intervention, for intracranial pressure  816 Surgical revascularization  852 Surgical treatment/management for spinal cord injury  829 for traumatic brain injury  789 for von Gierke’s disease  308–309 Susceptibility-weighted imaging (SWI)  83–84, e189–e190, e190f–e191f Suspected neurodevelopmental disabilities, approach to evaluation of child with  415–416 Swanson, Nolan and Pelham questionnaire (SNAP)  4, e5, e6f Sweet pea, associated with paralysis and muscular rigidity  e2684b Sweet taste  e129–e130 SWI/SNF chromatin-remodeling complex  997 Sydenham’s chorea  708–709, 935, e1600– e1601, e2145, e2166–e2167 Sylvian fissure, development of  249 Sympathetic afferents  1173, e2644 Sympathetic efferent pathways  1173, e2642–e2643 Sympathetic neurons  1173, e2642 Sympathetic skin response (SSR), for spinal cord injury  e1879 Sympathomimetics associated with tremor  e2685b sensorium changes  e2682b toxicity  1196b, 1200b Symptomatic brain involvement, in neuromyelitis optica  764 Synapse abnormal neuronal firing in  e1214–e1218, e1215f paroxysmal depolarization shift in  e1214– e1215, e1216f physiology of  507–508, e1212–e1214

Synapse (Continued) synaptic transmission in excitatory  508 inhibitory  507–508 synchronizing mechanisms in  e1215– e1216, e1216f Synaptic basal lamina associated congenital myasthenic syndromes  1093–1094, e2444–e2445 Synaptic transmission excitatory  e1214 inhibitory  e1212–e1214 Synaptotagmin-2 myasthenia  1093, e2444 Synchronized video-electroencephalographic recordings  e240 Syncope  660–663, 923, e1512, e2645–e2646 cardiovascular-mediated  660, e1512 clinical features of  660–661, e1513b convulsive  662, e1515 diagnostic evaluation of  661, e1514, e1514b drug-induced  e1516 epidemiology of  660, e1512 etiology of  660, e1512, e1513b hyperventilation  662, e1516 metabolic and drug-induced  662–663 neurocardiogenic  660, e1512 pathophysiology of  661, 661f, e1513– e1514, e1514f postural orthostatic tachycardia syndrome and  663–665 prognosis of  662 psychogenic  663 reflex  662, e1516 reflex (vasovagal)  e2646, e2648–e2650, e2650f situational  662, e1516 suffocation or strangulation  662, e1516 tilt-table testing for  661, e1514–e1515 treatment of  661–662, 662b, e1515–e1516 vaccine injection and  e2129 Syndactyly  271 Syndrome of inappropriate antidiuretic hormone secretion (SIADH)  1172, 1215, e2637–e2638, e2738 acute bacterial meningitis and  885–886 Syndromic hearing loss  47–49, 48t, e102–e104 SYNGAP1, mutations in  516 Syntax  433b, e1054b Syntaxin binding protein 1 (STXBP1)  514 Syphilis  890, e2021–e2022 clinical characteristics of  890–891 diagnosis of  891 epidemiology and pathogenesis of  890 treatment for  891 Syringomyelia  e2651 Systematic review (SR)  1276 Systemic autoimmunity, in neuromyelitis optica  765 Systemic cancer, in central nervous system  e2282–e2286 central nervous system leukemia and  e2282–e2283, e2283f Ewing’s sarcoma and  e2285 histiocytosis and  e2283–e2284 lymphoma and  e2283, e2283f neuroblastoma and  e2284 osteosarcoma and  e2284–e2285, e2284f rhabdomyosarcoma and  e2285 sarcoma and  e2284 Systemic infections  131, e310 Systemic juvenile idiopathic arthritis  e2162–e2164

Systemic lupus erythematosus (SLE)  851, 874–875, 947t, 949–951, e2168–e2174 classification of  949b, e2168b laboratory findings in  951, e2171 neuroimaging evaluation in  951, e2171–e2172, e2172f–e2174f neurologic manifestations of  950–951, e2169–e2171 cerebrovascular disease  950, e2170 chorea  950, e2169 CNS infections  950, e2170 cranial nerve, brainstem, and spinal cord dysfunction  950, e2170 drug-induced lupus syndrome  951, e2170–e2171 headache  950, e2169 hypertensive encephalopathy  950, e2170 lupus aseptic meningitis  950, e2170 myopathy  950, e2170 neuropsychiatric lupus  950, e2169 peripheral nervous system involvement  950, e2170 Reye-like syndrome  950, e2170 seizures  950, e2169 treatment of  951, e2172–e2173 neuropathology of  951, e2173–e2174 sinovenous thrombosis and  860

T

T-cell responses, multiple sclerosis and  e1722 T protein  290–291 T scores  66, e141 TAC3 gene  1167 Tachyarrhythmia  1161 Tachycardia, orthostatic intolerance without  e2650 TACR3 gene  1167 Tacrolimus  e2694, e2752 for dermatomyositis  1143 for juvenile myasthenia gravis  e2464 for myasthenia gravis  1102 for organ transplantation  1201 renal transplantation complications and  1220 sensorium changes  e2682b toxicity  1196b, 1200b tremor and  e2685b Tactile stimulation/motor movement commands, disorders of consciousness and  768, e1733 Taenia solium  915, 1146, e2102–e2103, e2103f Takayasu arteritis (TA)  874, 947t, 954–955, e1991–e1992, e1992f, e2181–e2182 Talin 1  993, e2244–e2245 Tangier disease  1083, e2415 Tapping  68t–69t, e143t–e146t Tardieu scale  472 modified  472 Tardive drug-induced movement disorders  729–731 diagnosis of  731 treatment of  732 Tardive dyskinesia, antipsychotic medications and  e1182t Tardive movement disorders  e1645–e1646 Target range  607, e1408 Tarui disease  314, e739–e740 Task-based functional MRI (t-fMRI)  97–98 Task-specific tremor  e1612 Tassinari syndrome  570, e1338

Index Taste  58–64, e124–139 clinical disorders of  59–60, e125–e128, e127b–e128b clinical significance of, in infants and children  60–62, 60b, 62t, e131–e132, e133t disturbances of, conditions associated with  60b, e127b dysfunction, drugs associated with  62t ontogeny of  e128–e132 bitter taste  e129t, e130–e131 fetus and preterm infants  e128–e129 newborns, infants, and young children  e129–e131, e129t salty taste  e131 sour taste  e130 sweet taste  e129–e130 umami taste  e130 perception and preferences, ontogeny of  60–62, 61t response to, developmental changes in  61t Taste system  58, 59f, e124, e125f–e126f Tay-Sachs disease (TSD)  107, 323–325, e277, e772t–e773t, e780, e781f, e1387 Taybi-Linder syndrome  210–211, e493 TCF4 gene, mutation in  1182 Teasing, childhood epilepsy and  640, e1477 Teenage-onset progressive myoclonus epilepsy  399 Telemedicine  1296 Telithromycin, in myasthenia gravis  1103b Tellurium, renal toxicity of  1225t, e2765t Temazepam, for restless legs syndrome  682, e1543 Temozolomide  982 for high-grade glioma  e2229–2230 Temperature control for hypoxic-ischemic encephalopathy  811 for traumatic brain injury  789 Temporal arteritis  947t, 954, e2181 Temporal bone, anomalies of  240 Temporal lobe epilepsy  576 and febrile seizures  521–522 repetitive transcranial magnetic stimulation for  621 Temporal lobectomy  617, e1429 Temporary dysfunction, resolution of, after CNS injury  1248 Ten-meter run/walk, in motor function scales  e2336 Tensilon test, in autoimmune myasthenia gravis  e2455–e2457 Tension-type headache  648, e1491 Tentorial notch  775 Teratogens, neural tube defects and  185– 186, e431–e432 Teratoma  1000 Terazosin  e2755b Term equivalent age (TEA)  97 Term infant cranial nerve examination  21–22, e42–e43, e42f cranial vault evaluation  20, e39, e41f developmental reflexes  20, e40 motor function  20–21, e40–e42 neurologic examination of  20–26, e39–e53, e40t observation  20, e39 Term newborn, hypoxic-ischemic brain injury in  138–146, e321–e338 Terminal illnesses  1243 challenges and  e2819 Test of Memory and Learning  e143t–e146t Test of Memory and Learning-2  68t–69t

1395

Test of variables of attention (TOVA)  71, 452–453, e143t–e146t Test of Word Reading Efficiency, 2nd Edition (TOWRE-2)  445 Tet-operon-repressor bi-transgenic system  e288–e289 Tetanus  1195, e2687 toxin  1198b associated with paralysis and muscular rigidity  e2684b vaccines for  922, e2128 Tetrabenazine, for tic disorders  745t Tetracyclines in myasthenia gravis  1103b renal toxicity of  1225t, e2765t Tetrahydrobiopterin  286, 355 deficiencies, and infantile onset epilepsies  560t–562t Tetrahydrocannabinol intoxication  1198, e2689–e2690 Tetrathiomolybdate, indications, Wilson’s disease  e2799 Tetrodotoxin  1198b, e1282 associated with paralysis and muscular rigidity  e2684b Thalamic clock theory  569, e1336–e1337 Thalidomide causing peripheral neuropathy  e2684b toxicity  1197b Thallium  e2688–e2689 associated with Parkinsonism  e2684b poisoning  1197 renal toxicity of  1225t, e2765t toxicity  1198b Theophylline abuse in  e2693 associated with tremor  e2685b Theophylline toxicity  1200b Theoretical approaches to ethics  e2859–e2863 casuistry in  e2862 common morality in  e2860 deontology in  e2860 ethics of care in  e2862 natural law in  e2860 spirituality in  e2862–e2863 utilitarianism in  e2859–e2860 virtue or character ethics in  e2861–e2862 Therapeutic plasma exchange (TPE) therapy  e2757 Thermocoagulation, stereotactic radiofrequency  617 Thermoregulation, abnormalities in, and orthostatic intolerance  e2646 Theta pointu alternant  552 Thiabendazole, for trichinosis  1146 Thiamine  373, e918t–e919t, e919 deficiency  e919 Wernicke’s encephalopathy  373 developing brain and  e947 pyrophosphokinase deficiency  373–374, e920 responsive maple syrup urine disease  288 Thiamine-responsive basal ganglia disease  373, e920 Thiamine-responsive encephalopathy  482t–486t Thiamine-responsive maple syrup urine disease  288, e680 Thiazide diuretic, for hyperkalemic periodic paralysis  1154 Thimerosal, autistic spectrum disorders and  e1099 Thimerosal-containing vaccines, developmental disorders and  e2128

1396

Index

Thinking, utilitarian  1264 Thiolases  e860 Thiopental, for refractory status epilepticus  549t Thiopurine methyltransferase (TPMT) deficiency  1102 Thioridazine  494 Thioridazine, for ASD  466 Thiouracil, neuroteratology  1203t Thomsen’s disease  1150–1151, 1151t see also Myotonia congenita Thomson disease  314–315, e741 Threshold effect  334 Thrombectomy, for arterial ischemic stroke  855 Thromboembolism, arterial ischemic stroke and  848, e1931–e1933 Thrombolysis for arterial ischemic stroke  855, e1944 for sinovenous thrombosis  862–863, e1964 Thrombophilia  877, 879t, e1997 acquired in arterial ischemic stroke  877–879, 878f, e1997–e2001 in cerebral sinovenous thrombosis  880– 881, e2002–e2003 genetic in arterial ischemic stroke  879–880, e2000t, e2001 in cerebral sinovenous thrombosis  881, e2003–e2004, e2003t Thrombosis, sinovenous thrombosis and  e1954–e1955 Thrombotic microangiopathies  e2756–e2757 Thrombotic thrombocytopenic purpura (TTP)  955, 1221–1222, e2182–e2183, e2756–e2757, e2757b THTR1 deficiency  e920 Thymectomy  1100–1101 for juvenile myasthenia gravis  e2461–e2462 Thymoma  1101 Thymus gland  1098 Thyroid disease, periodic paralysis with  1153t Thyroid gland  1169–1170 function disorders of  1169–1170, e2634–e2635 central hyperthyroidism  1170, e2635 central hypothyroidism  1170, e2635 thyroid physiology  1169–1170 normal physiology of  e2634–e2635 Thyroid peroxidase antibody (TPOab) , and ASD  461 Thyroid-stimulating hormone (TSH)  1165 deficiency  1170 Thyrotoxic periodic paralysis  1156, e2612–e2613 clinical features of  1156 genetics  1156 laboratory tests for  1156 pathophysiology of  1156 treatment for  1156 Thyrotropin-releasing hormone (TRH)  1165 Thyroxine  1170 Tiagabine  601t–602t for antiseizure drug therapy in children  e1402 pharmacokinetics of  604t–605t Tiapride, for tic disorders  745t

Tic disorders  741–742, e1664–e1665, e1664b anatomic abnormalities of  743 cortex  743 striatum  743–744 chronic  e1664 chronic motor or vocal  741 classification of  742b comorbid disorders and  742–743 ADHD  742 anxiety and depression  742 disruptive behaviors  742 OCD  742 cortex and  e1669 course of  742 due to generalized medical condition  742, e1665 epidemiology of  742 neuroanatomic localization of  e1666 neurobiology of  743–744, e1666 neurotransmitter abnormalities in  744, e1669 dopamine  744 GABA  744 glutamate  744 serotonin  744 not otherwise specified  742, e1665 provisional  741, e1664 striatum of  e1666–e1667 substance-induced  742, e1665 treatment for  744–745 nonpharmacologic  744 pharmacotherapy  744–745, 745t surgery  745 Tic Impairment Score (TIS)  741, e1664 Tick-borne flaviviruses  e2049 Ticks associated with paralysis and muscular rigidity  e2684b bites  1194, e2686 Ticlopidine  856 Tics  707, 707t, 741–745, e1599–e1600, e1663–e1679 assessment scales  741, e1664 characteristics of  741, e1663–e1664 course of  e1665 definition of  e1663 epidemiology of  e1665 misdiagnoses of  741, e1664 motor tics and  741 phenomenology of  741, e1663–e1664 premonitory urges and  741 simple versus complex  e1663 treatment of  e1667, e1671t vocal (phonic) tics and  741 Tier 1 medications, for Tourette syndrome  e1671 Tier 2 medications, for Tourette syndrome  e1671 Tigan. see Trimethobenzamide Tilt-table testing  e1514–e1515 for syncope  661 Time course, of neurologic impairment  e1– e2, e2f Timed testing  1049 of motor function  e2336–e2337 Timothy W. v Rochester  1284, 1284t, e2894 Tiopronin myopathies and  e2683b toxicity  1197b Tirilazad, for spinal cord injury  826–827, e1884–e1885 Tissue concentrations, of carnitine  e2549 Tissue plasminogen activator (tPA)  855

Titin  1032 Titubation  689 Tizanidine  e2835, e2835t for spasticity  473, 1251t spinal cord injury and  828 Tobacco associated with tremor  e2685b sensorium changes  e2682b Tocopherol  378–379 Todd’s paralysis  525 Togaviruses  896b Tolerance, in antiseizure drug therapy in children  e1404 Toluene, renal toxicity of  1225t, e2765t Tone, motor disturbances in, and ASD  465 Tongue biting, in syncope  1174 Tonic-clonic seizures, generalized  524–525 electroencephalographic findings  524–525 initial evaluation in  525 neuroimaging of  525 Tonic reflex  e50 in preterm infants  24 Tonic seizures  529, e1256, e1257f, e1266 electroencephalographic findings in  529 and Lennox-Gastaut syndrome  571, e1339, e1341f Tonsillar herniation  817t Tools of network science  99, 99f, 99t “Tooth-Fairy Project”  e296 Topiramate  601t–602t, e1176t, e1180–e1181, e1475–e1476 adverse effects of  609 for antiseizure drug therapy in children  e1402–e1403 behavioral and cognitive effects of  639 for Dravet syndrome  406 for generalized tonic-clonic seizures  e1251 for juvenile myoclonic epilepsy  e1276 ketogenic diets and  628–629 for Lennox-Gastaut syndrome  572 for migraine  652t pharmacokinetics of  604t–605t rectal administration of  606t for tic disorders  745t TORCH infections  897 Torticollis aromatic L-amino acid decarboxylase deficiency  357f benign paroxysmal  e1638–e1639 tyrosine hydroxylase deficiency and  358 Total Maturation Scale (TMS)  1205–1206, e2713–e2714, e2715f Total Tic Score (TTS)  741, e1664 Tourette syndrome (TS)  102t, 103, 741–745, 935–936, e265–e266, e1663–e1679, e2145 associated (comorbid) behaviors of  e1665–e1667 epidemiology of  e1665 etiology of  743, e1665–e1666 autoimmune  743 genetic  743 postinfectious  949, e2167 treatment of  e1667, e1671t see also Tic disorders Townes’ syndrome, with kidney malformation  1224t, e2764t Toxic neuropathies  1083–1084, e2417–e2419 antibiotic-induced  1084, e2417 chemotherapeutic agent-induced  1084, e2418 diphtheria  1083, e2417 heavy metal  1084, e2418–e2419

Toxic neuropathies (Continued) nitrous oxide-induced polyneuropathy  1084, e2417–e2418 pyridoxine-induced  1084, e2417 serum sickness  1083, e2417 vaccine-induced polyneuropathy  1084, e2418 Toxidromes  1193–1194, e2683–e2686 Toxocara canis  e2097 Toxocara cati  e2097 Toxoplasma gondii  911, 1146 Toxoplasmosis  911, 1146, e2087–e2088, e2087f, e2591–e2592 clinical features of  1146 laboratory features of  1146 treatment for  1146 TPCV, chemotherapy for low-grade glioma  988–989 TPDCV, chemotherapy for low-grade glioma  988–989 TPP1  e951t–e952t, e960–e961 Tract-based spatial statistics (TBSS)  97–98, e257 Traction response  17, e36 Traction test, for hypotonia  1052, e2342 Training concept of  1299 current workforce issues and  1302–1303 education and, of child neurologists and workforce issues  1299–1303 current approaches in  1300–1302, 1301t historical aspects in  1299–1300 future workforce issues and  1303 preceding child neurology  1302 Transcalvarial herniation  e1772 Transcranial direct current stimulation  622, e1439 Transcranial Doppler (TCD) for arteriopathy of sickle cell disease  873 for brain death determination  836 for cerebral perfusion measurements  e1912 for impairment of consciousness  e1752 intracranial pressure and  814 for sickle cell disease  880 Transcranial magnetic stimulation (TMS)  767, e1733 for arterial ischemic stroke  856, e1946 diagnostic  622 repetitive  621 Transcutaneous electrical nerve stimulation (TENS), for arterial ischemic stroke  e1946 Transfer  1270 Transferrin isoform analysis  318–319 Transgenic animals  115 Transgenic mice  115–116, 116f Transient cerebral arteriopathy  849–850, 849f, 871, e1986, e1987f Transient tic disorder. See Provisional tic disorder Transition  1270 models of care for  1273–1274, 1274b abandonment of specialized care  1273–1274 adult neurologist/internist, referral to  1274 adult rehabilitation program, referral to  1274 internal medicine/pediatric subspecialist, referral to  1274 internet-based support group  1274

Index Transition (Continued) joint pediatric/adult transition clinic  1274 nurse-run transition clinic, referral to  1274 poor/little development of process of, yields poor outcome  1273–1274 principles for  1271b Transitional care  1270–1275, e2871–e2879 barriers to  1270–1273, 1271b, e2871– e2875, e2872b–e2873b disorders childhood, with serious manifestations in adulthood  1272 cured in childhood, and have neurologic sequelae in adulthood  1272–1273 dangerous, in society  1271 lethal, and emerging treatments, in childhood and young adulthood  1271–1272 may/may not remit in childhood, and have persistent effects on adult social function  1273 problematic, and “static”  1272 treated in a way that is difficult to replicate in adult medicine  1273 uncomfortable for adult care  1273 models of care for transition  e2876– e2877, e2876b poorly managed  e2875–e2877 Transitional circulation  e2717 Translocations  257, 270, e637 Robertsonian  270 Transmembrane DAPs  e2485–e2486 Transport deficiencies  596 Transporters development of  e1219–e1220, e1219f glutamate  301 Transposition of the great arteries (TGAs)  1205, 1207f, e2713, e2715f fetal circulation in  1206–1207, 1208f, e2714–e2716, e2716f white matter injury in  e2719 Transsulfuration pathway  e685f Transtentorial downward herniation  775, e1748 Transtentorial herniation  817t, e1772 Transverse myelitis  759, 761f, 896, e1715, e1717f Tranylcypromine, for ADHD  455t–457t Trauma abusive head. see Abusive head trauma (AHT) acquired epilepsies from  590–593 in acute cerebellar ataxia  e1587 associated with birth, by location  e360–e365 brachial plexus injury  e364–e365, e364t, e365f caput succedaneum  e360 cephalohematoma  e360–e361 cerebral contusions  e362–e363, e363f epidural hemorrhage  e362 facial nerve injury  e363–e364, e364f, e364t intracranial hemorrhage  e362 intraparenchymal hemorrhage  e362– e363, e363f intraventricular hemorrhage  e363 phrenic nerve injury  e365 posterior fossa hemorrhage  e362, e363f radial nerve injury  e365 skull fractures  e361–e362 spinal cord injury  e363

1397

Trauma (Continued) subarachnoid hemorrhage  e362 subdural hemorrhage  e362 subgaleal hematoma  e361, e361f associated with specific obstetric maneuvers  159–160, e365–e366 extracranial complications of vacuum extraction  e366 fetal scalp electrodes  e366 forceps  e366 intracranial complications of vacuum extraction  e366 vacuum delivery  e365 vacuum extraction and prematurity  e365–e366 birth-associated, perinatal counseling for avoidance of  160 blunt  e360 head, EEG and  e237–e238 iatrogenic  e367 iatrogenic neurotrauma, during newborn period  160 intrauterine  156, e359 mimics  160, e368–e369 in motor neuron diseases  1072, e2385 neonatal nervous system  156–160 nervous system  e359–e371 penetrating  e359–e360 perinatal, by location  156–159 Traumatic arterial dissection, in traumatic brain injury  e1776 Traumatic brain injury  781–792, e1764–e1810 acute clinical syndromes of  784–787, e1771–e1780 abusive head trauma  785, 808, e1773–e1774, e1774f arterial dissection and aneurysms  785–786 cerebral contusion and laceration  785, e1776, e1776f concussion. see Concussion diffuse axonal injury  781, 784–785, e1772, e1773f diffuse cerebral swelling  784, e1772 epidural hematoma  785, e1775–e1776, e1775f herniation. see Herniation paroxysmal sympathetic hyperactivity  785, e1772–e1773 postconcussive syndromes in  e1777 scalp lacerations and hematomas  787, e1779–e1780 second-impact syndrome  786, e1778, e1779f skull fractures  786, e1779, e1779f sports concussion/repeated concussion  786, e1777–e1778 subarachnoid hemorrhage  785, e1774, e1774f subdural hematoma  e1774–e1775, e1775f traumatic arterial dissection and traumatic aneurysms in  e1776 anatomy  781, e1764–e1765, e1765f biomechanics of  781, e1765–e1766 changes in cerebral metabolism in  e1766 classification  590 “contre-coup”  781 “coup”  781 defined  590

1398

Index

Traumatic brain injury (Continued) diagnostic evaluation for  787–788, e1780–e1784 angiography  787 computed tomography  787 magnetic resonance imaging  787 skull x-rays  787 distinct neurovascular regulation in  e1766–e1767 and early posttraumatic seizures  592 epidemiology of  781, 782f, e1764, e1765f examination for  782–784, 784b, e1770–e1771, e1771b cranial nerve (CN) testing in  782 Glasgow Coma Scale in  782, 782t mental state in  782 sensorimotor  783 excessive sleepiness disorders  e1534 experimental models of  e1800 immediate management of  e1771 increased excitatory neurotransmission in  e1767 late clinical syndromes of  790–792, e1796–e1800 cognitive impairment and behavioral disorders  791, e1796–e1797 late complications of skull fracture  792 postconcussive syndrome  792, e1799–e1800 posttraumatic epilepsy  791, e1798 posttraumatic headache  791–792, e1799 posttraumatic hydrocephalus  791, e1797–e1798 skull fractures in  e1800 sleep disorders  791, e1797 spasticity and motor impairment  791, e1797 subacute and chronic subdural hematoma  791, e1798–e1799 vegetative and minimally conscious states  790, e1796 lumbar puncture in  e1782 management for  788–790 early posttraumatic seizures and seizure prophylaxis  789–790 immediate  784 intracranial pressure. see Intracranial pressure prevention of secondary injury  788 stabilization  788 supportive care  790 mild, general management of  e1789–e1793 in children over age 2 years, with brief loss of consciousness  e1792 in children over age 2 years, without loss of consciousness  e1792 in children under 2 years old  e1792–e1793 neuroimaging of  e1780 neurophysiological testing for  787–788, e1782–e1784 EEG  787 ongoing cerebral maturation in  e1767 pathophysiology of  781, e1766–e1769 patient history of  781–782, e1769–e1770 posttraumatic neurometabolic cascade  781, 783f, e1767–e1769, e1768f altered neurotransmission in  e1768 axonal disconnection in  e1769 cell death in  e1769 cerebral blood flow in  e1767–e1768

Traumatic brain injury (Continued) dynamic changes in cerebral metabolism in  e1767 glutamate release and ionic flux in  e1767 impaired plasticity in  e1769 prognosis and outcome of  778, 790, e1793–e1796 clinical predictors of  e1793–e1795 demographics in  e1794 injury characteristics in  e1794 neuroimaging and  e1795 neurophysiological testing and  e1795–e1796 physiologic measurement in  e1794–e1795 severe, general management for  e1784–e1789 intracranial pressure  e1784–e1788 posttraumatic seizures and seizure prophylaxis in  e1788–e1789 stabilization and prevention of secondary injury in  e1784 supportive care in  e1789 skull X-rays of  e1780–e1782 types of  e1765–e1766, e1766f vegetative state  770–771, 770b, 770t, 790 Traumatic hearing loss  e100 Treacher-Collins syndrome  48, e103 Treatable Intellectual Disability Endeavor (TIDE)  e1027, e1028t algorithm  429, 429t Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH) Program  469, e1113 Treatment decision support, computer resources and  1297–1298 Treatment of neurodevelopmental disorders  e1137–e1157, e1138t autism spectrum disorder  e1145 congenital hypothyroidism  e1154–e1155 Down syndrome  e1139–e1140 fragile X syndrome  e1141–e1145, e1142f general concepts in  e1137–e1138 inborn errors of metabolism  e1145–e1154, e1146t–e1150t, e1151f, e1152b newborn screening and  e1154 Rett syndrome  e1138–e1139 single-gene disorders  e1145 tuberous sclerosis  e1140–e1141, e1141f Trematodes  e2104–e2107 paragonimiasis in  e2106–e2107 schistosomiasis in  e2104–e2106 Tremor  707, 707t, 712–713, e1600, e1611–e1613 antiseizure drug therapy and  609 causes of  713b, e1612b classification of  e1611 essential  713 physiologic  713 primary  e1612 secondary  e1612 treatment of  713, e1612–e1613 Treponema pallidum, in syphilis  890 Triamterene  e2755b Triatoma spp.  912 Tricarboxylic acid cycle  1131 Trichinella spiralis  1145, e2099 Trichinellosis  e2098–e2100 Trichinosis  1145–1146, e2591, e2591f clinical features of  1146 laboratory features of  1146 treatment for  1146

Trichloroethylene Parkinsonism and  e2684b toxicity  1198b Trichothiodystrophy  e1690 hypomyelinating white matter and  751 Tricyclic antidepressants  490t, 491, 1200–1201, e1159t, e1165–e1167, e1165t for ADHD  454, 455t–457t, e1086, e1087t–e1089t adverse effects of  e1167 for cataplexy  675–676 clinical applications of  e1165–e1167 clinical management of  e1166–e1167 drug interactions of  e1167 pharmacology of  e1166 side effects of  491 behavioral  491 Trientine, Wilson’s disease  e2799 Trifluoperazine, for ASD  466 Trifunctional enzyme deficiency  1132b Trigeminal autonomic cephalalgia  648, e1491 Trigeminal nerve  9, e14–e15, e15f stimulation  621, e1438 Trigonocephaly  233, e569 Triheptanoin, for fatty acid oxidation disorders  1136, e2563 Trihexyphenidyl, for dystonia  473 Trimethadione associated with paralysis and muscular rigidity  e2684b in myasthenia gravis  1103b toxicity  1198b Trimethobenzamide, for cyclic vomiting syndrome  1229 Trimethoprim-sulfamethoxazole for blastomycosis  908 for Whipple’s disease  e2790 Triple-risk model, of sudden infant death syndrome  686 Triploidy  270 Trisomy  270 Trisomy 8  e643, e644f Trisomy 13  271, e641, e641f Trisomy 18  271, e641–e642, e642f with kidney malformation  1224t, e2764t Trisomy 21. see Down syndrome tRNA modifications, abnormal  341 Trochlear nerve  7–9, 8f, e13–e14, e13f, e13t Tropheryma whipplei  1233 Tropias  8–9 Tropomyosin 2 (beta)  1124t–1125t Tropomyosin 3  1124t–1125t Troponin  1124t–1125t Troponin T type 1  1124t–1125t Trousseau, Armand  925 TRPC6  121 Trust, in clinician-patient relationship  1239 Trypanosoma brucei  913 gambiense  913 rhodesiense  913 see also African sleeping sickness Trypanosoma cruzi  912, e2093 Trypanosoma gambiense  e2095f Trypanosomal infections  912–913, e2093–e2097 African sleeping sickness  913, e2094– e2095, e2095f Chagas disease  912–913, e2093–e2094 encephalitic stage of  e2095–e2097 hemolymphatic stage of  e2095 Trypanosomiasis African. see African sleeping sickness American. see Chagas disease Tryptophan, tic disorders and  744

Tryptophan hydroxylase deficiency  358, e876t, e881 Tryptophol  913 for Chagas disease  e2095 TSC1 gene mutations  479–480 and tuberous sclerosis complex  585–587 TSC2 gene mutations  479–480 and tuberous sclerosis complex  585–587 Tsetse fly  913 TTN-related myopathies  e2532 TTP. see Thrombotic thrombocytopenic purpura (TTP) TUBB4A mutations  e1606 Tuber cinereum, hamartoma of  1166 Tuberculous meningitis  890, e2020–e2021 clinical features of  890 diagnosis of  890 epidemiology and pathogenesis of  890 treatment for  890 Tuberous sclerosis  427, 958t with kidney malformation  1224t, e2764t surgical indications for  e1420 transitional care and  e2874 treatment of  e1138t, e1140–e1141, e1141f Tuberous sclerosis complex (TSC)  114, 364–368, 466, 479–480, 479t, 585–587, 586t, 1272, e894–e898, e1366 angiofibroma in  366f clinical characteristics of  365–367, e894–e896, e894b, e895f–e896f clinical laboratory testing of  367, e896–e898, e897f, e897t diagnostic criteria for  365b genetics of  367, e898 management of  367–368, e898 pathology of  367, e896–e898 Tubulinopathies  206, 219–220, e480, e519–e521 brain imaging of  e520 clinical features of  e520 common  e520–e521 genetic counseling of  e521 neuropathology of  e520 syndromes, genetics, and molecular basis  e520–e521 Tumor markers, in germinoma  e2258–e2259 Tumor-suppressor genes, in ependymomas  e2219t Tumors acquired epilepsies from  590–593 characteristics, treatment recommendations, and average prognosis  1013t classification of  957–958, e2193–e2194 clinical presentation of  959–960, e2195, e2195t–e2196t craniopharyngiomas  1167 detection of, in opsoclonus myoclonus syndrome  939, e2149 distribution of  958f, e2193f epilepsy associated with  593, e1376–e1377 epidemiology of  593 natural history and treatment of  593 risk factors  593 etiology of  957, e2192–e2193, e2194t gene therapy  961 human chorionic gonadotropin (hCG)-secreting  1166 incidence of  957, e2192, e2193f infratentorial, differential diagnosis of  960t location, neurologic features  1022f

Index Tumors (Continued) malignant, Turcot’s syndrome and  e2790 mortality in long term survivors  1021 pathology of  957–958, e2193–e2194 prognosis of  961, e2198 prolactinoma  1168 staging and stratification of  958–959, e2194–e2195 supratentorial, differential diagnosis  959t surgery  960 treatment of  960–961, e2195–e2198 biologic therapy  961, e2197–e2198 chemotherapy  961, e2197, e2198t gene therapy  961, e2198 immunotherapy  961, e2197–e2198 radiation therapy  960–961, e2196– e2197, e2197t surgery  960, e2195–e2196 vaccines  961, e2197–e2198 Tunnel sign  914 Turcot’s syndrome  958t, 1233, e2790 and medulloblastoma  963 type 2  e2201 Turner syndrome  272, e643–e645, e644f with kidney malformation  1224t, e2764t nonverbal learning disabilities and  440, e1064 Turricephaly  e568 TUSC3-CDG  320, e761 Twitcher (twi)  112, 114–115, e282 TYMP gene, mutations in  1230 Tympanometry  45, e97 Typhus fever group  e2076–e2077 Tyrosine hydroxylase deficiency  356t, 358, 482t–486t, e876t, e880–e881 Tyrosine metabolic pathway  e679f Tyrosinemia hepatorenal  287 type II  482t–486t

U

Ube3a-YFP  120 Ulcerative colitis  1231 Ullrich congenital muscular dystrophy  1121, e2491f, e2495–2496, e2508 serum CK levels found in  1039t Ultradian rhythm, electroencephalographic neonatal sleep as  90–91, e223–e224 Ultrasound  78 cranial  78 fetal  e2716–e2717 of traumatic brain injury  e1782 white matter injury  167, 167f Umami taste  e130 Unbalanced translocation  e614t Unbanded chromosomal analysis, in genetic diagnosis  1245t Uncal herniation  775, e1748 Uncertain test results, challenges and  e2818– e2819, e2818b Unconsciousness  770 Uncooked corn starch, for fatty acid oxidation disorders  e2557 Undermineralization of skull  238, e579 Undifferentiated syndromes, in juvenile idiopathic arthritis  e2165 Unfractionated heparin  855–856 for arterial ischemic stroke  e1945 Uniform Determination of Death Act (UDDA)  831 Unilateral cerebellar hypoplasia (UCH)  203, e472 Uniparental disomy  e614t

1399

Universal Curriculum  1300–1301, 1301t, e2920–e2921, e2922t Universal Nonverbal Intelligence Test  68t– 69t, e143t–e146t Unresponsive wakefulness syndrome  770– 771, e1737–e1739, e1738b Unverricht-Lundborg disease (ULD)  578– 579, e1277, e1354–e1355 Upgaze, intracranial pressure and  816t Urea cycle  298, 299f, e710, e711f Urea cycle disorders/defects  175, 279t, e412f, e413, e659t, e1384 alternative-pathway treatment of  299t associated medical conditions in  e714 clinical description of  298–300, e711–e714 N-acetylglutamate synthase deficiency  e711 argininemia  e713 argininosuccinic aciduria  e713 carbamoyl-phosphate synthase 1 deficiency  e711 citrullinemia  e712–e713 hyperornithinemia-hyperammonemiahomocitrullinuria syndrome  e714 ornithine transcarbamylase deficiency  e711–e712 clinical presentations of  e714 common clinical presentations of  300–301 differential diagnosis of  301–302, e716, e717f epilepsies and  596–597 histopathologic features of  301, e714–e715 and inborn errors of metabolism  482t–486t and infantile onset epilepsies  560t–562t long-term alternative-pathway treatment of  e711t mechanism of neuropathology  301, e715–e716 outcome of  304 therapies under investigation of  303–304 treatment of  302–303, e716–e719 dietary therapy  302–303 liver transplantation  303 management of hyperammonemic Crises  303 N-carbamyl-l-glutamate  303 Uremic encephalopathy  1216–1217, e2742–e2745 acute  e2743–e2744 clinical features of  1216–1217, e2742 congenital  e2745–e2746 diagnostic considerations in  1217, e2743–e2745 lethargy, somnolence in  e2744 management of  1217, e2745 mentation, disturbances of  e2744–e2745 muscle twitching/fasciculation in  e2744 neurologic manifestations in  1217 pathophysiology of  1217, e2742–e2743 seizures in  e2745 tremor in  e2744 Uremic myopathy  1219, e2750–e2751 Uremic neuropathy  1082, e2412–e2413 Uremic peripheral neuropathy  e2749–e2750 Uremic peripheral polyneuropathy  1219 Uridine diphosphogalactose-4-epimerase  305 deficiency  306 Uridine diphosphogalactose epimerase deficiency  e725–e726

1400

Index

Urinary porphobilinogen, measurement of  e2791 Urinary retention, in pediatric autonomic disorders  1175 Urinary urge incontinence, micturition disorders and  1188 Urodynamics  1189 Urothelium  1185 Usher syndrome  48, e103 Utilitarian theory  1263–1264 Utilitarianism  1263–1264, e2859–e2860 Utrophin  1034, e2306 Uveitis, in pauciarticular juvenile idiopathic arthritis  e2165

V

V sign  1141 Vaccine-induced polyneuropathy  1084, e2418 Vaccine Injury Compensation Program  918, 920t, e2122–e2123, e2124t Vaccines autistic spectrum disorders and  461–462, e1099 causality, assessing  918 combination, additives and  922–923 MMR and autism  922 thimerosal-containing vaccines, developmental disorders of childhood and  922–923 diphtheria  922 Haemophilus influenzae type b conjugate  889 hepatitis A  919 hepatitis B  922 human papillomavirus  922 influenza virus  918–919 injection related outcomes  923 measles  920–921 meningococcal  889 meningococcal conjugate  922 mumps  921 oral polio  921 pertussis, acellular  921 pneumococcal conjugated  889, 922 polio  918 rabies  919 related outcomes of  e2128–e2129 rotavirus  921 routine immunization of healthy infants and children  919t rubella  921 rubeola  920–921 small pox  921 tetanus  922 for tumors  961, e2197–e2198 types of  918–922, e2123–e2128, e2125t component  921–922, e2127 Haemophilus influenzae type b  922 live-attenuated viruses  920–921, e2125–e2127 recombinant  922, e2128 whole-killed organisms  918–919, e2123–e2125 varicella  921 whole-cell pertussis  919 Vagus nerve  10, e16 stimulation  619–620, e1436–e1437 Vagus nerve stimulator, for Lennox-Gastaut syndrome  572 Validity, in outcome measures  1289

Valproate  601t–602t for generalized epilepsy  501 for generalized tonic-clonic seizures  e1250 for genetic generalized epilepsies  580–581 for juvenile myoclonic epilepsy  e1276 for migraine prevention  e1500 pharmacokinetics of  604t–605t in renal failure  1225–1226, e2767 for status epilepticus  545, 547 Valproic acid  493, 511, e1176t, e1177–e1178, e1475, e2367–e2368 for antiseizure drug therapy in children  e1403 behavioral and cognitive effects of  639 for benign myoclonic epilepsy of infancy (BMEI)  538 for childhood absence epilepsy  569–570 for Dravet syndrome  406 hair changes and  609 for juvenile myoclonic epilepsy  539 for migraine  652t for myoclonic-astatic epilepsy of Doose  539 for myoclonic epilepsy in infancy  557 pharmacokinetics of  604t–605t protein binding  603 rectal administration of  606t for renal diseases  1224, e2765 Valsalva maneuver  e2647, e2648f Vancomycin, for acute bacterial meningitis  888 Vanderbilt assessment scales  4, e5, e7f Vanishing white matter  752f, 755 Variants of unknown significance (VUS)  1243 Varicella vaccines  921, e2126–e2127 Varicella zoster virus (VZV)  899t, e2041–e2042 cerebral arteriopathies and  875 vasculitis and  e1992 Vascular cerebellitis  e1587 Vascular endothelial growth factor (VEGF)  364 Vascular etiologies, in motor neuron diseases  e2384–e2385, e2385f Vascular malformations  e1968–e1985 intracranial hemorrhage and  865–870 Vascular stroke  283–284 metabolic disorders and  e666–e667 Vascular sympathetic function, measures of  e2646–e2647, e2647f–e2648f Vascular thrombus  e1997–e1998 Vasculitic diseases/disorders miscellaneous  955 Behçet’s disease  947t, 955 with neurologic-renal presentations  e2758 Vasculitic neuropathies  1084–1085, e2419–e2420 Vasculitis, central nervous system, cerebral arteriopathies and  874–875 fibromuscular dysplasia  875 primary  874 secondary  874–875 Vasculogenesis, in cerebrovascular system  841, e1921 Vasculopathy  e2746 AKI and  1217–1218 Vasoactive ligands, in cerebrovascular system  844–845 Vasoactive receptors, in cerebrovascular system  844–845 Vasopressin  e2636–e2637 Vegetative state  769f, 770–771, 770b, 770t, 790, e305, e1737–e1739, e1737t, e1738b, e1796

Vein of Galen malformations  868, e1975– e1976, e1975f epidemiology of  e1976 evaluation of  e1976 outcome of  e1976 pathogenesis of  e1975–e1976 presentation of  e1976 treatment of  e1976 Velocardiofacial (VCF) syndrome congenital heart defects and  1206t nonverbal learning disabilities and  440, e1065 Venezuelan equine encephalitis virus  e2045–e2046 Venlafaxine  e1171–e1172, e1171t for ADHD  455t–457t Veno-arterial ECMO  1211 Veno-venous ECMO  1211 Venous infarctions  130–131 Venous to arterial shunts  1205 Ventilation for coma  776 for impairment of consciousness  e1749–e1750 Ventral suspension test, for hypotonia  1054, e2342–e2344 Ventricular assist devices (VAD)  1211, e2722 Ventricular drain, external, for intracranial pressure monitoring  814 Ventricular fibrillation, cardiac arrest and  809 Ventricular septal defect  271 Ventricular theory, of syncope  661, 661f Ventricular zone (VZ)  107 Ventriculomegaly definition of  250 outcome  250 prenatal diagnosis of  250, e602–e603, e602f Ventriculoperitoneal (VP) shunting, for hydrocephalus  e559 Verapamil familial hemiplegic migraine  409 indications, Dravet syndrome  406 for migraine  652t Verbal auditory agnosia  434t, 435, e1055 Verbal dyspraxia  434, 434t, e1055 Verbal-performance IQ split, for nonverbal learning disabilities  438, e1061–e1062 Vermal lesions  689 Vermis agenesis, prenatal diagnosis of  254, e609 cerebellar  250 cerebellar hypoplasias primarily affecting  199–203, e470–e472 global CH with involvement of  203 hypoplasia, prenatal diagnosis of  253– 254, e609 Versive seizures  535, e1266–e1267 Vertebrobasilar system  848 Vertex waves  91 sleep patterns  e224, e224f Vertical expandable prosthetic titanium rib (VEPTR)  1159–1160, 1159f, e2618– e2619, e2619f Vertical suspension test, for hypotonia  1054, e2342–e2344 Vertigo  52–57, e116–e123 acute nonrecurring spontaneous  56, e121–e122 benign paroxysmal  e1588 definition of  52 disorders producing  54–57, 55t, e121–e123, e121t nonvertiginous disequilibrium  56–57

Vertigo (Continued) recurrent  56, e122 treatments of  57, e123 Very-long-chain acyl-CoA dehydrogenase, deficiency  1132b Vesicular monoamine transporter 2 deficiency  359, 482t–486t Vestibular aqueducts  e93 Vestibular-evoked myogenic potentials (VEMPs)  54, e121 Vestibular neuritis, vertigo and  56, e121–e122 Vestibulocerebellum  e1555 VGKC-complex  934t Videonystagmography (VNG)  53–54, e117–e119, e118f–e119f Vigabatrin  601t–602t, e1476 for antiseizure drug therapy in children  e1403 behavioral and cognitive effects of  640 for infantile spasms  541t, 542, e1285 myoclonus and  e2685b pharmacokinetics of  604t–605t toxicity  1199b Vimentin  1034 Vinblastine Parkinsonism and  e2684b toxicity  1198b, 1202 Vinca alkaloids  e2695 causing peripheral neuropathy  e2684b toxicity  1197b, 1202 Vincristine myopathies and  e2683b toxicity  1197b, 1202 VINDICATE  1, 2t, e1, e2t Vineland Adaptive Behavior Scales  68t–69t, e143t–e146t Second Edition (Vineland-II)  415, e1001t–e1004t Viral infections  895–906, 896b, e2031– e2064, e2032b alphaviruses  e2045–e2046 antiviral therapy for  e2038 arenaviruses  e2053–e2054 bunyaviruses  e2049 Chikungunya virus  e2057–e2058 clinical features of  896–897, e2033–e2038 acute cerebellar ataxia  e2034b encephalitis in  e2034, e2034b Guillain-Barré syndrome in  e2034b intrauterine and perinatal viral infections in  e2034b, e2035 meningitis in  e2034, e2034b myelopathy in  e2034b diagnosis of  898–900, e2035–e2037 cerebrospinal fluid  898, e2035, e2035t microbiological evaluation  898–899, 899t, e2036–e2037, e2037t neuroimaging  898, e2036, e2036f–e2037f emerging  e2057 epidemiology of  895–896, 897f, e2031–e2033, e2032f–e2033f flaviviruses  e2047–e2049 general considerations in  895, e2031 orthomyxoviruses  e2054–e2055 paramyxoviruses  e2050–e2052 parechoviruses  e2057 reoviruses  e2049–e2050 retroviruses  e2055–e2057 rhabdoviruses  e2052–e2053 rotavirus  e2050 rubella virus  e2046–e2047, e2046f

Index Viral infections (Continued) supportive care for  e2037–e2038, e2038t treatment of  899–900, e2037–e2038 specific medications  900 supportive care  899 Viral meningitis  896 Viral myositides  1145, e2591 Viral myositis, serum CK levels found in  1039t Virtue  1265 in theoretical approaches to ethics  e2861–e2862 Viruses  e2031 Vision autistic spectrum disorder and  e1107 blurry, in pediatric autonomic disorders  1175 Vision assessment in children  33–34, e69, e70f color vision  34 in infancy  33, e68–e69, e69f ocular motility  34 visual fields  34 Vision loss  33–42, e68–e88 associated with epilepsy  e77 in children  37–40, e77–e81 differential diagnosis of  37–40, e78–e81 examination of  e71 symptoms and signs of  37 transient episodic  40–41, 41t–42t, e83, e84t clinical features associated with  34–35, e70–e71 cortical visual impairment caused by  36 structural cerebral anomalies causing  36–37 cortical visual impairment and  e76–e77 epilepsy and  37 examination of children with  35 in infants  35–37 clinical manifestations of  35, e71–e73 differential diagnosis of  35–37, e73–e77 structural anomalies of  e73–e76 neurologic disease associated with  40t ocular anomalies causing  37–39, e78–e80 structural anomalies  35–36 symptoms and signs of  e77–e78 Visual acuity, assessment and quantification of  33–34, e68–e69 Visual development  33, e68 Visual-evoked potentials (VEPs)  141–142 for coma  777 for intracranial hypertension  819 Visual-evoked responses  e244–e245, e245f Visual fields, assessment of  34, e69 Visual imagery  e1733 disorders of consciousness and  768 Visual impairment CNS tumor posttreatment sequelae  1025 in neurosensory deficits  e2294–e2295 posttraumatic  796 Visual loss lysosomal storage diseases and  e782 optic neuritis  759 Visual reinforcement audiometry  e95–e96 Visual-spatial skills, nonverbal learning disabilities and  438, e1062 Vitamins  387–388 administration, drug-induced movement disorders and  e1647 cobalamin (vitamin B12)  387

1401

Vitamins (Continued) and cofactor deficiencies  1218, e2748 deficiency  1082, e2414 developing brain and  e945–e947 folate  387 and inborn errors of metabolism  482t–486t metabolism, disorders of  373–382, e660t, e917–e941 vitamin D  387–388 Vitamin A  388, e917–e921, e918t–e919t deficiency  e917 developing brain and  e943t, e947 intoxication  e917–e919 as nutrient  384t sensorium changes  e2682b teratogenesis  e919 toxicity  1196b Vitamin B1. see Thiamine Vitamin B2. see Riboflavin Vitamin B3. see Niacin Vitamin B6  374–375, e918t–e919t, e922– e923, e923f biomarkers of, inborn error of metabolism  375t deficiency, dependency, and responsiveness  375 dependency  e923 developing brain and  e947 responsiveness, pyridoxine versus PLP to test for  377 see also Pyridoxine Vitamin B12. see Cobalamin Vitamin C  1, 2t, e1, e2t, e918t–e919t, e928 deficiency  e928 Vitamin D  387–388, e918t–e919t, e928–e929 deficiency  e929 developing brain and  e946–e947 intoxication  e929 Vitamin dependency states, epilepsies and  597 Vitamin E  e918t–e919t, e929 deficiency ataxia with  378, 692 nutritional  e929 metabolism, disorders of  378 see also Tocopherol Vitamin H. see Biotin VLCAD deficiency, gene therapy approach for  e2563 Vocal (phonic) tics  741 Vocational Rehabilitation Act of 1973  1285, e2895 Voltage-dependent membrane conductance  e1211–e1212 depolarizing  506, e1211–e1212 hyperpolarizing  506–507, e1212 in seizures and epilepsy  506–507 Voltage-gated ion channels  405, 506 Voltage-gated potassium channel (VGKC) complex autoimmunity, in disorders of excessive sleepiness  e1535 Vomiting intellectual disability and  e1011b in ketogenic diets  629b von Gierke disease  307–309, e728–e732 biochemistry of  307 clinical characteristics of  307–308 clinical laboratory tests of  308 management of  308–309 pathology of  307 Von Hippel-Landau syndrome  958t

1402

Index

Von Hippel-Lindau disease  368, 1221, e898–e900, e2756 clinical characteristics of  368, e898–e899, e899f genetics of  368, e899–e900 management of  368, e899–e900, e900t pathology of  368 Voriconazole for aspergillosis  909 for blastomycosis  908 for granulomatous amebic encephalitis  911 Voxel-by-voxel morphometry (VBM)  97–98 VUS. see Variants of unknown significance (VUS)

W

Waardenburg-Shah syndrome  751 Waardenburg syndrome (WS)  47–48, e102–e103, e2780 Wada test, in epilepsy surgery  e1427 “Waddling” gait  e64 “Waiter’s tip” posture  15–16 Wake-promoting agents  675 Waking patterns  87, 88f EEG  e219–e220, e219f Walker falls, abusive head trauma and  e1824 Walker-Warburg syndrome (WWS)  317, 1120, e524–e525, e1386, e2507 prenatal diagnosis of  e604, e605f serum CK levels found in  1039t “Wandering eye”  34–35, e71 Warfarin  855–856, e2825t for arterial ischemic stroke  e1945 for dermatomyositis  1143 pharmacogenetics  1246t Warfarin Aspirin Recurrent Stroke Study (WARSS)  855 Warkany’s syndrome. see Trisomy 8 Water balance disorders  1171–1172, e2636–e2638 diabetes insipidus  1171–1172, e2637 syndrome of inappropriate antidiuretic hormone secretion  1172, e2637–e2638 Water disorders  e2738–e2740 AKI and  1215 Water hemlock, sensorium changes  e2682b Watershed pattern  140, e324–e325 Weakness CNS posttreatment sequelae  1021, e2288 Duchenne muscular dystrophy (DMD) and  1157 in pediatric neuromuscular disorders  1046 Weaver syndrome (WS)  214, e501 Wechsler Individual Achievement Test III  68t–69t, e143t–e146t Wechsler Intelligence Scale for Children  e1001t–e1004t Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V)  71, 444 Wechsler Memory Scales-IV  68t–69t, e143t–e146t Wechsler Preschool and Primary Scale of Intelligence  e1001t–e1004t Wechsler Primary and Preschool Intelligence Scale IV  68t–69t Wechsler Primary and Preschool Intelligence Scale V  e143t–e146t Wee Functional Independence Measure (WeeFIM)  778, e1753, e2829 Wegener’s granulomatosis  851 see also Granulomatosis with polyangiitis Weight, birth, cerebral palsy and  735

Weight gain antiseizure drug therapy and  608 and serotonin-dopamine antagonists  494 Weight loss, antiseizure drug therapy and  609 Werdnig-Hoffman disease  1057–1059, 1058t, e2355–e2357 West Nile virus  902, e2048–e2049, e2048f, e2384 clinical features of  902 diagnosis of  902 treatment and outcome of  902 West syndrome  513, 515, 566–567, e752t–e760t, e1229–e1232 EEG findings  566 in electroclinical syndrome, infantile onset  e1329–e1331 EEG findings in  e1329, e1330f etiology of  e1329 laboratory studies for  e1319t–e1323t, e1330 neuroimaging of  e1329–e1330 neurologic findings in  e1329 outcome of  e1331 seizures in  e1329 treatment of  e1330–e1331 etiology of  566 laboratory studies in  566–567 neuroimaging in  566 neurologic findings  566 outcomes for  567 seizures in  566 treatment for  567 Western equine encephalitis  e2045 “Wheelbarrow” maneuver  e37 Wheelchair, for spinal cord injury  828–829 Whiplash injury  820 Whipple’s disease  1233, e2789–e2790 White matter acquired disorders affecting  759–766, e1715–e1730 acute central nervous system demyelination as  e1715–e1718 relapsing demyelinating disorders as  e1718–e1726 genetic and metabolic disorder of  e1680– e1714, e1681t, e1682f with demyelination  e1691–e1704 hypomyelinating white matter disorders of  e1680–e1691, e1684f secondary leukoencephalopathies in  e1704–e1708, e1705t vanishing  e1685f, e1696–e1697 White-matter contusional tears, abusive head trauma and  e1820–e1821, e1821f White matter disorders demyelinating disorders. see Demyelinating disorders with demyelination  751–758, 752f genetic and metabolic  747–758, 748f–749f hypomyelinating  747–751 relapsing demyelinating disorders  761–765 multiphasic acute disseminated encephalomyelitis  764 multiple sclerosis. see Multiple sclerosis neuromyelitis optica  764 with white matter vacuolization and intramyelinic edema  754–755

White matter injury (WMI)  140, 161–170, 1209–1210, 1209f, e325, e372–e400, e2718–e2719, e2719f clinical presentation of  166–167, e387–e388 contusional tears  797 EEG of  e388 immature oligodendrocytes and  e387 inflammation/infection  e386–e387 management after NICU discharge  169–170 neuroimaging of  167–169, e388–e390 magnetic resonance imaging  e389– e390, e389f, e391f recommendations for, in preterm neonate and child born preterm  168–169, 168f, e390, e391f ultrasound  e388–e389, e388f–e389f neuropathology of  165, e385–e386 NICU management of  169 nutrition and  e387 outcome of  169, e390–e392, e390b cognitive  169, e391–e392 epilepsy  168f, 169, e392 motor  169, e392 social/behavioral  169, e392 visual  169, e392 pathogenesis of  165–166, 166b, e386– e387, e386b hypoxia-ischemia  165–166 inflammation/infection  166 vulnerability of immature white matter  166 postnatal corticosteroid use and  e387 of premature newborn  165–170, e384–e393 prevention and management of  169–170, e392–e393 after NICU discharge  e393 NICU  e393 risk factors for  166, e387 White matter vacuolization, white matter disorders with  e1696–e1698 Whole-bowel irrigation  1193 Whole-cell pertussis vaccines  919 Whole exome sequencing  420, e1004 progressive encephalopathies and  428 Wikipedia  1296 Wikis  1296, e2914 William-Beuren syndrome  273, e648 Williams-Beuren syndrome, congenital heart defects and  1206t Williams syndrome  462 central hypotonia and  1055t, e2346–e2347 Willis-Ekbom disease (WED)  678 Wilson’s disease  424, 482t–486t, 1235– 1236, e2797–e2800 Winterbottom sign  913 Wisconsin Card Sorting Test  68t–69t, e143t–e146t Withdrawal dyskinesia, antipsychotic medications and  e1182–e1183, e1182t Withdrawal emergent syndromes  e1644–1645 drug-induced movement disorders and  729–731 WMI. see White matter injury (WMI) Wolf-Hirschhorn syndrome  273–274, e649 and infantile onset epilepsies  558t–560t Wolman disease  e772t–e773t, e798–e799 Woodcock-Johnson Achievement Battery V  68t–69t, e143t–e146t

Woodcock-Johnson Cognitive Battery IV  68t–69t, e143t–e146t Word attack  445 Workforce issue, current  e2923–e2924 Workforce issues child neurologists and, training and education of  1299–1303 current  1302–1303 future  1303 Worm, as animal model, of SMA  e2365 Wormian bones  237–238, e575f, e577, e577f Wound botulism  1105, e2468 Wrinkly skin syndrome  e752t–e760t Writing recommendations  1280–1281 Wyburn-Mason syndrome  371, e906

X

X-linked adrenoleukodystrophy  349, 482t–486t, 751–753 newborn screening for  353 X-linked and mitochondrial inherited hearing loss  46 X-linked Charcot-Marie-Tooth disease  1076, e2397 X-linked ichthyosis  e651 X-linked lissencephaly, with abnormal genitalia  e519 X-linked muscular dystrophies  e2726 X-linked recessive disorders  278t X-linked spinal muscular atrophy (SMAX2)  1069, e2381

Index X-linked spinocerebellar ataxias  699 Xenon computed tomography for cerebral perfusion  836 for measurements of cerebral perfusion  e1912 Xeroderma pigmentosum  694 Xerostomia  1174–1175 XXX aneuploidy  272 XXY aneuploidy  272 Xylitol, renal toxicity of  1225t, e2765t

Y

Yale Global Tic Severity Scale (YGTSS)  741, e1664 Yersinia organisms, in pyomyositis  1146 Young Children’s Participation and Environment Measure (YC-PEM)  1290–1291 Youth self-report  4, e5

Z

Zellweger spectrum disorders  349–350, e862–e863 clinical and pathologic features of  349–350 laboratory diagnosis of  350 prenatal diagnosis of  350 therapy of  350 Zellweger syndrome  347–349, e863, e863f, e865t cerebrohepatorenal syndrome of  349f with kidney malformation  1224t, e2764t

1403

“Zero population growth”  1302 “Zero reject”  1285 Zidovudine associated with myopathies  e2683b toxicity  1197b Zinc  386 developing brain and  e943t, e945 as nutrient  384t sensorium changes  e2682b toxicity  1196b Ziprasidone  494, e1184t, e1187 for tic disorders  745t ZNF41 gene mutation  421t Zolmitriptan  650t Zolpidem sensorium changes  e2682b toxicity  1196b Zonisamide  511, 601t–602t, e1476 adverse effects of  609 for antiseizure drug therapy in children  e1403 behavioral and cognitive effects of  639 for headache in children  e1500 for infantile spasms  e1286 for juvenile myoclonic epilepsy  e1276 ketogenic diets and  628–629 for migraine  652t pharmacokinetics of  604t–605t for renal failure  1226, e2767 Zygomycosis  909, e2066t, e2070–e2072